Cell therapy for basement membrane-linked diseases

    Cell therapy for basement membrane-linked diseases Alexander Nystr¨om, Olivier Bornert, Tobias K¨uhl PII: DOI: Reference:

S0945-053X(16)30068-3 doi: 10.1016/j.matbio.2016.07.012 MATBIO 1288

To appear in:

Matrix Biology

Received date: Revised date: Accepted date:

28 April 2016 2 June 2016 7 July 2016

Please cite this article as: Nystr¨om, Alexander, Bornert, Olivier, K¨ uhl, Tobias, Cell therapy for basement membrane-linked diseases, Matrix Biology (2016), doi: 10.1016/j.matbio.2016.07.012

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Cell therapy for basement membrane-linked diseases Alexander Nyström*, Olivier Bornert# Tobias Kühl#

PT

Department of Dermatology, Medical Center – University of Freiburg, Freiburg, Germany

SC TE

D

MA

NU

Equal contribution

AC CE P

#

RI

* Address correspondence to Dr. Alexander Nyström, [email protected]

1

ACCEPTED MANUSCRIPT

Abstract

PT

For most disorders caused by mutations in genes encoding basement membrane (BM) proteins, there are at present only limited treatment options available. Genetic BM-linked disorders can be

RI

viewed as especially suited for treatment with cell-based therapy approaches because the

SC

proteins that need to be restored are located in the extracellular space. In consequence, complete and permanent engraftment of cells does not necessarily have to occur to achieve

NU

substantial causal therapeutic effects. For these disorders cells can be used as transient vehicles for protein replacement. In addition, it is becoming evident that BM-linked genetic

MA

disorders are modified by secondary diseases mechanisms. Cell-based therapies have also the ability to target such disease modifying mechanisms. Thus, cell therapies can simultaneously

D

provide causal treatment and symptomatic relief, and accordingly hold great potential for

TE

treatment of BM-linked disorders. However, this potential has for most applications and diseases

AC CE P

so far not been realized. Here, we will present the state of cell therapies for BM-linked diseases. We will discuss use of both pluripotent and differentiated cells, the limitation of the approaches, their challenges, and the way forward to potential wider implementation of cell therapies in the clinics.

Key words: Basement membrane, therapy, rare diseases, skin, kidney, muscle Abbreviations: BM, basement membrane; BMT, bone marrow transplantation; EB, epidermolysis bullosa; DEB, dystrophic epidermolysis bullosa; HSCs, hematopoietic stem cells; iPSCs, induced pluripotent stem cells; JEB, junctional epidermal bullosa; MSCs, mesenchymal stromal cells.

2

ACCEPTED MANUSCRIPT Introduction Basement membranes (BMs) are highly organized cell-adjacent extracellular matrices

PT

identifiable in various microscopy analyses by their sheet-like ultra-structural organization [1].

RI

Organ-specific synthesis of isoforms of the principal components laminin, collagen IV, nidogen, and perlecan (for which isoforms are generated posttranslationally), together with restricted

SC

temporal and spatial expression of specialized proteins, tailor BMs to adapt to the specific needs

NU

of individual organs (Fig. 1 and 2) [2, 3]. BMs have multifaceted functions, including establishing intra- and inter-organ communication, organizing developmental and regenerative events, and

MA

providing mechanical support [2]. It is therefore no surprise that BMs are a prerequisite for multicellular animal life [4, 5]. Genetic deficiency of proteins that serve as building blocks of BMs

D

and their associated structures causes diseases (Fig. 2) [2, 5]. In addition, BM proteins can be

TE

targeted by self-antibodies that promote damaging immune reactions or block vital proteinprotein interactions [6, 7]. Further, pathological changes of BMs also occur in acquired common

AC CE P

diseases [8, 9]. These changes are not the primary cause of disease, but rather a consequence of disease progression. We will here present and discuss cell-based therapy approaches for monogenic diseases linked to the BM. The group of diseases caused by mutations in genes encoding BM proteins and BMassociated proteins is a versatile collection of disorders that affects every major organ system [10]. We define BM-linked diseases as diseases for which the protein at fault can be part of basement membranes or their extended structures, although it does not necessarily always have such distribution. A causal link between mutation and disease has been established for over 20 genes encoding extracellular matrix proteins linked to the BM (Table 1). Mutations in these genes manifest in a severity spectrum that ranges from neonatal lethality to rather benign diseases. In addition, even different mutations in the same gene may cause an almost equally wide range of manifestations [2]. Currently, there are only limited treatment options available for

3

ACCEPTED MANUSCRIPT individuals affected with BM-linked disorders. This is in part due to the fact that multiple factors throw proverbial sticks in the wheel of causal therapy development for these diseases. Although

PT

the disease may be strongest manifested in one organ, multiple organ involvement is a norm rather than an exception. Accordingly, a systemic therapy would confer most benefit for the

RI

majority of the affected individuals. The multiple organs that need to be targeted to effectively

SC

treat a single disease make delivery of the therapeutic agent challenging. A major consideration that affects, at least commercial efforts to develop therapies, is the disease prevalence; all

NU

genetic BM-linked diseases are orphan and many of them fall into the subcategory of rare or

MA

even ultra-rare orphan diseases [11]. Although an orphan designation eases drug approval, this may not be sufficient to create an economic incentive for drug development, if the target population of the drug is exceedingly small. In addition, drugs for such diseases are at the risk of

D

becoming very expensive [12]. Thus, there are multiple obstacles for development of unique

TE

drugs for each single BM-linked disease in need of a therapy. An alternative is to use a common

AC CE P

agent to treat multiple diseases. Of the causal therapies, cell-based strategies offer a potential means to restore wild-type expression of numerous BM proteins with the same therapeutic agent, i.e. cell type. Because the proteins at fault occupy the extracellular space and many of them have an extended in vivo half-life [13, 14], it may be possible to achieve significant benefit even after low and transient engraftment.

Cell therapy The concept of using cells as a therapeutic agent is more than a century old. However, the first major progress in the field was made in the middle of the last century with the dawn of bone marrow transplantation [15]. In contrast to that time, when cells were only expanded in culture and reinjected, technical advancements have opened up possibilities to tailor the features of isolated cells to adjust them to a desired application [16], making cell therapies a 4

ACCEPTED MANUSCRIPT central tool in medical care [17]. 372 clinical trials were registered in 2014 with the intention to apply cells as therapeutic agents [18]. Although the number of cell therapy-based clinical trials

PT

and the number for Investigational New Drug submissions have been constantly growing during the last decade [19-21], the number of approved cellular products is remarkably low. To our

RI

knowledge there are presently only twelve Food and Drug Administration approved cell products

SC

[22] (of note is that half of them is for using cord blood in unrelated donor hematopoietic progenitor cell transplantation) and one European Medicines Agency approved application,

NU

which is for the treatment of limbal stem cell deficiency [23]. Recently, New Zealand and Canada

MA

approved the use of mesenchymal stromal cells (MSCs) for the treatment of graft-versus-host disease in children [17]. It is further interesting to note that although the number of clinical trials on cell therapy is increasing, the trial phase distribution has remained constant [17]. This

D

indicates that many trials are terminated in early phases. The vast majority of publications

TE

resulting from such trials reports only a few patients and does not include statistically verified

AC CE P

endpoints. Thus, although there is an extensive literature on clinical trials of cell-based therapies, it provides only limited information on the effectiveness of these therapies. Therefore, well-designed clinical trials are needed to support the continuous development and validation of cell-based therapies.

Depending on the disease, any cell type that has the capacity to improve disease symptoms through its bioactivity can be considered as a potential therapeutic agent (Fig. 1). In reality, however, constraints regarding cultivation and delivery reduce the range of suitable cells to pluripotent cells and some types of differentiated tissue-specific cells.

5

ACCEPTED MANUSCRIPT Differentiated cells

PT

Keratinocytes Grafting of epidermal sheets can be an effective treatment of especially problematic

RI

areas in patients suffering from epidermolysis bullosa (EB), caused by collagen VII, collagen

SC

XVII or laminin-332 deficiency (Fig. 2) [24]. Because keratinocytes are immunogenic, the highest success will be achieved with grafting of epidermal sheets composed of autologous

NU

keratinocytes. To this end, the synthesis of the proteins at fault would first need to be permanently restored by means of genome-editing [25], gene therapy [26, 27], vector-based

MA

trans-splicing therapy [28] or even by in vitro expansion of spontaneously corrected skin patches, so called revertant mosaicism [29, 30]. The latter approach has been successfully used

D

for treatment of a patient with junctional EB (JEB) from mutations in LAMB3 encoding the

TE

laminin beta 3 chain of laminin-332 [29]. The furthest advanced therapy, and already applied to

AC CE P

patients, is the correction of keratinocytes with gene therapy. Using lentiviral vectors, wild-type LAMB3 cDNA was introduced in epidermal stem cells from a patient with JEB. The patient carries mutations in the LAMB3 gene on both alleles. One causes a pre-terminal stop codon and the other mutation leads to E210K amino acid substitution that impairs assembly of laminin-332. Introduction of wild-type LAMB3 cDNA reinstated laminin-332 secretion by keratinocytes [31]. Subsequently, epidermal sheets were generated from the corrected keratinocytes and grafted onto the patient [31]. The treatment was successful and led to long-term restoration of laminin332 deposition and skin integrity [31, 32]. Follow-up studies indicated that epidermal stem- or pluripotent cells in the transplanted grafts maintained the ability to proliferate and differentiate [32]. Thus, the procedure allowed long-term or permanent restoration of skin and can be considered the first causal treatment of a genetic BM-linked disorders [32]. Interestingly, the borders of the graft remained clearly visible suggesting that the laminin-332 seems to not diffuse from the corrected graft. This would indicate that a relatively high density of engrafted cells in

6

ACCEPTED MANUSCRIPT other cell therapy approaches would be needed to achieve a causal effect. However, owing to safety concerns of the vector used, no further patients were treated. Development of safer

PT

vectors and increased safety profiling of the corrected keratinocytes have now allowed initiation of clinical trials for treatment of dystrophic EB (DEB), which is caused by collagen VII deficiency

RI

[33]. Nevertheless, that only selected areas can be treated and the high costs connected to the

NU

SC

treatment are obvious limitations.

MA

Fibroblasts

Fibroblasts are an attractive cell type for therapy as they can be easily isolated and

D

expanded in culture [34]. They have the potential to be used as a cell source for replacement of

TE

mesenchymally derived proteins. Because fibroblasts are immunomodulatory, with absent expression of MHC class II and reduced expression of MHC class I, they provide a low risk of

AC CE P

evoking adverse immune reactions [35-37]. Consequently, allogeneic fibroblasts can be used to replenish mesenchymally synthesized components of the BM. Efforts are also being taken to use genome edited or gene corrected autologous fibroblasts [38]. Nevertheless, it remains to be determined if these cells provide an advantage over allogeneic fibroblasts in an immune competent host.

So far fibroblasts have mainly been investigated as a therapeutic agent for DEB. Dermal fibroblasts together with epidermal keratinocytes are the natural producers of collagen VII in the skin (Fig. 1) [2]. Preclinical trials showed that high concentrations of intradermally injected dermal fibroblasts were able to deposit collagen VII at the extended epidermal BM zone and to promote stabilization of collagen VII deficient skin [39-41]. The effect was transient owing to no proliferation and limited lifespan of the injected cells [41]. Two phase I/II clinical trials [42, 43] that addressed the safety and efficacy of the treatment in DEB were subsequently performed (Table 1). The trials demonstrated that injections of allogeneic fibroblasts were well tolerated by 7

ACCEPTED MANUSCRIPT DEB patients, and that the treatment modestly improved wound healing. Nevertheless, it could not be shown that the injected fibroblasts deposited collagen VII and new questions arose

PT

concerning the efficacy compared to vehicle treatment alone [42]. A major obstacle was the application by repeated painful intradermal injections in inflamed DEB skin. This caused patients

RI

to drop out from the trial [43]. The focus has now shifted to use gene corrected allogeneic

SC

fibroblasts [38, 44]. However, to allow successful translation into the clinics of fibroblast-based DEB therapies, the questions that arose from the clinical trials and the apparent disconnect

NU

between the preclinical and clinical studies will likely have to first be addressed.

MA

Pluripotent cells Bone marrow transplantation

D

During the last 50 years significant effort has been put into the development of bone

TE

marrow transplantation (BMT). It is now used in patients for inherited diseases spanning from

AC CE P

primary immunodeficiency to metabolic disorders [45]. A recent prominent example of the therapeutic potential of BMT is treatment of multiple sclerosis [46]. Because bone marrow is principally constituted of hematopoietic stem cells (HSCs), which are progenitors of all blood cells lineages, BMT is most commonly used to treat acquired disorders such leukemia, lymphoma, Hodgkin's disease and multiple myeloma metabolism [45]. The principle of BMT is to replace the bone marrow with the aim to reconstitute the pool of blood cells at fault, either after in vitro expansion and/or genetic correction of body-own bone marrow (autograft) or by using a human leukocyte antigen matched healthy donor bone marrow (allograft) [45]. Studies have reported that bone marrow-derived stem cells can circulate in the blood, and contribute to tissue regeneration after damage [47]. Interestingly, but still controversial, these cells have been suggested to be able to trans-differentiate into non-hematopoietic cells in in vitro and some in vivo studies [48]. Thus, there is a scientific rationale for using BMT to treat non-hematological disorders. Indeed, BMT and purified HSCs have been shown in preclinical studies to improve

8

ACCEPTED MANUSCRIPT some symptoms of diseases like Duchenne muscular dystrophy [49], impaired cardiac function [50] and hepatic failure [51].

PT

In 2006, two studies reported that BMT was able to improve kidney function in the

RI

Col4a3 knockout mouse, which is a model of Alport syndrome [52, 53]. The disease is progressive and manifests in kidney malfunction, hearing loss and eye involvement. It is caused

SC

by mutations in the genes encoding for the collagen IV α3, 4 or 5 chains [54] (Fig. 2 and Table

NU

1). The studies showed that allogeneic transplantation of wild-type bone marrow to irradiated Alport mice improved kidney function and partially restored collagen IV (345) deposition,

MA

although collagen IV α3 expression was low [52, 53]. Prodromidi and colleagues even reported that BMT improved the survival of the mice [53]. However, in a later study it was shown that

D

irradiation alone could prolong the lifespan of Alport mice [55]. This observation argues that the

TE

improved survival after BMT might primarily be attributed to unidentified effects of irradiation.

AC CE P

Thus, benefit of BMT for Alport syndrome remains controversial. BMT has also been evaluated for the skin blistering disorders DEB and laminin-332 deficient JEB. Preclinical studies generated conflicting results regarding the ability of BMT to treat DEB. One study showed that in utero transplantation of wild-type whole bone marrow extended the life span of Col7a1 knockout mice and resulted in de novo synthesis of collagen VII [56]. However, another study showed that transplantation of wild-type bone marrow into newborn Col7a1 knockout mouse pups had no effect on survival. In this study transplantation of an enriched bone marrow subpopulation (CD150+ CD48-) was able to extend survival and to promote de novo deposition of collagen VII in skin [57]. Subsequently, the studies moved into phase I/II clinical trials. The initial treatment regimen was associated with high lethality related to the procedure or to complications of the disease. Most of the surviving patients showed some transient symptomatic benefit of the treatment [58, 59], e.g. reduction in bandage and dressing use. In patients with residual collagen VII synthesis an increase in collagen VII deposition was

9

ACCEPTED MANUSCRIPT seen at the epidermal BM zone [59]. However, whether this was mutant patient-own or wild-type collagen VII derived from the transplanted cells was not addressed. An improvement of

PT

resistance to suction-induced blisters was also noted which suggested stabilization of the interface between the basal keratinocytes and the BM [59, 60]. In patients that had received

RI

gender-mismatched transplantation, isolated donor cells could be observed in the epidermis and

SC

dermis. Nonetheless, the appearance of the donor cells within the epidermis did not suggest transdifferentation into epidermal stem/progenitor cells [59]. In following studies from the same

NU

and independent groups, the rate of survival after the procedure has been improved by reduced

MA

intensity of conditioning [61, 62]. In addition to DEB, patients with mutations in the LAMB3 gene encoding laminin beta 3 have also been treated with BMT [58] but the results from this trial have

D

so far not been published.

TE

These studies suggest that BMT has some benefits for BM-linked diseases, although the mechanisms promoting these benefits are at present enigmatic. There is limited evidence that

AC CE P

BMT is able to replace existing tissue residing stem cells with donor cells, or even to contribute to synthesis of therapy relevant wild-type proteins [63, 64]. What is known is that BMT is a very serious intervention. Graft-versus-host disease remains a major serious complication after allogeneic BMT [65]. Further, despite the increased understanding and improvement of the technique, there is still a 5-10% risk of fatality associated with the procedure [12]. Therefore, BMT should only be considered for patients with lethal diseases without any other treatment options and in which BMT has a proven and clearly defined effect.

Mesenchymal stromal cells Mesenchymal stem/stromal cells (MSCs) were conclusively described in the late 1960’s [66] and their name was coined in 1991 [67]. Despite efforts to unify the field [68], there is still a broad confusion about the terminology and the characteristics of MSCs [69]. Studies showing 10

ACCEPTED MANUSCRIPT that MSCs were capable to differentiate into multiple cell types of the mesenchymal lineage sparked an immense interest and hope in the regenerative medicine field (from 164 hits for

PT

“mesenchymal stem cell” in PubMed in 2000 to 5341 hits in 2015). However, what has become more and more evident is the fact that omnipotent MSCs do not simply spontaneously undergo

RI

organ-specific commitment after engraftment, and that in vitro differentiation prior to in vivo

SC

application does not guarantee functionality [70]. In spite of these facts, MSCs have shown undeniable and promising results in preclinical as well as clinical trials for a broad spectrum of

NU

diseases. An attractive feature that they share with fibroblasts is the absence of MHC class II

MA

expression and low expression of MHC class I [71], enabling use of allogeneic cells. Present evidence points to that the anti-inflammatory capacity of MSCs significantly contributes to their ability to improve disease symptoms [72, 73]. It has been shown by in vitro and in vivo studies

D

that MSCs maintain reciprocal interactions with cells of the innate immune system. These

TE

interactions establish a well-controlled equilibrium between pathogen clearance and anti-

AC CE P

inflammatory effects. Therefore, MSCs have the ability to modify the local microenvironment in order to limit tissue destruction and restore homeostasis. MSCs mediate their anti-inflammatory properties the best when they are introduced into an already inflamed area [72, 74]. This owes to the fact that a critical concentration of pro-inflammatory cytokines, such as interferon-γ or tumor necrosis factor-α is necessary to activate the cells. Activated MSCs facilitate, through release of proteins such as the secreted hyaladherin with anti-inflammatory properties tumor necrosis factor-inducible gene 6 protein (TSG6), the polarization of macrophages towards the antiinflammatory and immunomodulatory M2 type [72, 74]. There is a dual interest to use MSCs to treat BM-linked diseases. First, they can be utilized as a vehicle for replacement of mesenchymally synthesized protein. Second, they reduce damaging inflammation, which appear to be a strong disease modifier for BM-linked disorders [64, 75-77]. MSC-based therapies have been and are being evaluated in clinical trials for DEB. MSCs cultured under the same setting as dermal fibroblasts express substantial 11

ACCEPTED MANUSCRIPT amounts of collagen VII [78], thus making them a suitable cell source for causal therapy. A pilot study by Conget et al. [79], in which two individuals with DEB showed transient improvement of

PT

wound closure and de novo deposition of collagen VII after receiving 0.5 X106 MSC intradermally, provided cautious optimism. More recent unpublished reports from a clinical trial

RI

currently conducted in Japan have suggested long lasting skin-stabilizing effect of intradermally

SC

administered MSCs [24, 62]. Other trials have tried to elucidate the safety and efficacy of intravenously administered MSCs in children with DEB. The studies showed that the treatment

NU

was well tolerated. The treated children also displayed mild improvement of wound healing and

MA

reduced inflammation; however, de novo deposition of wild-type collagen VII in skin could not be confirmed [80, 81]. In parts, the discrepancy between intradermal and systemic administration of MSCs can be explained by the cell concentration used. In preclinical studies, we showed that a

D

critical concentration of MSCs within the skin is needed to provide clinical benefits, and that this

TE

concentration likely is too high to be reached in peripheral organs through systemic infusions, by The data so far point to that MSCs

AC CE P

virtue of high loss of cells through first pass effects [78].

are a promising tool for topical treatment of non-healing wounds or other problematic areas in patients with DEB. The cells do so, if applied in a sufficient concentration, by I) providing new collagen VII; II) shifting the microenvironment into a healing state. In addition to skin blistering diseases MSC-based therapies have been evaluated in preclinical and clinical trials for neuromuscular disorders [82, 83]. MSCs have shown some therapeutic benefits in pilot studies [84]; however, most of these studies were conducted on Duchenne muscular dystrophy, which is caused by deficiency of the intracellular linker protein dystrophin. Nevertheless, preclinical studies have also been performed on BM-linked muscular dystrophies. Alexeev et al. [85] showed that adipose-derived MSCs express a broad spectrum of ECM components, among them in a large amount collagen VI (Fig. 2). Based on this finding MSC administration was tested in the Col6a1-/- mouse, which is a model of Bethlem myopathy [86]. Intramuscular injection of MSCs resulted in production and deposition of collagen VI [85]. It 12

ACCEPTED MANUSCRIPT remains elusive if MSC injections will also provide additional non-causal therapeutic benefits for collagen VI-related myopathies.

PT

In Alport syndrome, MSCs have so far only been used in a few preclinical trials aimed to

RI

assess their potential to restore kidney function in the Col4a3 knockout mouse. In direct comparison to whole bone marrow transplantation, systemic infusion of MSCs did not improve

SC

disease signs [53]. Nevertheless, an effect on attenuation of fibrosis and chronic inflammation

NU

has been described [87]. Targeting inflammation processes will only delay disease progression; therefore, Gross and colleagues suggested a treatment strategy with mixed cells. MSCs would

MA

be used together with nephron progenitor cells to reduce inflammation and to restore the defective glomerular basement membrane, respectively [64].

D

As discussed, most BM-linked diseases are in need of systemic therapies. At present

TE

there is limited evidence to suggest that systemically administered MSCs will be able to engraft

AC CE P

in a sufficient number to promote functional restoration of the affected organ. In the future, this may become a reality because work is being undertaken to improve MSC engraftment by preconditioning cells prior infusion, [88] to develop new application techniques, and to promote homing [62, 89, 90].

Induced pluripotent stem cells The ability to generate stem cells from differentiated somatic cells, i.e. creation of induced pluripotent stem cells (iPSCs) represented a major leap forward in the regenerative medicine field. In 2006, Shinya Yamanaka Lab described reprogramming of mouse fibroblasts to a pluripotent state by retroviral gene transfer of specific transcription factors (Oct3/4, Sox2, Klf4 and cMyc) involved in the maintenance of pluripotency of embryonic stem cells [91]. The following year, they also applied this technique to human cells [92] and now iPSCs have already

13

ACCEPTED MANUSCRIPT reached the clinical trial phase [93]. A powerful approach would be to combine iPSC-generation from patient samples e.g. skin biopsy or urine, with genome editing [94]. This approach would

PT

minimize immunological challenges with non-autologous cell therapy. However, one study showed that induced expression of genes during the reprogramming and cultivation steps

RI

evoked a T-cell-dependent immune response after implantation of iPSCs in syngeneic recipients

SC

[95]. A subsequent study pointed to that the origin of the iPSCs was an important regulator of immunogenicity [96]. Ultimately the concerns of immunogenicity can only be fully addressed in

NU

patients. Hence, although promising, it is still too early to judge the future therapeutic prospects

MA

of autologous genome edited iPSCs.

For BM-linked diseases, iPSCs have been developed for JEB [97, 98], DEB [99-101],

D

and Alport syndrome [102, 103]. Recently, major advancements for use of iPSCs as an EB

TE

therapy were made. Sebastiano and colleagues were able to restore collagen VII synthesis in keratinocytes derived from DEB patient iPSCs, by AAV-mediated gene correction of the

AC CE P

COL7A1 gene [104, 105]. Another group took advantage of the spontaneous gene-correction, revertant mosaicism [30] that occurs in EB. The group created iPSCs from spontaneously corrected keratinocytes collected from a patient affected with collagen XVII deficient JEB (Fig. 2) [98]. After re-derivation into keratinocytes, these cells were able to produce wild-type collagen XVII in vitro, and in vivo. This approach circumvents some of the safety concerns related to gene therapy or genome editing. A similar approach has been proposed for DEB [99]. iPSCs have also been used to create fibroblasts for DEB cell therapy. Fibroblasts from a DEB mouse were reprogrammed to iPSCs, the collagen VII expression corrected, and the cells were then allowed to re-differentiate into fibroblasts. When these cells were intradermally injected in DEB mice, they restored collagen VII deposition at the epidermal BM zone and promoted skin stability [101]. One limitation with the study was that the gene correction was not directly patient relevant as it involved removal of the causal PGKneo cassette.

14

ACCEPTED MANUSCRIPT It is important to emphasize that although iPSCs possess a great therapeutic potential, they face the same challenges with delivery as other cell therapies. Therefore, at present, topical

PT

treatment of differentiated cells seems to have the highest prospect of success as a causal

SC

RI

therapy for genetic BM-linked disorders.

Outlook

NU

Cell therapy, either through application of undifferentiated or differentiated cells, has the

MA

theoretical potential to cure genetic BM-linked disorders. However, prior to realization of optimal therapeutic outcomes for cell-based therapies, a number of basic hurdles have to be overcome.

D

These include efficient homing, engraftment and differentiation after systemic delivery, and

TE

differentiation and long-term engraftment after topical application. The clinical trials that have evaluated cell therapies for BM-linked diseases so far, have provided relatively limited

AC CE P

information on the true potential of cell therapy approaches. Because the studied diseases are rare, the design of clinical trials is challenging. Patient number is a limitation leaving many studies underpowered. In addition, often the natural disease progression of these disorders is insufficiently known, which makes definition of adequate endpoints challenging. What further complicates interpretation of these clinical trials is that investigators have partially focused on searching for benefits of the treatment, even if these may not been directly linked to causal effects of the transplanted cells. It is imperative to first establish efficacy of cell-based therapies to correct diseasespecific manifestation in relevant pre-clinical models. For efficient treatment a systemic therapy would be most beneficial. Some systemic approaches using stem cells have suggested partial efficacy of such strategies in preclinical studies [52, 53, 56, 57]. There are, however, a number of basic questions to be resolved in regard to these approaches. The most elementary one is that the ability of circulating stem cells to significantly contribute to organ homeostasis in the 15

ACCEPTED MANUSCRIPT adult remains controversial [106, 107]. This is nicely illustrated in some genetic skin disorders, including BM-linked DEB and JEB, in which long lasting and static patches of spontaneously

PT

corrected skin is present in many patients [30]. Thus, even in disease-affected organs the ability to self-regenerate is kept, and there seems to be no selection pressure for cells expressing the

RI

corrected BM protein. However, in some diseases such as muscular dystrophy, there is

SC

evidence of depletion of stem cells during the course of the disease, e.g. collagen VI is a vital component of the satellite cell niche and consequently loss of collagen VI reduces self-renewal

NU

capacity after injury [108]. Because such diseases would require replenishment of stem cells,

MA

this could potentially occur from circulating cells. Nevertheless, loss of stem cells could not only be a consequence of tissue resident stem cells being exhausted by the high demand of tissue regeneration, but also be due to the destruction of the stem cell niche [108]. Destruction of stem

D

cell niches also occurs as a naturally process of aging [109]. Without a supportive

TE

microenvironment, engraftment of stem cells would have limited benefit.

AC CE P

The difficulties to get foreign cells or body own circulating cells to engraft in mature peripheral organs can be viewed as a safety mechanism – limiting the cells that can prosper in an organ will protect against foreign invasion and development of malignancies. A necessary step for the design of systemic cell therapies, and also for topical therapies with the aim of long term or permanent engraftment, is to better understand the unique microenvironmental niches in specific tissues that support uncommitted and committed cells, respectively. This knowledge could enable pretreatment regimens that would make selective niches available, or to expand such niches, allowing better engraftment and long-term survival of the transplanted cells. At present local administration of cells has the highest prospect as a causal treatment for BM-linked disorders [78]. With the important exception of epidermal skin grafts, long-term engraftment of topically transplanted cells does not occur but the cells can instead be used as transient vehicles for replacement of the protein at fault in the disease (Fig. 2). Topical cell

16

ACCEPTED MANUSCRIPT therapies have shown great promise in preclinical studies [41]; however, these therapies have met challenges when they have entered the clinical trial phase and have not lived up to the

PT

expectations [42, 43]. This should not be taken as an indication of general failure of efficacy of such therapies, but rather it emphasizes the very different considerations that need to be taken

RI

into account for preclinical studies and clinical drug development. Topical cell therapies for BM-

SC

linked cell therapies still hold great promise but the path into use in the clinics may not be as

NU

straightforward as once hoped for.

To conclude, cell-based therapies are well suited for treatment of BM-linked diseases.

MA

However, there is still a considerable distance to go until these therapies can become a realistic, safe, and efficacious option for casual treatment of these disorders. There are multiple

D

knowledge gaps that need to be filled, spanning from basic biological concepts to the specific

AC CE P

TE

challenges met by drug development.

Acknowledgement This work was supported by grants NY90/2-1 and NY90/3-2 from the German Research Foundation DFG and from the German Federal Ministry for Education and Research BMBF, under the frame of E-Rare-2 (SplicEB) to AN.

17

ACCEPTED MANUSCRIPT References [1] P.D. Yurchenco, Basement membranes: cell scaffoldings and signaling platforms, Cold

PT

Spring Harbor perspectives in biology 3(2) (2011).

RI

[2] C. Has, A. Nystrom, Epidermal Basement Membrane in Health and Disease, Curr Top Membr 76 (2015) 117-70.

SC

[3] R.V. Iozzo, R.D. Sanderson, Proteoglycans in cancer biology, tumour microenvironment and

NU

angiogenesis, Journal of cellular and molecular medicine 15(5) (2011) 1013-31. [4] N. Smyth, H.S. Vatansever, P. Murray, M. Meyer, C. Frie, M. Paulsson, D. Edgar, Absence of

MA

basement membranes after targeting the LAMC1 gene results in embryonic lethality due to failure of endoderm differentiation, J Cell Biol 144(1) (1999) 151-60.

D

[5] S. Scheele, A. Nystrom, M. Durbeej, J.F. Talts, M. Ekblom, P. Ekblom, Laminin isoforms in

TE

development and disease, J Mol Med (Berl) 85(8) (2007) 825-36.

(2012) 60-9.

AC CE P

[6] R. Gupta, D.T. Woodley, M. Chen, Epidermolysis bullosa acquisita, Clin Dermatol 30(1)

[7] T. Lahmer, U. Heemann, Anti-glomerular basement membrane antibody disease: a rare autoimmune disorder affecting the kidney and the lung, Autoimmunity reviews 12(2) (2012) 16973.

[8] M.P. Begieneman, F.R. van de Goot, P.A. Krijnen, J. Fritz, W.J. Paulus, M.D. Spreeuwenberg, V.W. van Hinsbergh, H.W. Niessen, The basement

membrane of

intramyocardial capillaries is thickened in patients with acute myocardial infarction, Journal of vascular research 47(1) (2010) 54-60. [9] A. Chronopoulos, K. Trudeau, S. Roy, H. Huang, S.A. Vinores, S. Roy, High glucose-induced altered basement membrane composition and structure increases trans-endothelial permeability: implications for diabetic retinopathy, Current eye research 36(8) (2011) 747-53. [10] F. Wiradjaja, T. DiTommaso, I. Smyth, Basement membranes in development and disease, Birth defects research. Part C, Embryo today : reviews 90(1) (2010) 8-31. 18

ACCEPTED MANUSCRIPT [11] http://www.orpha.net/consor/cgi-bin/Disease_Search_List.php?lng=EN, 2016). [12] R. Resta, ORPHAN—THE QUEST TO SAVE CHILDREN WITH RARE GENETIC

PT

DISORDERS. By Philip R. Reilly. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2015, Wiley Online Library, 2016.

RI

[13] T. Kuhl, M. Mezger, I. Hausser, L.T. Guey, R. Handgretinger, L. Bruckner-Tuderman, A.

SC

Nystrom, Collagen VII half-life at the dermal-epidermal junction zone: Implications for mechanisms and therapy of genodermatoses, J Invest Dermatol (2016) In press.

NU

[14] D. Urich, J.L. Eisenberg, K.J. Hamill, D. Takawira, S.E. Chiarella, S. Soberanes, A.

MA

Gonzalez, F. Koentgen, T. Manghi, S.B. Hopkinson, A.V. Misharin, H. Perlman, G.M. Mutlu, G.R. Budinger, J.C. Jones, Lung-specific loss of the laminin alpha3 subunit confers resistance to mechanical injury, J Cell Sci 124(Pt 17) (2011) 2927-37.

TE

2(3) (2002) 231-8.

D

[15] M.T. Little, R. Storb, History of haematopoietic stem-cell transplantation, Nat Rev Cancer

AC CE P

[16] M.L. Maeder, C.A. Gersbach, Genome-editing Technologies for Gene and Cell Therapy, Mol Ther 24(3) (2016) 430-46.

[17] A. Trounson, N.D. DeWitt, Pluripotent stem cells progressing to the clinic, Nat Rev Mol Cell Biol 17(3) (2016) 194-200.

[18] A. Bersenev, Cell therapy clinical trials–2014 report. CellTrials blog. January 22, 2015, 2015. [19] A. Trounson, R.G. Thakar, G. Lomax, D. Gibbons, Clinical trials for stem cell therapies, BMC medicine 9 (2011) 52. [20] A. Trounson, C. McDonald, Stem Cell Therapies in Clinical Trials: Progress and Challenges, Cell stem cell 17(1) (2015) 11-22. [21] M. Mendicino, A.M. Bailey, K. Wonnacott, R.K. Puri, S.R. Bauer, MSC-based product characterization for clinical trials: an FDA perspective, Cell stem cell 14(2) (2014) 141-5.

19

ACCEPTED MANUSCRIPT [22] http://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/de

PT

fault.htm, (2016). [23]

SC

an_med_001844.jsp&mid=WC0b01ac058001d124., 2016).

RI

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002450/hum

[24] J. Uitto, L. Bruckner-Tuderman, A.M. Christiano, J.A. McGrath, C. Has, A.P. South, B.

NU

Kopelan, E.C. Robinson, Progress toward Treatment and Cure of Epidermolysis Bullosa:

MA

Summary of the DEBRA International Research Symposium EB2015, J Invest Dermatol 136(2) (2016) 352-8.

[25] C. Chamorro, A. Mencia, D. Almarza, B. Duarte, H. Buning, J. Sallach, I. Hausser, M. Del

D

Rio, F. Larcher, R. Murillas, Gene Editing for the Efficient Correction of a Recurrent COL7A1

AC CE P

Nucleic acids 5 (2016) e307.

TE

Mutation in Recessive Dystrophic Epidermolysis Bullosa Keratinocytes, Molecular therapy.

[26] Z. Siprashvili, N.T. Nguyen, M.Y. Bezchinsky, M.P. Marinkovich, A.T. Lane, P.A. Khavari, Long-term type VII collagen restoration to human epidermolysis bullosa skin tissue, Hum Gene Ther 21(10) (2010) 1299-310.

[27] M. Titeux, V. Pendaries, M.A. Zanta-Boussif, A. Decha, N. Pironon, L. Tonasso, J.E. Mejia, A. Brice, O. Danos, A. Hovnanian, SIN retroviral vectors expressing COL7A1 under human promoters for ex vivo gene therapy of recessive dystrophic epidermolysis bullosa, Mol Ther 18(8) (2010) 1509-18. [28] E.M. Murauer, Y. Gache, I.K. Gratz, A. Klausegger, W. Muss, C. Gruber, G. Meneguzzi, H. Hintner, J.W. Bauer, Functional correction of type VII collagen expression in dystrophic epidermolysis bullosa, J Invest Dermatol 131(1) (2011) 74-83. [29] A. Gostynski, A.M. Pasmooij, M.F. Jonkman, Successful therapeutic transplantation of revertant skin in epidermolysis bullosa, J Am Acad Dermatol 70(1) (2014) 98-101.

20

ACCEPTED MANUSCRIPT [30] D. Kiritsi, M. Garcia, R. Brander, C. Has, R. Meijer, M. Jose Escamez, J. Kohlhase, P.C. van den Akker, H. Scheffer, M.F. Jonkman, M. Del Rio, L. Bruckner-Tuderman, A.M. Pasmooij,

PT

Mechanisms of Natural Gene Therapy in Dystrophic Epidermolysis Bullosa, J Invest Dermatol (2014).

RI

[31] F. Mavilio, G. Pellegrini, S. Ferrari, F. Di Nunzio, E. Di Iorio, A. Recchia, G. Maruggi, G.

SC

Ferrari, E. Provasi, C. Bonini, S. Capurro, A. Conti, C. Magnoni, A. Giannetti, M. De Luca, Correction of junctional epidermolysis bullosa by transplantation of genetically modified

NU

epidermal stem cells, Nat Med 12(12) (2006) 1397-402.

MA

[32] L. De Rosa, S. Carulli, F. Cocchiarella, D. Quaglino, E. Enzo, E. Franchini, A. Giannetti, G. De Santis, A. Recchia, G. Pellegrini, M. De Luca, Long-term stability and safety of transgenic cultured epidermal stem cells in gene therapy of junctional epidermolysis bullosa, Stem cell

D

reports 2(1) (2014) 1-8.

TE

[33] E.M. Murauer, U. Koller, G. Pellegrini, M. De Luca, J.W. Bauer, Advances in Gene/Cell

AC CE P

Therapy in Epidermolysis Bullosa, The Keio journal of medicine 64(2) (2015) 21-5. [34] A. Nystrom, L. Bruckner-Tuderman, J.S. Kern, Cell- and protein-based therapy approaches for epidermolysis bullosa, Methods in molecular biology 961 (2013) 425-40. [35] M.A. Haniffa, X.N. Wang, U. Holtick, D.C. Swan, S. Bullock, A.M. Dickinson, C.M. Hilkens, M.P. Collin, Mesenchymal stem cells and fibroblasts have similar immunoregulatory properties in vitro but distinct gene expression profiles: Implications for cellular therapy, Blood 110(11) (2007) 573a-573a. [36] T. Zuliani, S. Saiagh, A.C. Knol, J. Esbelin, B. Dreno, Fetal fibroblasts and keratinocytes with immunosuppressive properties for allogeneic cell-based wound therapy, PLoS One 8(7) (2013) e70408. [37] Q. Lu, M. Yu, C. Shen, X. Chen, T. Feng, Y. Yao, J. Li, H. Li, W. Tu, Negligible immunogenicity of induced pluripotent stem cells derived from human skin fibroblasts, PLoS One 9(12) (2014) e114949.

21

ACCEPTED MANUSCRIPT [38] J. Jackow, M. Titeux, S. Portier, S. Charbonnier, C. Ganier, S. Gaucher, A. Hovnanian, Gene-corrected fibroblast therapy for recessive dystrophic epidermolysis bullosa using a SIN

PT

COL7A1 retroviral vector, J Invest Dermatol (2016). [39] D.T. Woodley, G.G. Krueger, C.M. Jorgensen, J.A. Fairley, T. Atha, Y. Huang, L. Chan,

RI

D.R. Keene, M. Chen, Normal and gene-corrected dystrophic epidermolysis bullosa fibroblasts

SC

alone can produce type VII collagen at the basement membrane zone, J Invest Dermatol 121(5) (2003) 1021-8.

NU

[40] A. Fritsch, S. Loeckermann, J.S. Kern, A. Braun, M.R. Bosl, T.A. Bley, H. Schumann, D. von

MA

Elverfeldt, D. Paul, M. Erlacher, D. Berens von Rautenfeld, I. Hausser, R. Fassler, L. BrucknerTuderman, A hypomorphic mouse model of dystrophic epidermolysis bullosa reveals mechanisms of disease and response to fibroblast therapy, J Clin Invest 118(5) (2008) 1669-79.

D

[41] J.S. Kern, S. Loeckermann, A. Fritsch, I. Hausser, W. Roth, T.M. Magin, C. Mack, M.L.

TE

Muller, O. Paul, P. Ruther, L. Bruckner-Tuderman, Mechanisms of fibroblast cell therapy for

AC CE P

dystrophic epidermolysis bullosa: high stability of collagen VII favors long-term skin integrity, Mol Ther 17(9) (2009) 1605-15.

[42] S.S. Venugopal, W. Yan, J.W. Frew, H.I. Cohn, L.M. Rhodes, K. Tran, W. Melbourne, J.A. Nelson, M. Sturm, J. Fogarty, M.P. Marinkovich, S. Igawa, A. Ishida-Yamamoto, D.F. Murrell, A phase II randomized vehicle-controlled trial of intradermal allogeneic fibroblasts for recessive dystrophic epidermolysis bullosa, J Am Acad Dermatol 69(6) (2013) 898-908 e7. [43] G. Petrof, M. Martinez-Queipo, J.E. Mellerio, P. Kemp, J.A. McGrath, Fibroblast cell therapy enhances initial healing in recessive dystrophic epidermolysis bullosa wounds: results of a randomized, vehicle-controlled trial, Br J Dermatol 169(5) (2013) 1025-33. [44] C. Georgiadis, F. Syed, A. Petrova, A. Abdul-Wahab, S.M. Lwin, F. Farzaneh, L. Chan, S. Ghani, R.A. Fleck, L. Glover, J.R. McMillan, M. Chen, A.J. Thrasher, J.A. McGrath, W.L. Di, W. Qasim, Lentiviral Engineered Fibroblasts Expressing Codon-Optimized COL7A1 Restore Anchoring Fibrils in RDEB, J Invest Dermatol 136(1) (2016) 284-92.

22

ACCEPTED MANUSCRIPT [45]

M.T.

de

la

Morena,

R.A.

Gatti,

A

history

of

bone

marrow

transplantation,

Hematology/oncology clinics of North America 25(1) (2011) 1-15.

PT

[46] R.A. Nash, G.J. Hutton, M.K. Racke, U. Popat, S.M. Devine, L.M. Griffith, P.A. Muraro, H. Openshaw, P.H. Sayre, O. Stuve, D.L. Arnold, M.E. Spychala, K.C. McConville, K.M. Harris, D.

RI

Phippard, G.E. Georges, A. Wundes, G.H. Kraft, J.D. Bowen, High-dose immunosuppressive

SC

therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report, JAMA neurology 72(2) (2015) 159-69.

NU

[47] Y. Wu, J. Wang, P.G. Scott, E.E. Tredget, Bone marrow-derived stem cells in wound

MA

healing: a review, Wound Repair Regen 15 Suppl 1 (2007) S18-26. [48] I. Catacchio, S. Berardi, A. Reale, A. De Luisi, V. Racanelli, A. Vacca, R. Ria, Evidence for bone marrow adult stem cell plasticity: properties, molecular mechanisms, negative aspects, and

D

clinical applications of hematopoietic and mesenchymal stem cells transdifferentiation, Stem

TE

cells international 2013 (2013) 589139.

AC CE P

[49] E. Gussoni, Y. Soneoka, C.D. Strickland, E.A. Buzney, M.K. Khan, A.F. Flint, L.M. Kunkel, R.C. Mulligan, Dystrophin expression in the mdx mouse restored by stem cell transplantation, Nature 401(6751) (1999) 390-4.

[50] K.A. Jackson, S.M. Majka, H. Wang, J. Pocius, C.J. Hartley, M.W. Majesky, M.L. Entman, L.H. Michael, K.K. Hirschi, M.A. Goodell, Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells, J Clin Invest 107(11) (2001) 1395-402. [51] E. Lagasse, H. Connors, M. Al-Dhalimy, M. Reitsma, M. Dohse, L. Osborne, X. Wang, M. Finegold, I.L. Weissman, M. Grompe, Purified hematopoietic stem cells can differentiate into hepatocytes in vivo, Nat Med 6(11) (2000) 1229-34. [52] H. Sugimoto, T.M. Mundel, M. Sund, L. Xie, D. Cosgrove, R. Kalluri, Bone-marrow-derived stem cells repair basement membrane collagen defects and reverse genetic kidney disease, P Natl Acad Sci USA 103(19) (2006) 7321-7326.

23

ACCEPTED MANUSCRIPT [53] E.I. Prodromidi, R. Poulsom, R. Jeffery, C.A. Roufosse, P.J. Pollard, C.D. Pusey, H.T. Cook, Bone marrow-derived cells contribute to podocyte regeneration and amelioration of renal

PT

disease in a mouse model of Alport syndrome, Stem Cells 24(11) (2006) 2448-2455. [54] J.H. Miner, C. Baigent, F. Flinter, O. Gross, P. Judge, C.E. Kashtan, S. Lagas, J. Savige, D.

RI

Blatt, J. Ding, D.P. Gale, J.P. Midgley, S. Povey, M. Prunotto, D. Renault, J. Skelding, A.N.

SC

Turner, S. Gear, The 2014International Workshop on Alport Syndrome, Kidney international 86(4) (2014) 679-84.

NU

[55] K. Katayama, M. Kawano, I. Naito, H. Ishikawa, Y. Sado, N. Asakawa, T. Murata, K. Oosugi,

MA

M. Kiyohara, E. Ishikawa, M. Ito, S. Nomura, Irradiation prolongs survival of Alport mice, Journal of the American Society of Nephrology : JASN 19(9) (2008) 1692-700. [56] T. Chino, K. Tamai, T. Yamazaki, S. Otsuru, Y. Kikuchi, K. Nimura, M. Endo, M. Nagai, J.

D

Uitto, Y. Kitajima, Y. Kaneda, Bone marrow cell transfer into fetal circulation can ameliorate

AC CE P

Pathol 173(3) (2008) 803-14.

TE

genetic skin diseases by providing fibroblasts to the skin and inducing immune tolerance, Am J

[57] J. Tolar, A. Ishida-Yamamoto, M. Riddle, R.T. McElmurry, M. Osborn, L. Xia, T. Lund, C. Slattery, J. Uitto, A.M. Christiano, J.E. Wagner, B.R. Blazar, Amelioration of epidermolysis bullosa by transfer of wild-type bone marrow cells, Blood 113(5) (2009) 1167-74. [58] J. Tolar, J.E. Wagner, Management of severe epidermolysis bullosa by haematopoietic transplant: principles, perspectives and pitfalls, Exp Dermatol 21(12) (2012) 896-900. [59] J.E. Wagner, A. Ishida-Yamamoto, J.A. McGrath, M. Hordinsky, D.R. Keene, D.T. Woodley, M. Chen, M.J. Riddle, M.J. Osborn, T. Lund, M. Dolan, B.R. Blazar, J. Tolar, Bone marrow transplantation for recessive dystrophic epidermolysis bullosa, N Engl J Med 363(7) (2010) 62939. [60] U. Kiistala, K.K. Mustakallio, Dermo-epidermal separation with suction. Electron microscopic and histochemical study of initial events of blistering on human skin, J Invest Dermatol 48(5) (1967) 466-77.

24

ACCEPTED MANUSCRIPT [61] M.B. Geyer, K. Radhakrishnan, R. Giller, N. Umegaki, S. Harel, M. Kiuru, K.D. Morel, N. LeBoeuf, J. Kandel, A. Bruckner, S. Fabricatore, M. Chen, D. Woodley, J. McGrath, L. Baxter-

PT

Lowe, J. Uitto, A.M. Christiano, M.S. Cairo, Reduced Toxicity Conditioning and Allogeneic Hematopoietic Progenitor Cell Transplantation for Recessive Dystrophic Epidermolysis Bullosa,

RI

The Journal of pediatrics 167(3) (2015) 765-9 e1.

SC

[62] E. Rashidghamat, J. Mellerio, A. Martinez, J. McGrath, Mesenchymal stem cell therapy for recessive dystrophic epidermolysis bullosa: prospects and clinical progress, Expert Opinion on

NU

Orphan Drugs 4(4) (2016) 343-345.

MA

[63] P.P. Bornert Olivier , Bremer Jeroen, Koller Ulrich , van den Akker Peter C. , Aartsma-Rus Annemieke, Pasmooij Anna M. G., Murauer Eva M. , Nyström Alexander RNA-based therapies for genodermatoses, submitted (2016).

D

[64] O. Gross, L. Perin, C. Deltas, Alport syndrome from bench to bedside: the potential of

TE

current treatment beyond RAAS blockade and the horizon of future therapies, Nephrology,

AC CE P

dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 29 Suppl 4 (2014) iv124-30. [65] M. Szyska, I.K. Na, Bone Marrow GvHD after Allogeneic Hematopoietic Stem Cell Transplantation, Frontiers in immunology 7 (2016) 118. [66] A.J. Friedenstein, K.V. Petrakova, A.I. Kurolesova, G.P. Frolova, Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues, Transplantation 6(2) (1968) 230-47. [67] A.I. Caplan, Mesenchymal stem cells, J Orthop Res 9(5) (1991) 641-50. [68] M. Dominici, K. Le Blanc, I. Mueller, I. Slaper-Cortenbach, F. Marini, D. Krause, R. Deans, A. Keating, D. Prockop, E. Horwitz, Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement, Cytotherapy 8(4) (2006) 315-7.

25

ACCEPTED MANUSCRIPT [69] P. Bianco, X. Cao, P.S. Frenette, J.J. Mao, P.G. Robey, P.J. Simmons, C.Y. Wang, The meaning, the sense and the significance: translating the science of mesenchymal stem cells into

PT

medicine, Nat Med 19(1) (2013) 35-42. [70] P. Bianco, "Mesenchymal" stem cells, Annu Rev Cell Dev Biol 30 (2014) 677-704.

RI

[71] K. Le Blanc, D. Mougiakakos, Multipotent mesenchymal stromal cells and the innate

SC

immune system, Nature reviews. Immunology 12(5) (2012) 383-96.

[72] M.E. Bernardo, L.M. Ball, F. Locatelli, W.E. Fibbe, Immunomodulatory Properties of MSCs,

NU

Mesenchymal Stromal Cells, Springer2013, pp. 107-134.

MA

[73] K. English, Mechanisms of mesenchymal stromal cell immunomodulation, Immunology and cell biology 91(1) (2013) 19-26.

[74] M.E. Bernardo, W.E. Fibbe, Mesenchymal stromal cells and hematopoietic stem cell

D

transplantation, Immunol Lett 168(2) (2015) 215-21.

TE

[75] A. Nystrom, K. Thriene, V. Mittapalli, J.S. Kern, D. Kiritsi, J. Dengjel, L. Bruckner-Tuderman,

AC CE P

Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms, EMBO molecular medicine (2015). [76] S. Meinen, S. Lin, M.A. Ruegg, Angiotensin II type 1 receptor antagonists alleviate muscle pathology in the mouse model for laminin-alpha2-deficient congenital muscular dystrophy (MDC1A), Skeletal muscle 2(1) (2012) 18. [77] J. Holmberg, A. Alajbegovic, K.I. Gawlik, L. Elowsson, M. Durbeej, Laminin alpha2 ChainDeficiency is Associated with microRNA Deregulation in Skeletal Muscle and Plasma, Frontiers in aging neuroscience 6 (2014) 155. [78] T. Kuhl, M. Mezger, I. Hausser, R. Handgretinger, L. Bruckner-Tuderman, A. Nystrom, High Local Concentrations of Intradermal MSCs Restore Skin Integrity and Facilitate Wound Healing in Dystrophic Epidermolysis Bullosa, Mol Ther 23(8) (2015) 1368-79. [79] P. Conget, F. Rodriguez, S. Kramer, C. Allers, V. Simon, F. Palisson, S. Gonzalez, M.J. Yubero, Replenishment of type VII collagen and re-epithelialization of chronically ulcerated skin

26

ACCEPTED MANUSCRIPT after intradermal administration of allogeneic mesenchymal stromal cells in two patients with recessive dystrophic epidermolysis bullosa, Cytotherapy 12(3) (2010) 429-31.

PT

[80] M. El-Darouti, M. Fawzy, I. Amin, R. Abdel Hay, R. Hegazy, H. Gabr, Z. El Maadawi, Treatment of dystrophic epidermolysis bullosa with bone marrow non-hematopoeitic stem cells:

RI

a randomized controlled trial, Dermatologic therapy 29(2) (2016) 96-100.

SC

[81] G. Petrof, S.M. Lwin, M. Martinez-Queipo, A. Abdul-Wahab, S. Tso, J.E. Mellerio, I. SlaperCortenbach, J.J. Boelens, J. Tolar, P. Veys, M. Ofuya, J.L. Peacock, A.E. Martinez, J.A.

NU

McGrath, Potential of Systemic Allogeneic Mesenchymal Stromal Cell Therapy for Children with

MA

Recessive Dystrophic Epidermolysis Bullosa, J Invest Dermatol 135(9) (2015) 2319-21. [82] M. Meregalli, A. Farini, D. Parolini, S. Maciotta, Y. Torrente, Stem cell therapies to treat muscular

dystrophy:

progress

to

date,

BioDrugs

:

clinical

immunotherapeutics,

D

biopharmaceuticals and gene therapy 24(4) (2010) 237-47.

TE

[83] E. Negroni, A. Bigot, G.S. Butler-Browne, C. Trollet, V. Mouly, Cellular Therapies for

26.

AC CE P

Muscular Dystrophies: Frustrations and Clinical Successes, Hum Gene Ther 27(2) (2016) 117-

[84] T.E. Ichim, D.T. Alexandrescu, F. Solano, F. Lara, N. Campion Rde, E. Paris, E.J. Woods, M.P. Murphy, C.A. Dasanu, A.N. Patel, A.M. Marleau, A. Leal, N.H. Riordan, Mesenchymal stem cells as anti-inflammatories: implications for treatment of Duchenne muscular dystrophy, Cellular immunology 260(2) (2010) 75-82. [85] V. Alexeev, M. Arita, A. Donahue, P. Bonaldo, M.L. Chu, O. Igoucheva, Human adiposederived stem cell transplantation as a potential therapy for collagen VI-related congenital muscular dystrophy, Stem cell research & therapy 5(1) (2014) 21. [86] P. Bonaldo, P. Braghetta, M. Zanetti, S. Piccolo, D. Volpin, G.M. Bressan, Collagen VI deficiency induces early onset myopathy in the mouse: an animal model for Bethlem myopathy, Hum Mol Genet 7(13) (1998) 2135-40.

27

ACCEPTED MANUSCRIPT [87] A.F. Wise, S.D. Ricardo, Mesenchymal stem cells in kidney inflammation and repair, Nephrology 17(1) (2012) 1-10.

PT

[88] C. Perdoni, J.A. McGrath, J. Tolar, Preconditioning of mesenchymal stem cells for improved transplantation efficacy in recessive dystrophic epidermolysis bullosa, Stem cell research &

RI

therapy 5(6) (2014) 121.

SC

[89] K. Tamai, T. Yamazaki, T. Chino, M. Ishii, S. Otsuru, Y. Kikuchi, S. Iinuma, K. Saga, K. Nimura, T. Shimbo, N. Umegaki, I. Katayama, J. Miyazaki, J. Takeda, J.A. McGrath, J. Uitto, Y.

NU

Kaneda, PDGFRalpha-positive cells in bone marrow are mobilized by high mobility group box 1

MA

(HMGB1) to regenerate injured epithelia, Proc Natl Acad Sci U S A 108(16) (2011) 6609-14. [90] S. Iinuma, E. Aikawa, K. Tamai, R. Fujita, Y. Kikuchi, T. Chino, J. Kikuta, J.A. McGrath, J. Uitto, M. Ishii, H. Iizuka, Y. Kaneda, Transplanted bone marrow-derived circulating

D

PDGFRalpha+ cells restore type VII collagen in recessive dystrophic epidermolysis bullosa

TE

mouse skin graft, J Immunol 194(4) (2015) 1996-2003.

AC CE P

[91] K. Takahashi, S. Yamanaka, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors, Cell 126(4) (2006) 663-76. [92] K. Takahashi, K. Tanabe, M. Ohnuki, M. Narita, T. Ichisaka, K. Tomoda, S. Yamanaka, Induction of pluripotent stem cells from adult human fibroblasts by defined factors, Cell 131(5) (2007) 861-72.

[93] E.A. Kimbrel, R. Lanza, Current status of pluripotent stem cells: moving the first therapies to the clinic, Nature reviews. Drug discovery 14(10) (2015) 681-92. [94] A. Hotta, S. Yamanaka, From Genomics to Gene Therapy: Induced Pluripotent Stem Cells Meet Genome Editing, Annual review of genetics 49 (2015) 47-70. [95] T. Zhao, Z.N. Zhang, Z. Rong, Y. Xu, Immunogenicity of induced pluripotent stem cells, Nature 474(7350) (2011) 212-5. [96] T. Zhao, Z.N. Zhang, P.D. Westenskow, D. Todorova, Z. Hu, T. Lin, Z. Rong, J. Kim, J. He, M. Wang, D.O. Clegg, Y.G. Yang, K. Zhang, M. Friedlander, Y. Xu, Humanized Mice Reveal

28

ACCEPTED MANUSCRIPT Differential Immunogenicity of Cells Derived from Autologous Induced Pluripotent Stem Cells, Cell stem cell 17(3) (2015) 353-9.

PT

[97] J. Tolar, L. Xia, C.J. Lees, M. Riddle, A. McElroy, D.R. Keene, T.C. Lund, M.J. Osborn, M.P. Marinkovich, B.R. Blazar, J.E. Wagner, Keratinocytes from induced pluripotent stem cells in

RI

junctional epidermolysis bullosa, J Invest Dermatol 133(2) (2013) 562-5.

SC

[98] N. Umegaki-Arao, A.M. Pasmooij, M. Itoh, J.E. Cerise, Z. Guo, B. Levy, A. Gostynski, L.R. Rothman, M.F. Jonkman, A.M. Christiano, Induced pluripotent stem cells from human revertant

NU

keratinocytes for the treatment of epidermolysis bullosa, Science translational medicine 6(264)

MA

(2014) 264ra164.

[99] J. Tolar, J.A. McGrath, L. Xia, M.J. Riddle, C.J. Lees, C. Eide, D.R. Keene, L. Liu, M.J. Osborn, T.C. Lund, B.R. Blazar, J.E. Wagner, Patient-specific naturally gene-reverted induced

TE

(2014) 1246-54.

D

pluripotent stem cells in recessive dystrophic epidermolysis bullosa, J Invest Dermatol 134(5)

AC CE P

[100] M. Itoh, N. Umegaki-Arao, Z. Guo, L. Liu, C.A. Higgins, A.M. Christiano, Generation of 3D skin equivalents fully reconstituted from human induced pluripotent stem cells (iPSCs), PLoS One 8(10) (2013) e77673.

[101] D. Wenzel, J. Bayerl, A. Nystrom, L. Bruckner-Tuderman, A. Meixner, J.M. Penninger, Genetically corrected iPSCs as cell therapy for recessive dystrophic epidermolysis bullosa, Science translational medicine 6(264) (2014) 264ra165. [102] W. Chen, J. Huang, X. Yu, X. Lin, Y. Dai, Generation of induced pluripotent stem cells from renal tubular cells of a patient with Alport syndrome, International journal of nephrology and renovascular disease 8 (2015) 101-9. [103] B. Song, J.C. Niclis, M.A. Alikhan, S. Sakkal, A. Sylvain, P.G. Kerr, A.L. Laslett, C.A. Bernard, S.D. Ricardo, Generation of induced pluripotent stem cells from human kidney mesangial cells, Journal of the American Society of Nephrology : JASN 22(7) (2011) 1213-20.

29

ACCEPTED MANUSCRIPT [104] V. Sebastiano, H.H. Zhen, B. Haddad, E. Bashkirova, S.P. Melo, P. Wang, T.L. Leung, Z. Siprashvili, A. Tichy, J. Li, M. Ameen, J. Hawkins, S. Lee, L. Li, A. Schwertschkow, G. Bauer, L.

PT

Lisowski, M.A. Kay, S.K. Kim, A.T. Lane, M. Wernig, A.E. Oro, Human COL7A1-corrected

Science translational medicine 6(264) (2014) 264ra163.

RI

induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa,

SC

[105] S.P. Melo, L. Lisowski, E. Bashkirova, H.H. Zhen, K. Chu, D.R. Keene, M.P. Marinkovich, M.A. Kay, A.E. Oro, Somatic correction of junctional epidermolysis bullosa by a highly

NU

recombinogenic AAV variant, Mol Ther 22(4) (2014) 725-33.

MA

[106] N.D. Theise, D.S. Krause, S. Sharkis, Comment on "Little evidence for developmental plasticity of adult hematopoietic stem cells", Science 299(5611) (2003) 1317; author reply 1317. [107] A.J. Wagers, R.I. Sherwood, J.L. Christensen, I.L. Weissman, Little evidence for

D

developmental plasticity of adult hematopoietic stem cells, Science 297(5590) (2002) 2256-9.

TE

[108] A. Urciuolo, M. Quarta, V. Morbidoni, F. Gattazzo, S. Molon, P. Grumati, F. Montemurro,

AC CE P

F.S. Tedesco, B. Blaauw, G. Cossu, G. Vozzi, T.A. Rando, P. Bonaldo, Collagen VI regulates satellite cell self-renewal and muscle regeneration, Nat Commun 4 (2013) 1964. [109] H. Matsumura, Y. Mohri, N.T. Binh, H. Morinaga, M. Fukuda, M. Ito, S. Kurata, J. Hoeijmakers, E.K. Nishimura, Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis, Science 351(6273) (2016) aad4395. [110] A. Naba, K.R. Clauser, H. Ding, C.A. Whittaker, S.A. Carr, R.O. Hynes, The extracellular matrix: Tools and insights for the "omics" era, Matrix Biol (2015). [111] W. Nishie, D. Kiritsi, A. Nystrom, S.C. Hofmann, L. Bruckner-Tuderman, Dynamic interactions of epidermal collagen XVII with the extracellular matrix: laminin 332 as a major binding partner, Am J Pathol 179(2) (2011) 829-37. [112] Y. Hara, B. Balci-Hayta, T. Yoshida-Moriguchi, M. Kanagawa, D. Beltran-Valero de Bernabe, H. Gundesli, T. Willer, J.S. Satz, R.W. Crawford, S.J. Burden, S. Kunz, M.B. Oldstone,

30

ACCEPTED MANUSCRIPT A. Accardi, B. Talim, F. Muntoni, H. Topaloglu, P. Dincer, K.P. Campbell, A dystroglycan mutation associated with limb-girdle muscular dystrophy, N Engl J Med 364(10) (2011) 939-46.

PT

[113] C. Huze, S. Bauche, P. Richard, F. Chevessier, E. Goillot, K. Gaudon, A. Ben Ammar, A. Chaboud, I. Grosjean, H.A. Lecuyer, V. Bernard, A. Rouche, N. Alexandri, T. Kuntzer, M.

RI

Fardeau, E. Fournier, A. Brancaccio, M.A. Ruegg, J. Koenig, B. Eymard, L. Schaeffer, D. Hantai,

function, Am J Hum Genet 85(2) (2009) 155-67.

SC

Identification of an agrin mutation that causes congenital myasthenia and affects synapse

NU

[114] R.A. Maselli, J.M. Fernandez, J. Arredondo, C. Navarro, M. Ngo, D. Beeson, O. Cagney,

MA

D.C. Williams, R.L. Wollmann, V. Yarov-Yarovoy, M.J. Ferns, LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin, Hum Genet 131(7) (2012) 1123-35.

D

[115] E. Plaisier, O. Gribouval, S. Alamowitch, B. Mougenot, C. Prost, M.C. Verpont, B. Marro, T.

TE

Desmettre, S.Y. Cohen, E. Roullet, M. Dracon, M. Fardeau, T. Van Agtmael, D. Kerjaschki, C.

AC CE P

Antignac, P. Ronco, COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps, N Engl J Med 357(26) (2007) 2687-95. [116] M.E. Meuwissen, D.J. Halley, L.S. Smit, M.H. Lequin, J.M. Cobben, R. de Coo, J. van Harssel, S. Sallevelt, G. Woldringh, M.S. van der Knaap, L.S. de Vries, G.M. Mancini, The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature, Genetics in medicine : official journal of the American College of Medical Genetics 17(11) (2015) 843-53. [117] J.C. Zenteno, J. Crespi, B. Buentello-Volante, J.A. Buil, F. Bassaganyas, J.I. Vela-Segarra, J. Diaz-Cascajosa, M.T. Marieges, Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity, Graefes Arch Clin Exp Ophthalmol 252(11) (2014) 1789-94.

31

ACCEPTED MANUSCRIPT [118] D.B. Gould, F.C. Phalan, S.E. van Mil, J.P. Sundberg, K. Vahedi, P. Massin, M.G. Bousser, P. Heutink, J.H. Miner, E. Tournier-Lasserve, S.W. John, Role of COL4A1 in small-

PT

vessel disease and hemorrhagic stroke, N Engl J Med 354(14) (2006) 1489-96. [119] D.S. Kuo, C. Labelle-Dumais, M. Mao, M. Jeanne, W.B. Kauffman, J. Allen, J. Favor, D.B.

RI

Gould, Allelic heterogeneity contributes to variability in ocular dysgenesis, myopathy and brain

SC

malformations caused by Col4a1 and Col4a2 mutations, Hum Mol Genet 23(7) (2014) 1709-22. [120] Y. Yoneda, K. Haginoya, M. Kato, H. Osaka, K. Yokochi, H. Arai, A. Kakita, T. Yamamoto,

NU

Y. Otsuki, S. Shimizu, T. Wada, N. Koyama, Y. Mino, N. Kondo, S. Takahashi, S. Hirabayashi, J.

MA

Takanashi, A. Okumura, T. Kumagai, S. Hirai, M. Nabetani, S. Saitoh, A. Hattori, M. Yamasaki, A. Kumakura, Y. Sugo, K. Nishiyama, S. Miyatake, Y. Tsurusaki, H. Doi, N. Miyake, N. Matsumoto, H. Saitsu, Phenotypic spectrum of COL4A1 mutations: porencephaly to

D

schizencephaly, Annals of neurology 73(1) (2013) 48-57.

TE

[121] M.S. van der Knaap, L.M. Smit, F. Barkhof, Y.A. Pijnenburg, S. Zweegman, H.W. Niessen,

AC CE P

S. Imhof, P. Heutink, Neonatal porencephaly and adult stroke related to mutations in collagen IV A1, Annals of neurology 59(3) (2006) 504-11. [122] M. Jeanne, C. Labelle-Dumais, J. Jorgensen, W.B. Kauffman, G.M. Mancini, J. Favor, V. Valant, S.M. Greenberg, J. Rosand, D.B. Gould, COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke, Am J Hum Genet 90(1) (2012) 91-101. [123] C. Labelle-Dumais, D.J. Dilworth, E.P. Harrington, M. de Leau, D. Lyons, Z. Kabaeva, M.C. Manzini, W.B. Dobyns, C.A. Walsh, D.E. Michele, D.B. Gould, COL4A1 mutations cause ocular dysgenesis, neuronal localization defects, and myopathy in mice and Walker-Warburg syndrome in humans, PLoS genetics 7(5) (2011) e1002062. [124] Y. Yoneda, K. Haginoya, H. Arai, S. Yamaoka, Y. Tsurusaki, H. Doi, N. Miyake, K. Yokochi, H. Osaka, M. Kato, N. Matsumoto, H. Saitsu, De novo and inherited mutations in COL4A2, encoding the type IV collagen alpha2 chain cause porencephaly, Am J Hum Genet 90(1) (2012) 86-90.

32

ACCEPTED MANUSCRIPT [125] C. Badenas, M. Praga, B. Tazon, L. Heidet, C. Arrondel, A. Armengol, A. Andres, E. Morales, J.A. Camacho, X. Lens, S. Davila, M. Mila, C. Antignac, A. Darnell, R. Torra, Mutations

PT

in theCOL4A4 and COL4A3 genes cause familial benign hematuria, Journal of the American Society of Nephrology : JASN 13(5) (2002) 1248-54.

RI

[126] T. Mochizuki, H.H. Lemmink, M. Mariyama, C. Antignac, M.C. Gubler, Y. Pirson, C.

SC

Verellen-Dumoulin, B. Chan, C.H. Schroder, H.J. Smeets, et al., Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome, Nat Genet

NU

8(1) (1994) 77-81.

MA

[127] S. Anazi, E. Al-Sabban, F.S. Alkuraya, Gonadal mosaicism as a rare cause of autosomal recessive inheritance, Clinical genetics 85(3) (2014) 278-81. [128] H.H. Lemmink, W.N. Nillesen, T. Mochizuki, C.H. Schroder, H.G. Brunner, B.A. van Oost,

D

L.A. Monnens, H.J. Smeets, Benign familial hematuria due to mutation of the type IV collagen

TE

alpha4 gene, J Clin Invest 98(5) (1996) 1114-8.

AC CE P

[129] P. Cochat, P. Guibaud, R. Garcia Torres, B. Roussel, V. Guarner, F. Larbre, Diffuse leiomyomatosis in Alport syndrome, The Journal of pediatrics 113(2) (1988) 339-43. [130] L. Heidet, K. Dahan, J. Zhou, Z. Xu, P. Cochat, J.D. Gould, K.A. Leppig, W. Proesmans, C. Guyot, M. Guillot, et al., Deletions of both alpha 5(IV) and alpha 6(IV) collagen genes in Alport syndrome and in Alport syndrome associated with smooth muscle tumours, Hum Mol Genet 4(1) (1995) 99-108. [131] L. Heidet, L. Cohen-Solal, E. Boye, P. Thorner, M.J. Kemper, A. David, L. Larget Piet, J. Zhou, F. Flinter, X. Zhang, M.C. Gubler, C. Antignac, Novel COL4A5/COL4A6 deletions and further characterization of the diffuse leiomyomatosis-Alport syndrome (DL-AS) locus define the DL critical region, Cytogenetics and cell genetics 78(3-4) (1997) 240-6. [132] G.J. Jobsis, H. Keizers, J.P. Vreijling, M. de Visser, M.C. Speer, R.A. Wolterman, F. Baas, P.A. Bolhuis, Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures, Nat Genet 14(1) (1996) 113-5.

33

ACCEPTED MANUSCRIPT [133] A.K. Lampe, K.M. Bushby, Collagen VI related muscle disorders, J Med Genet 42(9) (2005) 673-85.

PT

[134] A. Nadeau, M. Kinali, M. Main, C. Jimenez-Mallebrera, A. Aloysius, E. Clement, B. North, A.Y. Manzur, S.A. Robb, E. Mercuri, F. Muntoni, Natural history of Ullrich congenital muscular

RI

dystrophy, Neurology 73(1) (2009) 25-31.

SC

[135] T.C. Pan, R.Z. Zhang, D.G. Sudano, S.K. Marie, C.G. Bonnemann, M.L. Chu, New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame

NU

deletion in the COL6A1 gene causes a severe phenotype, Am J Hum Genet 73(2) (2003) 355-

MA

69.

D

[136] R.J. Butterfield, A.R. Foley, J. Dastgir, S. Asman, D.M. Dunn, Y. Zou, Y. Hu, S.

TE

Donkervoort, K.M. Flanigan, K.J. Swoboda, T.L. Winder, R.B. Weiss, C.G. Bonnemann, Position

AC CE P

of glycine substitutions in the triple helix of COL6A1, COL6A2, and COL6A3 is correlated with severity and mode of inheritance in collagen VI myopathies, Hum Mutat 34(11) (2013) 1558-67. [137] O. Camacho Vanegas, E. Bertini, R.Z. Zhang, S. Petrini, C. Minosse, P. Sabatelli, B. Giusti, M.L. Chu, G. Pepe, Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI, Proc Natl Acad Sci U S A 98(13) (2001) 7516-21. [138] N.L. Baker, M. Morgelin, R.A. Pace, R.A. Peat, N.E. Adams, R.J. Gardner, L.P. Rowland, G. Miller, P. De Jonghe, B. Ceulemans, M.C. Hannibal, M. Edwards, E.M. Thompson, R. Jacobson, R.C. Quinlivan, S. Aftimos, A.J. Kornberg, K.N. North, J.F. Bateman, S.R. Lamande, Molecular consequences of dominant Bethlem myopathy collagen VI mutations, Annals of neurology 62(4) (2007) 390-405. [139] E. Demir, P. Sabatelli, V. Allamand, A. Ferreiro, B. Moghadaszadeh, M. Makrelouf, H. Topaloglu, B. Echenne, L. Merlini, P. Guicheney, Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy, Am J Hum Genet 70(6) (2002) 1446-58.

34

ACCEPTED MANUSCRIPT [140] D. Kiritsi, J.S. Kern, H. Schumann, J. Kohlhase, C. Has, L. Bruckner-Tuderman, Molecular mechanisms of phenotypic variability in junctional epidermolysis bullosa, J Med Genet 48(7)

PT

(2011) 450-7. [141] M.R. Passos-Bueno, S.K. Marie, M. Monteiro, I. Neustein, M.R. Whittle, M. Vainzof, M.

RI

Zatz, Knobloch syndrome in a large Brazilian consanguineous family: confirmation of autosomal

SC

recessive inheritance, American journal of medical genetics 52(2) (1994) 170-3. [142] A.L. Sertie, V. Sossi, A.A. Camargo, M. Zatz, C. Brahe, M.R. Passos-Bueno, Collagen

NU

XVIII, containing an endogenous inhibitor of angiogenesis and tumor growth, plays a critical role

MA

in the maintenance of retinal structure and in neural tube closure (Knobloch syndrome), Hum Mol Genet 9(13) (2000) 2051-8.

[143] P. Dincer, B. Balci, Y. Yuva, B. Talim, M. Brockington, D. Dincel, S. Torelli, S. Brown, G.

D

Kale, G. Haliloglu, F.O. Gerceker, R.C. Atalay, C. Yakicier, C. Longman, F. Muntoni, H.

TE

Topaloglu, A novel form of recessive limb girdle muscular dystrophy with mental retardation and

8.

AC CE P

abnormal expression of alpha-dystroglycan, Neuromuscular disorders : NMD 13(10) (2003) 771-

[144] T. Hamada, V. Wessagowit, A.P. South, G.H. Ashton, I. Chan, N. Oyama, A. Siriwattana, P. Jewhasuchin, S. Charuwichitratana, D.M. Thappa, B. Jeevankumar, P. Lenane, B. Krafchik, K. Kulthanan, H. Shimizu, T.I. Kaya, M.E. Erdal, M. Paradisi, A.S. Paller, M. Seishima, T. Hashimoto, J.A. McGrath, Extracellular matrix protein 1 gene (ECM1) mutations in lipoid proteinosis and genotype-phenotype correlation, J Invest Dermatol 120(3) (2003) 345-50. [145] D. Tranel, B.T. Hyman, Neuropsychological correlates of bilateral amygdala damage, Archives of neurology 47(3) (1990) 349-55. [146] A. Slavotinek, C. Li, E.H. Sherr, A.E. Chudley, Mutation analysis of the FRAS1 gene demonstrates new mutations in a propositus with Fraser syndrome, American journal of medical genetics. Part A 140(18) (2006) 1909-14.

35

ACCEPTED MANUSCRIPT [147] L. McGregor, V. Makela, S.M. Darling, S. Vrontou, G. Chalepakis, C. Roberts, N. Smart, P. Rutland, N. Prescott, J. Hopkins, E. Bentley, A. Shaw, E. Roberts, R. Mueller, S. Jadeja, N.

PT

Philip, J. Nelson, C. Francannet, A. Perez-Aytes, A. Megarbane, B. Kerr, B. Wainwright, A.S. Woolf, R.M. Winter, P.J. Scambler, Fraser syndrome and mouse blebbed phenotype caused by

RI

mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein, Nat Genet 34(2)

SC

(2003) 203-8.

[148] A.M. Alazami, R. Shaheen, F. Alzahrani, K. Snape, A. Saggar, B. Brinkmann, P. Bavi, L.I.

NU

Al-Gazali, F.S. Alkuraya, FREM1 mutations cause bifid nose, renal agenesis, and anorectal

MA

malformations syndrome, Am J Hum Genet 85(3) (2009) 414-8. [149] L.I. Al-Gazali, M. Bakir, O.A. Hamud, S. Gerami, An autosomal recessive syndrome of nasal anomalies associated with renal and anorectal malformations, Clinical dysmorphology

D

11(1) (2002) 33-8.

TE

[150] Y. Shafeghati, A. Kniepert, G. Vakili, M. Zenker, Fraser syndrome due to homozygosity for

529-31.

AC CE P

a splice site mutation of FREM2, American journal of medical genetics. Part A 146A(4) (2008)

[151] D. Kiyozumi, N. Sugimoto, K. Sekiguchi, Breakdown of the reciprocal stabilization of QBICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser syndrome-like defects, Proc Natl Acad Sci U S A 103(32) (2006) 11981-6. [152] S.D. Handmaker, J.A. Campbell, L.D. Robinson, O. Chinwah, R.J. Gorlin, Dyssegmental dwarfism: a new syndrome of lethal dwarfism, Birth defects original article series 13(3D) (1977) 79-90. [153] E. Arikawa-Hirasawa, W.R. Wilcox, A.H. Le, N. Silverman, P. Govindraj, J.R. Hassell, Y. Yamada, Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene, Nat Genet 27(4) (2001) 431-4. [154] D. Viljoen, P. Beighton, Schwartz-Jampel syndrome (chondrodystrophic myotonia), J Med Genet 29(1) (1992) 58-62.

36

ACCEPTED MANUSCRIPT [155] S. Nicole, C.S. Davoine, H. Topaloglu, L. Cattolico, D. Barral, P. Beighton, C.B. Haida, H. Hammouda, C. Cruaud, P.S. White, D. Samson, J.A. Urtizberea, F. Lehmann-Horn, J.

PT

Weissenbach, F. Hentati, B. Fontaine, Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic

RI

myotonia), Nat Genet 26(4) (2000) 480-3.

SC

[156] K.A. Aldinger, S.J. Mosca, M. Tetreault, J.C. Dempsey, G.E. Ishak, T. Hartley, I.G. Phelps, R.E. Lamont, D.R. O'Day, D. Basel, K.W. Gripp, L. Baker, M.J. Stephan, F.P. Bernier, K.M.

NU

Boycott, J. Majewski, G. University of Washington Center for Mendelian, C. Care4Rare, J.S.

MA

Parboosingh, A.M. Innes, D. Doherty, Mutations in LAMA1 cause cerebellar dysplasia and cysts with and without retinal dystrophy, Am J Hum Genet 95(2) (2014) 227-34. [157] A. Poretti, M. Hausler, A. von Moers, B. Baumgartner, K. Zerres, A. Klein, C. Aiello, F.

D

Moro, G. Zanni, F.M. Santorelli, T.A. Huisman, J. Weis, E.M. Valente, E. Bertini, E. Boltshauser,

TE

Ataxia, intellectual disability, and ocular apraxia with cerebellar cysts: a new disease?,

AC CE P

Cerebellum 13(1) (2014) 79-88.

[158] H. Xu, X.R. Wu, U.M. Wewer, E. Engvall, Murine muscular dystrophy caused by a mutation in the laminin alpha 2 (Lama2) gene, Nat Genet 8(3) (1994) 297-302. [159] A. Helbling-Leclerc, X. Zhang, H. Topaloglu, C. Cruaud, F. Tesson, J. Weissenbach, F.M. Tome, K. Schwartz, M. Fardeau, K. Tryggvason, et al., Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy, Nat Genet 11(2) (1995) 216-8. [160] F. Vidal, C. Baudoin, C. Miquel, M.F. Galliano, A.M. Christiano, J. Uitto, J.P. Ortonne, G. Meneguzzi, Cloning of the laminin alpha 3 chain gene (LAMA3) and identification of a homozygous deletion in a patient with Herlitz junctional epidermolysis bullosa, Genomics 30(2) (1995) 273-80. [161] S. Kivirikko, J.A. McGrath, C. Baudoin, D. Aberdam, S. Ciatti, M.G. Dunnill, J.R. McMillan, R.A. Eady, J.P. Ortonne, G. Meneguzzi, et al., A homozygous nonsense mutation in the alpha 3

37

ACCEPTED MANUSCRIPT chain gene of laminin 5 (LAMA3) in lethal (Herlitz) junctional epidermolysis bullosa, Hum Mol Genet 4(5) (1995) 959-62.

PT

[162] R. Knoll, R. Postel, J. Wang, R. Kratzner, G. Hennecke, A.M. Vacaru, P. Vakeel, C. Schubert, K. Murthy, B.K. Rana, D. Kube, G. Knoll, K. Schafer, T. Hayashi, T. Holm, A. Kimura,

RI

N. Schork, M.R. Toliat, P. Nurnberg, H.P. Schultheiss, W. Schaper, J. Schaper, E. Bos, J. Den

SC

Hertog, F.J. van Eeden, P.J. Peters, G. Hasenfuss, K.R. Chien, J. Bakkers, Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in

NU

cardiomyocytes and endothelial cells, Circulation 116(5) (2007) 515-25.

MA

[163] F. Radmanesh, A.O. Caglayan, J.L. Silhavy, C. Yilmaz, V. Cantagrel, T. Omar, B. Rosti, H. Kaymakcalan, S. Gabriel, M. Li, N. Sestan, K. Bilguvar, W.B. Dobyns, M.S. Zaki, M. Gunel, J.G. Gleeson, Mutations in LAMB1 cause cobblestone brain malformation without muscular or ocular

D

abnormalities, Am J Hum Genet 92(3) (2013) 468-74.

TE

[164] M. Zenker, T. Aigner, O. Wendler, T. Tralau, H. Muntefering, R. Fenski, S. Pitz, V.

AC CE P

Schumacher, B. Royer-Pokora, E. Wuhl, P. Cochat, R. Bouvier, C. Kraus, K. Mark, H. Madlon, J. Dotsch, W. Rascher, I. Maruniak-Chudek, T. Lennert, L.M. Neumann, A. Reis, Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities, Hum Mol Genet 13(21) (2004) 2625-32. [165] G. Jarad, J. Cunningham, A.S. Shaw, J.H. Miner, Proteinuria precedes podocyte abnormalities inLamb2-/- mice, implicating the glomerular basement membrane as an albumin barrier, J Clin Invest 116(8) (2006) 2272-9. [166] B.W. Darbro, V.B. Mahajan, L. Gakhar, J.M. Skeie, E. Campbell, S. Wu, X. Bing, K.J. Millen, W.B. Dobyns, J.A. Kessler, A. Jalali, J. Cremer, A. Segre, J.R. Manak, K.A. Aldinger, S. Suzuki, N. Natsume, M. Ono, H.D. Hai, T. Viet le, S. Loddo, E.M. Valente, L. Bernardini, N. Ghonge, P.J. Ferguson, A.G. Bassuk, Mutations in extracellular matrix genes NID1 and LAMC1 cause autosomal dominant Dandy-Walker malformation and occipital cephaloceles, Hum Mutat 34(8) (2013) 1075-9.

38

ACCEPTED MANUSCRIPT [167] L. Pulkkinen, A.M. Christiano, T. Airenne, H. Haakana, K. Tryggvason, J. Uitto, Mutations in the gamma 2 chain gene (LAMC2) of kalinin/laminin 5 in the junctional forms of epidermolysis

PT

bullosa, Nat Genet 6(3) (1994) 293-7. [168] A. Nakano, S.C. Chao, L. Pulkkinen, D. Murrell, L. Bruckner-Tuderman, E. Pfendner, J.

RI

Uitto, Laminin 5 mutations in junctional epidermolysis bullosa: molecular basis of Herlitz vs. non-

SC

Herlitz phenotypes, Hum Genet 110(1) (2002) 41-51.

[169] T. Barak, K.Y. Kwan, A. Louvi, V. Demirbilek, S. Saygi, B. Tuysuz, M. Choi, H. Boyaci, K.

NU

Doerschner, Y. Zhu, H. Kaymakcalan, S. Yilmaz, M. Bakircioglu, A.O. Caglayan, A.K. Ozturk, K.

MA

Yasuno, W.J. Brunken, E. Atalar, C. Yalcinkaya, A. Dincer, R.A. Bronen, S. Mane, T. Ozcelik, R.P. Lifton, N. Sestan, K. Bilguvar, M. Gunel, Recessive LAMC3 mutations cause malformations of occipital cortical development, Nat Genet 43(6) (2011) 590-4.

D

[170] A.G. Bassuk, D. McLone, R. Bowman, J.A. Kessler, Autosomal dominant occipital

AC CE P

TE

cephalocele, Neurology 62(10) (2004) 1888-90.

39

ACCEPTED MANUSCRIPT Figure legends Fig. 1. Cell and BM interactions in cornea, lung alveolar, skin, kidney and muscle. These

PT

schematic drawings represent the cellular organization and the interactions of these cells with the BM in organs affected by BM-linked diseases. Both epithelial and mesenchymal cells

RI

contribute to the BM; some proteins are exclusively produced by either epithelial cells or

SC

mesenchymal cells, whereas other proteins are expressed by both. Thus, the cell type suitable

NU

for use in therapy depends on the protein that needs to be restored.

MA

Fig. 2. Heterogeneity of basement membrane composition. Schematic illustration of three BMs that are frequently affected by BM-linked diseases. Specific and selected proteins present at the

D

epidermal BM in skin, the skeletal muscle BM, and the glomeruli BM in kidney are shown.

TE

Selected interactions among BM proteins, and in addition, their binding to essential cell surface

AC CE P

receptors are displayed. What can be appreciated is that although similar on an ultrastructural level, the BMs are quite heterogeneous in their molecular composition. This contributes to the organ-specific disease manifestations caused by genetic deficiency of individual BM proteins and the challenges to develop treatments for these diseases. Proteins, deficiencies in which lead to disease manifestation in the specific organs, are listed on the left. Integrins, which are part of the adhesome [110] are not considered BM-proteins, whereas collagen XVII, which exists in two forms; one linked cell membrane and one deposited in the BM [111], and the -dystroglycan subunit, which is exclusively present extracellularly are considered BM proteins [112].

40

AC CE P

TE

D

MA

NU

SC

RI

PT

ACCEPTED MANUSCRIPT

41

ACCEPTED MANUSCRIPT

AC CE P

TE

D

MA

NU

SC

RI

PT

Fig. 1

42

AC CE P

TE

D

MA

NU

SC

RI

PT

ACCEPTED MANUSCRIPT

Fig. 2

43

ACCEPTED MANUSCRIPT

AC CE P

TE

D

MA

NU

SC

RI

PT

Table 1. BM-linked diseases, thier disease manifestations and present status of cell-base therapies.

44

Congenital myashenic syndrome

615120

Muscle

Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome

611773

Multi-organ involvement

Retinal arterial tortuosity

180000

Eye

Small vessel disease (with or without ocular anomalies)

607595

Porencephaly-1

175780

Brain

614519

Brain

-

Multi-organ involvement

Hemorrhagic stroke

Multi-organ involvement

203780 104200

Kidney

141200

Kidney

Alport syndrome

203780

Kidney

Thin basement membrane nephropathy (benign familial hematuria)

141200

Kidney

Alport syndrome

301050

Kidney

Diffuse leiomyomatosis with Alport syndrome

308940

Multi-organ involvement

Diffuse leiomyomatosis with Alport syndrome

308940

Multi-organ involvement

Bethlem myopathy-1

158810

Muscle

Ullrich congenital muscular dystrophy-1

254090

Muscle

Alport syndrome Collagen IV α3

Collagen IV α6

Collagen VI α1

AC CE P

Collagen IV α5

TE

D

Thin basement membrane nephropathy (benign familial hematuria)

Collagen IV α4

Brain / Eye

614483 614519

Intracerebral haemorrhage

MA

Collagen IV α2

NU

Walker-Warburg syndrome

45

Cell Therapy Status

PT

Collagen IV α1

organ

RI

Agrin

Primarily affected ACCEPTED MANUSCRIPT Disease OMIM Nr

SC

Affected Protein/subunit

Preclinical

Preclinical

Preclinical

Affected Protein Collagen VI α2

Primarily affected Disease OMIM Nr ACCEPTED MANUSCRIPT organ 158810

Muscle

Ullrich congenital muscular dystrophy-1

254090

Muscle

Bethlem myopathy-1

158810

Muscle

Ullrich congenital muscular dystrophy-1

254090

Muscle

Collagen VII

Dystrophic epidermolysis bullosa

226600 131750

Collagen XVII*

Junctional epidermolysis bullosa

226650

Collagen XVIII

Knobloch syndrome

267750

α-dystroglycan*

Limb-girdle muscular dystrophy

Extracellular matrix protein 1

Lipoid proteinosis

FRAS1

Fraser syndrome

FRAS1-related extracellular matrix protein 1 FRAS1-related extracellular matrix protein 2

RI

SC 613818 616538

NU

Collagen VI α3

PT

Bethlem myopathy-1

Skin

Clinical Phase I / II

Skin

Preclinical

Eye

Muscle, Brain, Eye Skin, Brain

219000

Eye, multi organ

Bifid nose with or without anorectal and renal anomalies syndrome

608980

Multi-organ involvement

Fraser syndrome

219000

Eye, multi organ

Dyssegmental dysplasia Type SilvermanHandmaker

224410

Lethal neonatal dwarfism

Schwartz-Jampel syndrome

255800

Dwarfism, Eye, Muscle

Poretti-Boltshauser syndrome

615960

Brain

Laminin α2

Congenital muscular dystrophy type 1a

607855

Muscle, Nerve

Laminin α3

Junctional epidermolysis bullosa

226700 226650

Skin

Cardiomyopathy

615235

Heart

Laminin β1

Lissencephaly-5

615191

Brain

Laminin β2

Pierson syndrome

609049

Kidney, Eye

Laminin α4

D

TE

AC CE P

Laminin α1

MA

247100

Perlecan

46

Cell Therapy Status

[

ACCEPTED MANUSCRIPT Disease

OMIM Nr

Primarily affected organ

Cell Therapy Status

Laminin β3

Junctional epidermolysis bullosa

226700 226650

Skin

Clinical Phase I / II

Laminin γ1

Dandy-Walker malformation with occipital cephalocele

609222

Brain

Laminin γ2

Junctional epidermolysis bullosa

226700 226650

Laminin γ3

Occipital cortical malformations

614115

Nidogen 1

Dandy-Walker malformation with occipital cephalocele

609222

SC

RI

PT

Affected Protein

Skin

Brain Brain

After shedding collagen XVII is deposited in the BM; the α-dystroglycan subunit is located

*

NU

extracellularly. **

MA

Single patients with heterozygous nonsense or misense mutations reported.

Basement membrane-linked diseases are a versatile group of disorders that affect every major organ system.



AC CE P



TE

D

Highlights Cell therapy for basement membrane-linked diseases

Cell-based therapies are attractive for basement membrane-linked diseases as curative effects can be achieved with incomplete and even transient engraftment of cells.



Disease-modifying mechanisms may also be targeted with cell-based therapies.



Multiple knowledge gaps need to be filled to allow wider clinical implementation, and to retrieve the full potential of cell-based therapies for the treatment of basement membrane-linked diseases.



At present localized therapies have the highest therapeutic potential.

47