Cell-based immunomodulatory therapy approaches for type 1 diabetes mellitus

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Teaser This review highlights the possibility of achieving the restoration of euglycemia in T1DM by induction of hematopoietic chimerism without recipient conditioning by supplementing bone marrow graft with MHC-disparate mesenchymal cells.

Cell-based immunomodulatory therapy approaches for type 1 diabetes mellitus Q2

Labe Black and Tatiana Zorina

Thomas Jefferson University, Jefferson College of Health Professions, Department of Medical Laboratory Science Q3 and Biotechnology, Philadelphia, PA, USA

Physiologically sufficient b cell regeneration can be achieved by the induction of hematopoietic chimerism in a type 1 diabetes mellitus (T1DM) mouse model. However, pancytopenia and graft-versus-host disease (GVHD) limits the clinical adaptation of this modality. In this review, we discuss new perceptions on the induction of chimerism, without bone marrow (BM) recipient conditioning, via supplementation of mesenchymal stem cells (MSCs) to support engraftment of allogeneic HSCs. The use of haploidentical, gender-matched, predisposing T1DM genotype-free HSCs in combination with MHC-disparate MSCs could lead to the development of a safe protocol for the induction of hematopoietic chimerism for the treatment of T1DM.

Introduction A significant improvement has been achieved in the quality and longevity of life of patients with T1DM subjected to advanced therapeutic regimens. However, the overall outcomes are still far from desirable. Allogeneic BM transplantation (BMT) was shown to sustain b cell regeneration to a physiological level of insulin metabolism in the mouse model [1,2]. However, the morbidity associated with induction of allogeneic chimerism is a serious limiting factor for its adaptation to the clinic, particularly for use in pediatrics. Nonetheless, the list of disorders treated with BMT continues to grow. Originally, it was limited to the treatment of hematopoietic malignancies [3,4]. More recently, it has been explored as a therapy for a large cohort of non-malignant disorders [5–7] comprising autoimmune conditions, including T1DM [8,9], pancytopenia [10], and the induction of tolerance for a solid organ transplantation [11–15]. In this review, we provide an update on new perceptions and emerging concepts for achieving allogeneic hematopoietic chimerism without its major adverse effects: pancytopenia and GVHD. The aptness of the long-believed concept that successful allogeneic HSC engraftment requires host conditioning for clearing up space and/or HSC niches is examined. Whether conditioning is a requirement for the induction of allogeneic chimerism is being challenged and even refuted by numerous studies [16,17]. We discuss, as a means to circumvent the potential complication of pancytopenia, the possibility of eliminating conditioning before BMT, in light of new knowledge

Labe Black is a spectroscopist who specializes in singlemolecule methodologies, including single molecule localization microscopy, fluorescence correlation spectroscopy, and singlemolecule FRET. Using advanced microcopy techniques, he has studied yeast cell-size homeostasis by determining quantitative transcription factor copy numbers, dynamics, and activity. He has also used singlemolecule fluorescence methods to elucidate G protein (intracellular GPCR signal transducers) dynamics, on a millisecond-to-nanosecond timescale, showing that this was correlated with function while bound to either small-molecule nucleotides or proteins with nucleotide exchange activity. Tatiana Zorina was awarded a PhD in immunology in St Petersburg, Russia. After immigrating to the USA, she was involved in developing a protocol for dendritic cell (DC) propagation, used for DC-based antitumor vaccination methodologies. Later, the focus of her research was on immunomodulatory approaches for the treatment of type 1 diabetes mellitus (T1DM). She and colleagues were the first to demonstrate the possibility of physiologically sufficient b cell regeneration in the nonobese diabetic (NOD) mouse model of T1DM by induction of allogeneic hematopoietic chimerism after onset of hyperglycemia. Additionally, the role of the regulatory T cells in the restoration of euglycemia was studied using this model.

Corresponding author: Zorina, T. ([email protected]) 1359-6446/ã 2019 Published by Elsevier Ltd. https://doi.org/10.1016/j.drudis.2019.11.016

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of bone marrow dynamic structure, which ensures the balance between short-term and long-term HSC populations (ST-HSC and LT-HSC, respectively), allowing fluid cell migration with the ability to adapt to environmental conditions. Another serious complication of BMT is the onset of GVHD. The idea of eliminating donor-derived instigators of GVHD while supplementing the donor HSC inoculum with cells aiding their engraftment led to a search for ‘facilitating cells’ (FCs). Many candidates for FCs among hematopoietic and nonhematopoietic stem, precursor, immature, and mature cell populations with various phenotypes have been proposed by numerous studies [18–23], and the search remains in progress. We now know that some of the major cellular players that sustain hematopoiesis in physiological conditions, by regulating the balance between shortterm progenitor and long-term self-renewal HSC populations, are cells from the mesenchymal stroma and mesenchymal stem and precursor cells. We discuss the role of these cells in the regulation of autologous hematopoietic homeostasis and the prospect of using them to sustain allogeneic HSC engraftment in a clinical setting. The long-known ability of MSCs to crosstalk with HSCs across allogeneic disparity [24,25] is beneficial for the development of a new protocol for the induction of allogeneic chimerism Q4 in T1DM using MSC-based therapies.

Mesenchymal stromal anomalies and therapeutic approaches in T1DM Anomalies of mesenchymal stroma in T1DM The basic pathology in T1DM is a loss of self-tolerance towards b cell-related antigens. This hematopoietic aberration leading to autoimmunity is found in strong association with BM-HSC anomalies [26,27]. The major cellular component of HSC niches in BM is represented by MSCs, which have a significant role in hematopoiesis and immunomodulatory processes. A detailed understanding of cellular and molecular mechanisms that regulate the mesenchymal component of HSC niches is needed to achieve an appropriate therapeutic rectification of autoimmunity in T1DM. The role of mesenchymal stroma, specifically, osteoblast-populations sustaining the balance between LT-HSC and ST-HSC niches, is known to be important for all hematopoiesis-related pathologies, including autoimmune disorders. The CXCL12/CXCR4 axis is one of the major regulators of HSC and MSC mobility, homing, and retention within different locations of BM and controls the balance between the LT-HSC and ST-HSC niches. The status and alterations of this axis in T1DM has been addressed in numerous studies, some of which are discussed below. The role of mesenchymal stroma compartments in the pathophysiology of T1DM includes remodeling of BM structure [28,29]. BM remodeling results in: (i) changes in the osteoblast progenitor pool (as part of the altered bone architecture) [30–32]; (ii) hypoperfusion of stem cell niches (resulting from microangiopathy) [29,33]; and (iii) premature apoptosis of BM-MSCs as part of neuropathy [34– 36]. BM remodeling, together with hyperglycemia and an accumulation of advanced glycation end (AGE) products, leads to mobilopathy [37], which refers to the altered migrating capacity of stem and progenitor hematopoietic cells and their retention in BM. Mobilopathy produces a skewed ratio of stem cells in BM and in peripheral blood cell subsets [38]. In vitro experiments showed that MSCs exposure to AGE products induces deficiencies similar to that found 2

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in MSCs of diabetic origin [31,39]. Diabetic mobilopathy is a contributing factor leading to the development of diabetes-related clinical complications. This is because of the impaired mobilization of stem and progenitor cells into the peripheral circulation, which has a crucial role in end stage-organ failure as a result of jeopardized vascular integrity and tissue repair [40]. The CXCL12/CXCR4 axis was shown to be impaired in T1DM [41,42]. A comprehensive study by Ferraro et al., is supportive of the suggestion that the CXCL12/CXCR4 axis is a key player in the observed reduced migratory ability of HSCs in T1DM. This study demonstrated that the impaired features of mesenchymal stromal cells is part of the pathogenesis for both T1DM and T2DM. This axis anomaly correlates with hyperglycemia and is independent of insulin blood concentrations [41]. The altered expression of CXCL12 and reduced size of osteoblastic populations were found to be in direct correlation with the decreased mobilizing ability of hematopoietic stem and precursor cells (HSPCs) in hyperglycemic animals. This finding was further confirmed by using AMD3100, which directly blocks the CXCR4/CXCL12 axis interaction [41]. These data indicate that defects in microenvironmental stroma, responsible for mobilopathy, are one of the major contributing factors to the pathogenesis of T1DM. A question regarding the role of mesenchymal stroma in diabetesassociated complications was also asked from a clinical point-ofview; that is, with respect to the high susceptibility of patients with T1DM to bacterial infections, a serious condition leading, in some cases, to lower extremity amputations [43]. Numerous studies using in vitro and in vivo experimental and clinical approaches demonstrated that MSPCs in diabetic models are quantitatively and functionally deficient [37]. MSCs isolated from patients and animals with T1DM have lower levels of colony-forming-unit fibroblasts (CFU-F) [39,44] in correlating with their functional deficiencies [44–46]. These stromal stem cells were shown to be ineffective when applied as treatment for ischemic limbs [47] and had reduced antibacterial potential [48] compared with MSCs from a healthy donor. These anomalies, which cause diabetes-associated morbidity, were found in direct association with impaired function of MSCs and correlated with decreased expression of CXCL12 [42].

Therapeutic applications of MSCs for the treatment of T1DM T1DM is one of the most common severe autoimmune diseases, with 1 in 300 children affected in the USA alone [49]. Moreover, the incidence of pediatric cases of T1DM is rapidly increasing, especially in children under the age of 5 [50]. Despite improvements in the current modalities of exogenous insulin administration, the life expectancy for patients with diabetes is reduced by up to 15 years [51]. Strict glycemic control improves long-term prognosis by reducing the incidence of microvascular complications. However, it is associated with a higher risk of episodes of hypoglycemia, which cause another set of detrimental complications [52]. Substantial morbidity and the increasing costs of insulin continues to be a driving force for the development of new therapeutic approaches. Even though mesenchymal cells are still under investigation with respect to their functional role in human homeostasis and a variety of pathological conditions, they have already emerged as a strong candidate for cell-based therapeutic applications [53]. Attempts are already underway for their adaptation as treatment

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MSCs for the treatment of T1DM via direct immunomodulatory and reparative input MSCs have been shown to ameliorate autoimmunity in T1DM [64]. MSC-based therapies focus on two objectives: recovering euglycemia via b cell regeneration and amelioration of autoimmunity [63]. Human MSCs have low immunogenicity [65] because they lack expression of MHC-Class II [66] and of costimulatory molecules CD80, CD86, CD40, and CD40L [67,68]. Thus, MSCs have a strong immunoregulatory function. They inhibit the proliferation and function of T, B, and natural killer (NK) cells, activate CD4+/Foxp3+ regulatory T cells (Tregs), and modulate dendritic cell (DC) function both in vivo and in vitro [69,70]. Based on these findings, positive outcomes associated with MSC-based therapies for T1DM are commonly attributed to the immunomodulatory ability of these cells. However, Murai et al. showed that intrapancreatic injection of human BM-derived MSCs resulted in a decrease in hyperglycemia, which correlated with increased pancreatic islets size in streptozotocin-induced diabetic mice. These data suggest that MSC reparative properties, rather than, or in association with, their immunomodulatory function, facilitate the amelioration of diabetic hyperglycemia [71]. In addition to immunomodulatory capacities, MSCs are also well known for their ability to produce lineage-specific progenies. An in vitro assay showed the possibility of enhanced control of insulinproducing cell differentiation from adipose-derived MSCs [72]. Takahashi and Yamanaka developed a new technology to induce pluripotency in mature stromal cells, termed ‘inducible pluripotential stem cells’ (iPSCs) [73,74]. Discovery of iPSCs opens the way for the development of therapeutic strategies for T1DM by transplantation of autologous stem cells that can be transformed into b cells sustaining euglycemia under physiological control [75–77]. Preclinical trials comprising the transplantation of undifferentiated MSCs as well as MSCs differentiated into b islet cells in vitro showed potential as a safe and effective treatment for patients with T1DM [78]. Clinical trials in which MSC transplantation is used for therapy in both T1DM and T2DM are in progress. Cellonis Biotechnology Co. is currently conducting trials to evaluate the feasibility, efficacy, and safety of bone and umbilical cord-derived MSCs in the treatment of both T1DM and T2DM [79,80]. Bhansali et al. showed that MSCs are an effective means to improve b cell function in patients with T2DM [81–84]. In a human clinical study, Wang et al. incorporated autologous MSCs in a cotransplantation of islets to test their efficacy and safety in patients with

T1DM [85]. This study showed that MSC and islet cotransplantation was safe and improved islet engraftment after transplantation. However, Cho et al. showed that MSC-based regimens used as a treatment for T1DM were inconclusive, despite the ability of MSCs to differentiate into iPSCs and induce Treg differentiation [86]. Thus, a clinically successful therapeutic protocol, which would significantly improve the quality and longevity of life of patients with T1DM through physiologically sustained euglycemia, has yet to be developed. An alternative approach to achieve euglycemia in patients with T1DM is the induction of allogeneic chimerism. To achieve this goal, a better understanding of the underlying cellular and molecular mechanisms that regulate the mesenchymal component of HSC niches within BMT in T1DM is needed. Long-term hematopoietic homeostasis sustained by either autologous or transplanted allogeneic BM depends on the physiological function of LT-HSC niches. Here, we review current understanding of anomalies at the cellular, genetic, and protein levels, which have been found to correlate with the impaired function of mesenchymal stromal cell populations, supporting autologous and transplanted LT-HSC niches.

MSCs for the treatment of T1DM via hematopoietic chimerism-sustained input Autoimmunity in T1DM presents as a strong association with HSC anomalies [26,27]. Logically, one would expect transplantation of healthy donor-derived HSCs to resolve the problem. However, approaches for abrogation of autoimmune reactions associated with T1DM were not perceived as clinically relevant because almost all b cells are already destroyed by the time of diagnosis. Nonetheless, research aimed at elucidating the pathogenesis of T1DM showed that there is a potential treatment modality based on BM-HSC transplantation despite b cell destruction. It was shown during the early 1990s that induction of allogeneic chimerism in young (8–10-week-old) nonobese diabetic (NOD) mice before the onset of hyperglycemia arrested the progress of insulitis, and these animals did not develop hyperglycemia [87]. To avoid complications associated with allogeneic BMT, the use of autologous MSCs is under exploration in an attempt to ameliorate autoimmunity in T1DM. Promising outcomes of these therapeutic adaptations using autologous BM-derived MSCs in vitro [88], in animal models [89,90] and clinical studies [91,92] have been reported. However, a significant drawback into the use of autologous MSCs are their T1DM-related anomalies. In addition to the possibility that functionally compromised BM-MSCs are therapeutically ineffective, there is also a concern that T1DM-derived MSCs might contribute to the development of comorbidities [28].

Hematopoietic chimerism: complications and challenges As demonstrated in the NOD mouse model, autologous b cell regeneration is possible, even after the onset of hyperglycemia, with recovery of physiological metabolic homeostasis lasting throughout the life of the animal [1,2]. This finding prompted the exploration of a venue to restore euglycemia in patients with T1DM via induction of hematopoietic chimerism. However, there are many complications and obstacles associated with BMT that are too harmful for pediatric patients. This begs the question: is www.drugdiscoverytoday.com

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of severe cases of systemic autoimmune disorders, such as lupus erythematosus (le) and systemic scleroderma [54–56]. In the context of T1DM, the potential integration of MSCs into therapeutic regimens aiming at b cell regeneration and normalization of insulin metabolism after the clinical onset of the disease has already been shown to be possible in vitro studies [57], using animal models [58–60], and in clinical trials [61–63]. However, a clinically successful therapeutic protocol using MSCs, which would significantly improve the quality and longevity of life of patients with T1DM, has yet to be established. Therapeutic modalities using MSCs have two approaches: (i) via direct MSCmediated input; and (ii) through MSC sustained hematopoietic chimerism. Here, we discuss these two approaches and potential for their clinical adaptation.

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morbidity in T1DM severe enough to subject these patients to complications associated with the induction of hematopoietic chimerism? Two major obstacles that need to be overcome are: (i) the detrimental consequences of BMT conditioning; and (ii) the potential onset of GVHD. Here, we discuss these issues in light of new perspectives on the therapeutic potential of the mesenchymal stroma-sustained induction of hematopoietic chimerism.

Pancytopenia as a result of conditioning required for allogeneic BMT Pancytopenia (presented as different degrees and combinations of leukopenia, anemia, and thrombocytopenia) is a syndrome of multifactorial genesis. It can be a primary condition as, for example, in the case of Fanconi anemia [93] and idiopathic thrombocytopenia purpura [94], a part of an autoimmune disorder [95], or an acquired complication of different malignancies [96,97] and infections [98,99]. It also can be the result of long-term exposure to biohazardous materials, as in case of benzene-induced hematotoxicity, a serious occupational problem, particularly in China [100]. Pancytopenia can also develop as a secondary condition of iatrogenic origin. Radiation, antibody-based, and other cytoreductive regimens used as part of conditioning for BMT are among therapeutic regimens that can cause pancytopenia. Secondary pancytopenia unfortunately, and ironically, is a growing problem hindering more aggressive treatments necessary for advanced disease states. More aggressive, albeit successful, cytoreductive regimens are almost unavoidably associated with serious and potentially fatal pancytopenia. Conditioning for BMT encompasses a range of regimens adapted for specific research projects or clinical circumstances depending on the objective of the study and/or the patient’s disease and condition. In the context of T1DM, current advances in MSC-based approaches could be used to limit the probability of developing pancytopenia as a complication resulting from a cytoreductive regimen utilized as conditioning before BMT. Given that outcomes of radiation-induced pancytopenia are more consistent compared with those arising in response to treatment with different chemo-, cytoreductive or immunosuppressive drugs, our discussion is within the context of radiation therapy.

Radiation therapy as a myeloablative regimen for BMT That roentgen rays damage connective tissues was first reported some 100 years ago [101–104]. At the beginning of the 20th century, Alexander Maximow stressed the importance of studying ‘the influence of X-rays upon cellular processes within the loose connective tissues’. He cautioned ‘against using high doses of rays, since the extremely important defense reaction of connective tissue is apt in such a case to be imperiled or weakened’ [101]. We are still working on elucidating the mechanisms regulating stromal cell functions and their critical role in tissue maintenance and repair, and the pathogenesis of their ‘weakened’ state as a result of cytoreductive therapies. Weissman’s group showed that, after conditioned transplantation, only a small subset of engrafted HSC clones were involved in differentiation. However, after unconditioned transplantation, all engrafted HSCs were shown to undergo uniformed differentiation and self-renewal [105]. This shows the adverse effects of conditioning on HSC transplantation and gives a foundation for a new perspective on the pathogenesis of pancytopenia. It is well known 4

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that the potential capacity of quiescent subpopulations of HSCs responsible for self-renewal is enormous. For example, it takes many years to exhaust their ability to replenish CD4+ T cell populations devoured by HIV. By contrast, once subjected to chemotherapeutic regimens for the treatment of malignancies, immunosuppressive protocols for the induction of allogeneic chimerism and graft acceptance or amelioration of autoimmune disorders, the development of cytopenia is an almost unavoidable complication with an onset within a few weeks. A question arises as to whether pancytopenia is a result, not from the destruction of the highly proliferative lineage-committed HSC subset, but of the impaired function of MSCs acting as the ‘nursing’ cells of HSC niches. This would explain the pathogenesis of cytopenia as a result of a lack of support for quiescent subsets of HSCs by MSCs. In the case of BM transplantation, although intended to create HSC niches, could it be that they are instead destroyed by damaging MSCs, one of the major cellular components necessary for sustaining niche integrity? This premise is supported by recent studies that showed that irradiation used for conditioning before BMT might itself be responsible for BM graft rejection. Mouse models with stromal insufficiency demonstrate a limited ability for establishing allogeneic chimerism. Abbuehl and colleagues showed that irradiation commonly used for BMT permanently damages BM stroma [106]. In this study, up to 98% reduction of colony-forming-unit fibroblasts (CFU-F) was observed in mice that received 9 Gy of total body irradiation (TBI). Hematopoietic reconstitution of these mice was achieved by intrabone transplantation from primary bone marrow stromal cell (BMSC) subsets with a NT5E+/CD73+/ENG-/ CD105-/LY6A+/SCA1+ phenotype. BMSC cotransplantation induced successful donor-derived HSC engraftment and significantly reduced neutropenia and other clinically relevant adverse effects associated with BMT. Administration of cell populations harvested from irradiated donors did not reproduce this effect. The hematopoietic chimerism induced by this protocol was stable and multilinear. The authors speculated that the observed hematopoietic reconstitution was the result of an enhancement in the quality of HSC niches because of the recipient population being restored by no-irradiated BMSCs. These findings, if confirmed in humans, could lead to new approaches for BMT. Over 40 years ago, experimental evidence started to accumulate that stromal fibroblasts have the ability to support hematopoiesis [25,107]. Proposed then and confirmed now, the role of mesenchymal stroma in the maintenance of hematopoiesis implies that consequences of marrow stromal damage will lead to impaired LTHSC population function and engraftment [108–111]. In a review of BM regeneration after radiation injury by Patt et al., in parallel with BM stroma being acknowledged to have a role in hematopoiesis, it was suggested that ‘marrow stroma is the limiting factor in recovery’ from cytopenia ‘evolved in response to radiation within a 1000 rad range’ [112].

Mechanisms involved in the reduction of hematopoiesis-supportive function of BM stroma as a result of conditioning regimens used for hematopoietic chimerism induction It is well-established that there is a loss of HSC proliferative capacity in mice subjected to TBI [109]. In patients, this leads to

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an onset of hypoplastic syndrome following chemotherapy and radiation used as therapy or conditioning before BMT [110,113– 115]. Although MSCs constitute a minuscule fraction (0.001– 0.01%) of BM cells [116], it is well accepted that reconstitution of hematopoiesis after myeloablative regimens depends on MSC number and functional status [117]. However, another adverse effect of chemotherapy and radiation is the decreased ability of BM stroma to support hematopoiesis [108,118,119]. Interestingly, this defect was found in both allogeneic [120] and autologous [121] BMT. Here, we summarize the accumulated evidence for the mechanisms involved in a reduction of hematopoiesis because of mesenchymal stroma supportive functions with respect to cellular, genetic, and protein (soluble and cell-expressed) level anomalies in T1DM and as a result of conditioning regimens used for the induction of hematopoietic chimerism. Physiological hematopoietic homeostasis is maintained by the balance between HSC selfrenewal (LT-HSC) and differentiating (ST-HSC) populations in their respective niches. Most cells in LT-HSC niches remain in the quiescent-G0 state (with Ki-67Lo expression), whereas most cells in ST-HSC niches are in a proliferative state of the cell cycle (with Ki-67Hi expression). The factors and/or conditions skewing this balance toward the latter cell population lead to exhaustion of the replenishing potential of HSPC populations and results in pancytopenia. G0 cell populations include three different cell subsets. The first two cell populations include: (i) stem cells in the quiescent state; and (ii) committed, but not dividing precursor cells. In both cases, this is a reversible state and these cells could be triggered into the cell cycle by either physiological or pathological stimuli; and (iii) there is a third cell type harboring in G0 cell populations, which are not dividing, although still alive. These cells are in an irreversible, senescent state without the ability to enter into the cell cycle and, therefore, do not contribute to hematopoietic repopulation. The senescent cell state and its impact on the onset of pancytopenia is discussed here.

Cellular-level anomalies leading to a reduction in the hematopoiesis supportive function of mesenchymal stroma in cytoreductive regimens Evidence suggests that the damage response pathway affects multipotent stromal stem cells less than HSCs. HSC are more sensitive to the toxic effects of chemotherapy and radiation regimens and are less resistant to cell death with respect to MSCs [122–124]. However, numerous studies have demonstrated that ionizing radiation could reduce the number of CFU-Fs by up to 90% from normal levels [108,114,120,121,125–127]. This observation suggests two possibilities for MSC responses to cytoreductive regimens: (i) cell death; or (ii) adoption of a senescent state. Further studies supported a decreased ability of radiation-exposed MSCs to form CFUFs, resulting in a pool of permanently damaged MSCs [126,127]. These data are in favor of the possibility that MSCs subjected to conditioning acquire the senescent state. A promising exception, and relevant to pediatric T1DM, is the observation that BM stroma damage was reversible in young children under the age of 4. In this cohort of patients, a full recovery of CFU-F numbers was observed during an extended follow-up [120]. This was not the case for adults with damaged MSCs, which cannot reverse once senescent status has been

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induced. The fact that BM stroma damage could be reversible (based on recovered CFU-F numbers) in young children might reflect that some MSCs in the BM still have the ability to resist the process of irreversible stroma transition into a senescent state. Reduction of the pool of osteoblasts (OBs) in response to radiation applied as conditioning for BMT was proposed as another potential mechanism leading to the impaired ability of mesenchymal stroma to support hematopoiesis [128]. There are two phenotypically distinct subtypes of osteoblasts, each with a different functional impact on HSCs. Osteopontin-expressing OBs contribute to HSC migration toward endosteal regions and potently suppress their proliferation [129]. Another subtype of OBs among ‘negative’ regulators of HSC proliferation are the N-cadherin-positive SNO cells, which directly interact with HSCs [130] and also provide ‘quiescence’ signaling [129,131]. Moreover, it was shown in a follow-up study that osteoblasts not only survive radiation assault, but also respond by proliferation and expansion. Phenotyping of these expanding osteoblasts in response to radioablation demonstrated that they carry the markers of quiescence-inducing subtypes of osteoblasts [30]. Dominici et al. proposed new insights into the mechanisms of BM stroma function in normal hematopoiesis, reactions during allogeneic HSC transplantation, and response to chemotherapy and radiation-induced injury. This group used RT-PCR and ELISAs to evaluate different subsets of mesenchymal stroma cells for their proliferative and functional capacities as well as their specific distribution in bone [30]. An expansion of proliferating Ki-67+ osteoblasts in the endosteum was detected in response to radiation. The observed thickening and increased proliferation rates within the endosteal osteoblast populations was shown to be associated with, and crucial for, effective engraftment of donor HSCs [32]. The authors identified a novel CD45–F4/80lo cell type that was found to reside among osteoblasts in the endosteal area and, at least transiently, survived radioablation. This newly identified marrow cell population was involved in the regulation of HSC engraftment. In another study, depletion of hematopoietic cells by intravenous administration of diphtheria toxin 24 h before radioablation (TBI with 1000 cGy) resulted in flattened osteoblasts and abrogated allogeneic HSC engraftment [132]. This suggests that, although osteoblast proliferation is necessary, it is not sufficient for successful LT-HSC engraftment [133]. The proliferation of osteoblasts, supported by CD45–F4/80lo cells, was crucial for efficient HSC homing, retention, and engraftment in the marrow. These findings are of potential clinical relevance because of the existence of the human homolog of F4/80, the eosinophil-specific receptor EMR1 [134].

Genetic-level anomalies leading to a reduction in the hematopoiesis supportive function of mesenchymal stroma in cytoreductive regimens Adoption of senescence is one of the responses of stem cells after exposure to DNA-damaging agents [135–137]. Induction of cell cycle arrest could be mediated by several different pathways. p16INK4a is one of the regulators of senescence and is used as a marker for the in vivo detection of senescent cells [138,139]. Carbonneau et al. showed, in a mouse model, that aberration of hematopoietic homeostasis following infrared exposure was associated with the loss of the regenerative potential of MSCs because www.drugdiscoverytoday.com

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of an adoption of the senescent state that is p16INK4a dependent [140]. Another well-known pathway resulting in the induction of cell cycle arrest is achieved through an increase of p53 and p53inducible cell cycle regulator 21 [123,141,142]. Evidence suggests that an adoption of the senescence state, rather than apoptosis, is the major pathway of MSC response to DNA-damaging regimens. BM-derived stromal cells under the influence of DNA-damaging agents (such as chemotherapy and radiation therapies) acquire the senescent phenotype linked to induced expression of INK4a and ARF proteins. These proteins act as direct effectors of cellular senescence by preventing cell cycle progression [138–140,143]. Nuclear factor, erythroid 2-like 2 (Nrf2) is a transcription factor that is also involved in the regulation of stress-related responses [144]. Under nonstress conditions, Nrf2 undergoes rapid ubiquitination and degradation [145]. Nrf2 is an important factor that regulates HSC niche function in physiological conditions and in response to radiation. The loss of Nrf2 in knockout (KO) mice appears to be radiosensitizing. ST-HSCs (Lin /Sca-1+/c-Kit+/CD34+/Flt3 ), HSPCs (Lin /Sca-1+/c-Kit+/ CD34+/Flt3+) and hematopoietic lineage-committed cells, but not LT-HSCs have elevated levels of Nrf2-null compared with wild-type (WT) mice [146]. Rana et al. found that Nrf2 is crucial for the survival of osteoblasts that support LT-HSC niches after ablative irradiation [147]. Nrf2 deficiency drives LT-HSCs from a quiescent to a proliferative state. This results in hematopoietic exhaustion and reduced engraftment after myoablative irradiation. The question of whether the induction of Nrf2 in LT-HSC enhances hematopoietic reconstitution after BM transplantation remains to be addressed [148]. In summary, accumulated experimental evidence indicates that myeloablative conditioning damages mesenchymal stroma by driving MSC subsets in HSC niches to the senescence state. These damaged MSCs, in a senescent state, instead of supporting hematopoietic homeostasis, respond to cytoreductive regimens by quenching multipotent HSC differentiation and, as a result, promote the development of pancytopenia.

Protein-level anomalies leading to a reduction in the hematopoiesis supportive function of mesenchymal stroma in cytoreductive regimens Signaling through the CXCL12–CXCR4 axis is essential for hematopoiesis [149]. Treatment with a CXCR4-selective antagonist induced an increase in HSCs into the peripheral blood, suggesting that CXCL12 has a role in the migration and homing of HSCs within hematopoietic organs [150–152]. Alterations in the expression and function of the CXCL12–CXCR4 axis contributes to the pathogenesis of pancytopenia of any origin (primary, secondary, or induced experimentally through targeted deletion of genes expressing these molecules). It was reported that loss of stromasecreted CXCL12 decreases the quiescent state population of HSPCs and alters the pattern of hematopoietic regeneration after myelosuppression in adult mice [153]. Deletion of CXCR4 resulted in a reduction in HSC numbers and increased sensitivity to myelotoxic injury. Arai et al. demonstrated that the CXCL12–CXCR4 axis is essential for the interaction between HSCs and reticular stromal cells in perisinusoidal niches [151]. In adult BM, CXCL12 is expressed in a variety of mesenchymal cells, including osteoblasts [153,154], reticular cells [151], and stromal cells in culture 6

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[155]. The role of this molecule in the suppression of hematopoiesis under myelosuppression was shown using the Hoechst side population (SP) analysis in combination with LSK (Lin /Sca-1+/cKit+) phenotyping in WT and CXCL12-KO mice [153]. In addition to cell-expressed receptors and ligands, soluble proteins are also involved in the regulation of allogeneic HSC engraftment. Stromal proteoglycans (PGs), comprising a core protein and glycosaminoglycan (GAG) chains, has a crucial role in supporting hematopoiesis [156]. Hyaluronan (HA) participates in defining the properties of pericellular matrices and in transducing signals in proliferating and migrating cells [157,158]. As such, HA was found to organize the BM extracellular matrix in a way that can decrease the capacity of BM stroma to support hematopoiesis [159,160]. Zweegman et al. performed gene expression profiling to assess the molecular pathways involved in the chemotherapeutic treatment of the M210B4 murine fibroblastic stromal cell line. They found significant alterations in the synthesis of GAGs, especially HA. The authors concluded that one of the mechanisms involved is a reduced supportive capacity of BM stroma in response to chemotherapy mediated via changes in the glycosaminoglycan profile [161].

MSC-sustained hematopoietic chimerism: benefits and prospects for treatment of T1DM The latest advances in therapeutic adaptations that incorporate multipotent mesenchymal stromal cells (MMSCs) and MPSCs, which promote allogeneic HSC engraftment and reduce the risk of GVHD, have been shown to be effective and provide an alternative approach for sustaining BM engraftment [162–168]. However, from a regulatory point of view, since 2001, every product for advanced therapy is considered a drug and must be subjected to clinical trials to demonstrate its application safety and effectiveness. MSC use in therapeutic modalities are no exception. Promising readouts utilizing MSCs for improved outcomes associated with BMT in animal models and in vitro studies prompted attempts for their clinical adaptations. The overall outcomes of initial trials utilizing cotransplantation of HSCs and BM-derived MSCs in patients with malignancies, at 1–2  106 cells per kg, unanimously support the safety of the regimen. MSCs represent a heterogeneous cell population with different phenotypes and functions depending on their genetic profile, origin of their isolation, and processing and/or culturing conditions [169,170]. Once isolated from different body sites and fluids (adipose tissue, BM, cord blood, and others), MMSCs and MSPCs are processed and/or cultured and often propagated before their use in an in vivo and/or in vitro experimental or therapeutic setting. Concerns that multipotent cells propagated in vitro have a higher risk for accumulation of DNA impairment and result in malignant transformations, as shown in cultured murine multipotent cells [171], do not appear to be relevant to humans. Malignant transformation of human MSCs propagated in culture is uncommon [172,173]. However, there are reported differences in the outcomes for therapeutic uses of allogeneic versus autologous MSCs. Allogenic MSC are reported to have tumor-suppressive properties, whereas autologous MSCs have tumor-promoting effects [171]. Overall, based on analyses from clinical trials, MSC-based therapy appears

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to be a safe modality, although its clinical efficacy remains uncertain [162,163,174–179].

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[175,181,193] and clinical practice [175]. These data suggest that the limitations of MSC engraftment can be circumvented by the application of large cell doses in the transplanted inoculum.

MSCs used to promote allogenic HSC engraftment MSCs used to promote allogenic HSC engraftment in diabetes mellitus In many instances, the origin of a pathological disorder, such as chronic inflammation and autoimmunity, can be traced to BMderived mesenchyme. Compromised BM mesenchyme can lead to stem cell mobilopathy, as in the case of both T1DM and T2DM. In these cases, it would be advantageous to explore the therapeutic potential of mesenchymal stroma replacement. Hiwase et al. evaluated the efficacy of placenta mesenchymal stromal cells as a cotransplant to see whether they would enhance BM engraftment in NOD and severe combined immunodeficiency (SCID) mice [183]. Mice that received mesenchyme showed a 3.5fold engraftment enhancement compared with HSC transplantation alone. Serial transplantation in secondary mice recipients infused with engrafted human BM-HSCs from primary mice showed increased engraftment ranges when HSCs where cotransplanted with cord blood MSCs. This study showed engraftment enhancements that accompanied cotransplantation of MSCs into mice that have autoimmune deficiencies. In a similar study by Asari et al., NOD mice were subjected to hematopoietic chimerism with cotransplantation of MSCs [194]. This study had similar engraftment results, with 63% of mice displaying hematopoietic chimerism. Additionally, none of the chimeric mice developed GVHD. Importantly, the effects of MSC-facilitated hematopoietic chimerism reported in these studies resulted in the prevention of insulitis and overt diabetes. Results from MSC cotransplantation studies in NOD mice led to the development of treatment modalities for DM using MSC-HSC cotransplantation in humans. In a meta-analysis by Gan et al., the efficacy of stem cell treatment was derived from 22 selected studies that met their pre-established criteria [195]. The study showed that stem cell treatment, specifically high doses of stem cells of mesenchymal origin, resulted in a decrease in glycosylated hemoglobin and a lower level of insulin required to control glucose levels. However, the patient’s ability to achieve strict glycemic control and the level of chimerism were not evaluated, which limits the interpretation of these results.

MSCs for amelioration of GVHD Clinical trials are also underway for the efficacy of MSCs in the prevention of GVHD in addition to prevention of disease reoccurrence following BMT as part of therapy for hematologic malignancy [196,197]. MSCs have been shown to induce tolerance through their immunomodulatory properties, in addition to enhancing the efficiency of BM graft acceptance. This suggests that MSCs could ameliorate the onset of GVHD associated with BM transplantation. Le Blanc et al. were the first to report a therapeutically successful intravenous administration of haploidentical MSCs for the treatment of grade IV acute GVHD in pediatric patients [164]. The improvement of survival rates in pediatric and adult patients with GVHD in response to allogeneic MSC administration was confirmed by several reports [165–168]. The US Food and Drug Administration (FDA) has since approved MSCs for use in pediatric steroid-refractory acute GVHD [198]. However, despite the success www.drugdiscoverytoday.com

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Several studies have shown that MSCs have immunomodulatory properties and the capacity to promote allogeneic BM engraftment while accelerating hematopoietic reconstitution in patients subjected to cytoreductive therapeutic regimens [180]. MSC co-infusion was first demonstrated to enhance engraftment of HSCs in animal models [181–183]. Data showed the ability of MSCs to promote BM engraftment, particularly when relatively low doses of HSCs were transplanted. Additionally, hematopoietic reconstitution was not lineage specific. Both myeloid and lymphoid progenies were equally recovered, which is clinically relevant [183]. This raises the question as to whether the mechanism of action for MSCs for promoting HSC engraftment is mediated via cell–cell interaction or a result of donor MSC-secreted cytokines. The answer is likely both, although this remains under investigation. The ability of MSCs to home into BM is supported by several studies using different labeling and/or trafficking methodologies [184,185]. For transplanted MSCs to sustain either autologous or donor-derived hematopoiesis, they must have the ability to migrate and home into BM. MSC migration is supported through the CXCL12–CXCR4 axis. CXCL12 (SDF-1) ligand is significantly expressed on CD34+ proliferative subsets of HSCs. Wynn et al. addressed the question as to whether CXCR4 (counterpart receptor of CXCL12) is expressed on MSCs and potentially has a role in the homing of these cells into BM [185]. Using the CD45-/CD34–/SH2+ phenotype for cultured MSC and CD34+/Lin– phenotype for HSC populations, a significant variation in detection of CXCR4 was found in different cellular compartments of BM MSCs. Very low levels were expressed on the cell surface, whereas up to 98% of cells showed high intracellular presence. The authors suggested that the type of cytokines produced by the MSCs control the balance between the levels of CXCR4 present in the intracellular versus extracellular cell domains. Additionally, this study demonstrated that CXCR4 on the surface of MSCs is a contributing factor to the ability of these cells to migrate toward HSC niches. In another confirmatory study, administration of neutralizing anti-CXCR4 antibodies inhibited the ability of MSCs to migrate into the BM [185]. In addition to the regulatory influence of MSC-derived cytokines on HSCs and their respective niche types (LT and ST), other inducing stimuli from other physiological or pathological conditions should be explored. Earlier reports regarding the ability of allogeneic MSCs to engraft as part of conventional BMTs are controversial. Many studies supported the notion that MSCs have a limited ability to engraft, even in cases where HSC engraftment was successful [186–190]. An exception to this trend was a study that detected donor-derived MSCs in the recipient’s BM in the presence of osteogenesis imperfecta (i.e., abnormal host stroma) [191]. It was speculated that healthy donor MSCs have a competitive advantage compared with compromised recipient stroma [184]. Using the baboon model, Devine et al. explored the hypothesis that stromal cell engraftment is not detected because of the limited number mesenchymal cells present in transplanted BM inoculum [116,184,192]. This finding is in agreement with other reports in various animal models

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of preliminary data using animal models and preclinical trials, one study reported that co-infusion of in vitro propagated parental MSCs prevented acute GVHD but did not improve HSC engraftment in pediatric patients undergoing allogeneic umbilical cord blood transplantation [162]. Osiris Therapeutics conducted clinical trials for a MSC treatment of GVHD [199]. Bartholomew et al. showed that MSCs suppress activated lymphocytes specific to allogeneic cells and tissues [200]. Lazarus et al. showed that cotransplantation of HLA-identical sibling MSCs were safe and feasible for the suppression of GVHD and Le Blanc et al. showed that treatment of a GVHD was possible with third-party haploidentical MSCs [176,201,202]. Kuzmina et al. compared the use of MSCs in the prevention of GVHD following HSC transplantation [203]. Graft rejection and the development of GVHD was similar between patients who received MSCs and those who did not. However, the MSC arm had significantly higher overall survival rates, (95% versus 84%).

Concluding remarks Restoration of physiological metabolic homeostasis after the onset of hyperglycemia has been achieved by induction of allogeneic chimerism in the NOD mouse model [1,2]. Whether this outcome is reproducible in humans remains to be established. However, both amelioration of autoimmunity and the potential for b cell regeneration and recovery of insulin independence by induction of allogeneic chimerism is worth exploring as a therapeutic approach for T1DM. The major problems hindering this therapeutic modality are two adverse effects associated with BMT: (i) pancytopenia (resulting from conditioning, a required step of BMT protocols); and (ii) the potential onset of GVHD. Here, we presented evidence for a new understanding of: (i) the dynamic structure of BM; and (ii) the role of mesenchymal stroma in supporting hematopoiesis. It might be time to reconsider whether before BMT treatment of non-malignant disorders, resulting in pancytopenia associated with BMT, is required. Clearing niche space for donor HSCs might not be necessary for a successful allogeneic HSC engraftment. It appears that, instead of creating niches, conditioning protocols damage niche stromal components, which compromises hematopoietic reconstitution [105,106,204]. HSC niches have been shown to be dynamic structures with either long- or short-term stem cell reconstitution potentials. Multipotent and precursor cells migrate between niche types in response to physiological or pathological stimuli [205– 213]. This suggests the possibility for donor-derived HSCs to compete with autologous HSCs in occupying niche space. Additionally, BM was shown to have empty or unoccupied niches [214]. Healthy donor HSCs were shown to have the ability to outcompete diseased host HSCs for niche space during engraftment [17,215]. Finally, more efficient and lineage-balanced reconstitution of hematopoietic homeostasis was observed in hosts that did not receive conditioning before BMT compared to recipients that did [105,216,217]. MMSCs and MSPC sustain a twofold damage in BMT recipients with T1DM: disease-related diabetic mobilopathy [37] and injury resulting from conditioning [105,106,204]. Adoption of a senes-

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cent state by multipotent MSCs in response to conditioning is a potential contributing factor to the pathogenesis of pancytopenia as a result of their impaired ability to sustain hematopoiesis [140,147]. It appears that the use of mesenchymal stromal cells (the particular subset or multicellular composition yet to be defined based on recently acquired knowledge of MSC phenotypic and functional diversity) can be used to promote allogeneic chimerism induction. The unique ability of MSCs to sustain hematopoiesis as part of both LT-HSC and ST-HSC niches [23,218–220], along with their immunomodulatory ability [55,61,221], including suppression of GVHD reactions [164–168], makes them a strong candidate for supplementation into purified HSC populations used in hematopoietic chimerism induction protocols. Engraftment efficiency of donor stem cells within the graft inoculum is dose dependent [16,193,222,223]. An additional benefit of using MSCs for promoting HSC engraftment is the ability of these cells to crosstalk despite allogeneic disparity [224–226]. This allows the use of MSCs from unrelated donors (or commercially available sources), thus overcoming the limitation of their relatively low percentage within BM [117]. There are a few T1DM-specific advantages of the use of MSCbased allogeneic chimerism. In studies by Zorina’s group, the donors for induction of hematopoietic chimerism in the mouse model were known to be T1DM-presiposing genotype-free [1,2]. The genetic profile of T1DM, determined by the Type 1 Diabetes Genetics Consortium efforts, allows the transfer of this modality into the clinical setting by the selection of HSC and MSC donors based on their T1DM predisposed and preventive genetic profiles [227,228]. In addition, as shown earlier in the mouse model, chimerism as low as 1% is sufficient to abrogate insulites and to preclude the development of hyperglycemia [229]. A specific benefit for pediatric patients (i.e., most T1DM cases) would be transplantation of a haploidentical (from parents and siblings) and gender-matched HSCs to avoid minor histocompatibility discrepancy reactions. Finally, patients under 4 years of age have been shown to have MSCs recovered from the senescent state that might aid in hematopoietic homeostasis recovery [120]. In summary, new insights into the composition and function of multipotent HSC and MSC niche structure and dynamics provide a new potential for the conditioning-free, MSC-based induction of chimerism for its clinical adaptation. This approach could have the potential to limit the adverse effects associated with traditional hematopoietic chimerism and to prevent GVHD. Multiple Phase I clinical trials have confirmed the safety of MSC administration in humans [79,80] and Phase II trials exploring the effectiveness of MSC-based approaches for the induction of hematopoietic chimerism are in progress [81–85]. These trials seek to find an optimal cellular composition of HSCs supplemented with MMSC/MMPCs, based on the genotype, phenotype, origin, processing/culturing conditions, and dosage of the stem cells. A new MSC-based protocol has the potential to eliminate conditioning for BMT, thus improving clinical outcomes in the induction of allogeneic hematopoietic chimerism aiming at the physiological recovery of b cells and restoration of euglycemia in patients with T1DM. Q5

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