- Email: [email protected]
Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality
JBUR-4625; No. of Pages 8 burns xxx (2015) xxx–xxx
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/burns
Review
Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality Kui Ma a,1, Zhijun Tan b,1, Cuiping Zhang a,*, Xiaobing Fu a a
Key Research Laboratory of Tissue Repair and Regeneration of PLA, and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, PR China b Tianjin Medical University, Tianjin, PR China
article info
abstract
Article history:
Sweat glands play important roles in homeostasis maintenance and body temperature
Received 3 November 2014
regulation. In patients with deep burns, the injury can reach the muscle tissues and damage
Received in revised form
sweat glands. However, the plasticity of mesenchymal stem cells (MSCs) may offer the
18 February 2015
possibility to regenerate sweat glands after severe burn. In particular, recent studies have
Accepted 17 April 2015
changed the possibility to reality. Here, we analyze the barriers of sweat gland regeneration
Available online xxx
in situ after deep burns, propose the possibilities of MSCs in regeneration of sweat glands, summarize the recent researches into sweat gland regeneration with MSCs, and sum up the
Keywords:
possible mechanisms during this process. In addition, the advantage and disadvantage of
Mesenchymal stem cells
sweat gland regeneration with MSCs from different tissues have been discussed. So this
Burns
review will provide meaningful guidance in the clinic for sweat gland regeneration with
Transdifferentiation
MSCs. # 2015 Elsevier Ltd and ISBI. All rights reserved.
Sweat glands Regenerative medicine
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regeneration barriers of sweat glands after deep burns Possibility of MSCs in regeneration of sweat glands. . . . Regeneration of sweat glands with MSCs . . . . . . . . . . . . 4.1. BM-MSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. MSCs from umbilical cord . . . . . . . . . . . . . . . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
000 000 000 000 000 000
* Corresponding author at: Wounds Repair and Tissue Regeneration Laboratory, Burn Institution, The First Affiliated Hospital, General Hospital of PLA, 51 Fu Cheng Road, Beijing 100048, PR China. Tel.: +86 10 68210077x867396; fax: +86 10 68989955. E-mail address: [email protected] (C. Zhang). 1
These authors contributed equally to this work. Abbreviations: SGL, sweat-gland-like; BM-MSCs, bone marrow mesenchymal stem cells; UCB, umbilical cord blood; WJ, Wharton’s jelly; ERK, extracellular regulated protein kinase; MAPK, mitogen-activated protein kinase; EGF, epidermal growth factor; FGF-10, fibroblast growth factor-10; HGF, hepatocyte growth factor; EDAR, Ectodysplasin-A1 receptor; HED, hypohidrotic ectodermal dysplasia; EDARADD, EDAR-associated death domain; NF, nuclear factor; IKK, IkB kinase. http://dx.doi.org/10.1016/j.burns.2015.04.005 0305-4179/# 2015 Elsevier Ltd and ISBI. All rights reserved.
Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005
JBUR-4625; No. of Pages 8
2
burns xxx (2015) xxx–xxx
5.
6.
1.
Mechanism of sweat gland regeneration by MSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. ERK signaling pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Ectodysplasin-A1 (EDA-A1)/Ectodysplasin-A1 receptor (EDAR) signaling pathway 5.3. NF-kB signaling pathway. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Wnt/b-catenin signaling pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and future issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
Recently, the regeneration of cutaneous appendages during the repair of damaged skin has become an important direction in the field of stem cells and regenerative medicine [1]. Sweat gland is a kind of important appendage of the skin, which plays some key roles in homeostasis maintenance and body temperature regulation. The skin of patients with an extensive deep burn is repaired by a hypertrophic scar [2] without regeneration of sweat glands, and therefore loses the function of perspiration. Burns survivors feel the heat very much and have to rest at home in summer, which affects their quality of life. Therefore, regeneration of sweat glands in the skin has become a focus of modern medical study [3]. Meanwhile, the recent progress in stem cell research in regenerative medicine is remarkable [4–6]. Cell therapy with MSCs holds enormous promise for the treatment of damaged organs using regenerative technology [7]. MSCs can be obtained from adult tissue such as bone marrow [8,9], adipose tissue [10], umbilical cord [11] and others. Under suitable conditions, MSCs can differentiate into various types of cells such as neural cells [12,13], osteocytes [14,15], adipose cells [16], muscle cells [17] and vascular endothelial cells [18]. The unique property of MSCs highlights the potential for sweat gland regeneration. In this review, we focus on the barriers of sweat gland regeneration after deep burns and the possibilities, recent researches and possible mechanisms of MSCs in regeneration of sweat glands after deep burns.
2. Regeneration barriers of sweat glands after deep burns The sweat glands develop from the cells in epidermis during embryonic development [19]. Recent studies indicated that mature sweat glands still contain stem cells or progenitor cells [20–23]. However, in most cases of deep burns, above stem cells in the injured sweat glands cannot achieve the regeneration of sweat glands. Furthermore, after scar healing, the new epidermal stem cells also fail to differentiate into sweat gland cells, which results in the loss of sweating function in the wound healed with scarring. Therefore, understanding the effects of scar healing on sweat gland regeneration by epidermal stem cells will be helpful to guide the study of sweat gland regeneration. The microenvironment surrounding the stem cells is called the stem cell niche [24]. Modulation of proliferation and differentiation of epidermal stem cells by the stem cell niche mainly involves cell–cell and cell–extracellular matrix interactions. In addition, cytokines play important roles in
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
000 000 000 000 000 000 000 000
transmitting information between cells and the extracellular matrix [25]. Regeneration of sweat gland cells is also regulated by the above factors because the sweat gland cells are homologous with the basal epidermal stem cells [26]. However, under the condition of scar formation after deep burns, the internal and external environments for self-renewal of the stem cells have changed. First, the cell quantity and types in the scar are different from those in normal skin. Second, the extracellular matrix metabolism related to sweat gland development is disordered. Third, the basal membrane of scar tissues loses the normal structure and function. All these factors will affect sweat gland regeneration by endogenous stem cells in scars. After wound healing by scarring, the absence of perspiration in healed areas does not necessarily indicate that there is no sweat gland tissue in the scar. A previous study indicated that there were expressions of carcinoembryonic antigen and cytokeratin 8, which are thought to be markers of sweat gland cells, in the scar tissue [27]. Therefore, it has been proposed that there is a biological basis and potential for sweat gland regeneration in the wound after burns. The reason for the lack of re-construction of sweat glands in proliferative scars is related to the excessive speed of scar repairing over sweat gland regeneration. The proliferative scar then forms a barrier that prevents sweat gland regeneration. To solve the difficulty of perspiration in deep burn patients, scar needs to be removed, followed by transplantation of sweat gland cells or tissue-engineered skin containing sweat gland cells. However, the sweat gland cells in patients are very few and seriously damaged, therefore, researchers are trying to obtain sweat gland cells from mesenchymal stem cells.
3. Possibility of MSCs in regeneration of sweat glands MSCs have proved to be an attractive cell type for various cell therapies due to their ability to differentiate into various cell lineages, multiple donor tissue types, and relative resilience in ex vivo expansion, as well as immunomodulatory effects during transplants. Recent findings of both experimental studies and clinical trials demonstrated that MSCs were able to repair skin. First, MSCs can differentiate into epidermal-like cells [28] and enhance the reepithelialization during wound repair. Animal autografting experiments with MSCs showed the increased number of epidermal ridges and thickness of the regenerated epidermis [29]. It is interesting to find in one animal experiment that GFP-labeled marrow stem cells were noted in hair follicle, epidermis, and sebaceous glands [30]. Second, MSCs can promote revascularization of the wound
Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005
JBUR-4625; No. of Pages 8 burns xxx (2015) xxx–xxx
bed. There is evidence that MSCs can differentiate into endothelial cells to yield new vessels [31]. In addition, MSCs naturally produce a variety of pro-angiogenic factors that stimulate endothelial cell proliferation and tube formation in the wound bed [32]. Third, MSCs have several effects on fibrotic phenotypes in the wound, and thus play a major role in reducing scar formation following wound healing [33]. Fourth, mesenchymal stem cells have recently been shown to hold a variety of immunomodulatory effects on host immune cells in both wound healing and transplant biology contexts. For example, donor MSCs are able to suppress host T cell proliferation, a key activity in reducing wound bed inflammation [34]. The participation of MSCs in cutaneous repair implies that MSCs may have the potentiality to regenerate sweat glands [35].
4.
Regeneration of sweat glands with MSCs
4.1.
BM-MSCs
BM-MSCs are non- hematopoietic stem cells in the bone marrow and are derived from the mesoderm. Under suitable conditions, BM-MSCs can differentiate into ectoderm-derived tissue [36]. Cell therapy with BM-MSCs holds enormous promise for the treatment of a large number of diseases [37]. In the field of sweat gland regeneration, BM-MSCs are the most studied and widely used stem cells. The advantages of BM-MSCs include lower immunogenicity and less graft-versushost reactions. In addition, BM-MSCs exist in the bone marrow that receives less direct damage from large areas of trauma and burns. Therefore, BM-MSCs have significant theoretical and practical value for the repair of skin and sweat gland regeneration [35]. The potential of BM-MSCs to differentiate into epidermal keratinocytes has been described [38,39]. In theory, epidermal cells derived from BM-MSCs can differentiate into SGL cells. Fortunately, BM-MSCs have been induced successfully to differentiate directly into SGL cells bypassing an intermediate state of epidermal stem cells. Li et al. [40]
3
found that direct co-culture of BM-MSCs with heat-shocked sweat gland cells resulted in differentiation of BM-MSCs into SGL cells. The SGL cells were then transplanted into the wounds of nude mice and significantly promoted the repair and regeneration of damaged sweat glands. Recently, the theory and technique of sweat gland regeneration by stem cells have been partially translated and applied in the clinic (Fig. 1). The major steps include removal of the scar, placement of SGL cells on the wound, and transplantation of a micro-skin autograft [41] or allogeneic skin to cover the wound. These treatments allow the sweat glands to grow in the center of the scar and solve the problem of the lack of perspiration in deep burn patients. Sheng et al. [42] reported that a SGL structure grew in the wound of a patient after transplantation of SGL cells reprogrammed from autologous MSCs. Further investigation showed that the SGL structure performed perspiration that continued during the 3 year follow-up period. Although there are obvious advantages in using BM-MSCs for sweat gland regeneration, there are still issues that need to be considered. First, BM-MSCs are isolated from the bone marrow of patients, which increases their physical and mental stress. Second, in vitro differentiation requires a long time, which makes it difficult to obtain enough SGL cells from stem cells in a timely manner. Finally, the long-term effect of induction remains to be studied. Therefore, whether this method can be directly and effectively used for sweat gland regeneration in burn patients remains to be further studied in the clinic.
4.2.
MSCs from umbilical cord
During the late 1980s, scientists found that the umbilical cord, which is discarded after birth, contains a high concentration of stem cells. MSCs can be derived from umbilical cord blood (UCB) or Wharton’s jelly (WJ). It has been indicated that UCBMSCs can differentiate into skin cells [43,44]. However, there are a limited number of UCB-MSCs which are difficult to be isolated and cultured in vitro. Therefore, scientists have performed extensive studies of WJ-MSCs. Compared with BM-MSCs, WJ-MSCs are more primitive, express similar
Fig. 1 – Sweat gland regeneration after implantation of SGL cells derived from MSCs in a patient recovered from burn. Three months after the surgery, we performed an iodine/starch-based sweat test on burn areas with patient’s informed consent after scar removal and cell transplantation. This procedure detects sweat, reflective of a functional gland. Iodine-starch test was negative on control area (A), but treated area responded to the assay by displaying indigo-black dots (black arrow), indicative of sweat production (B). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005
JBUR-4625; No. of Pages 8
4
burns xxx (2015) xxx–xxx
surface markers, are easier to be obtained, have lower immunogenicity, and therefore are more suitable for allogeneic transplantation [11]. Recent studies indicate that WJMSCs can differentiate into neural cells, osteocytes, adipose cells, muscle cells and vascular endothelial cells [12,14,45–47]. But whether WJ-MSCs have the potential to differentiate into epidermal cells and SGL cells remains to be verified. Xu et al. [48] co-cultured WJ-MSCs with heat-shocked sweat gland cells to induce the differentiation of WJ-MSCs into SGL cells. After one week, immunohistochemical and flow cytometric examinations verified that the SGL cells showed the phenotype of sweat gland cells, suggesting that the heat-shocked microenvironment of sweat glands can induce WJ-MSCs to reprogram into SGL cells. The SGL cells obtained by the above method can be used for sweat gland regeneration at the early stages of burns, but the detailed biological characteristics, safety, and possibility of growing to form sweat gland tissues after transplantation remain to be further studied.
5. Mechanism of sweat gland regeneration by MSCs Although the mechanism of sweat gland regeneration by MSCs remains unclear, there are many indications suggesting that the various cytokines and signaling pathways involved in the regeneration and development of sweat glands play important regulatory roles. In addition, different cytokines
can activate the same signaling pathway, whereas one cytokine can activate different signal pathways and there is complicated crosstalk among different signal pathways (Fig. 2).
5.1.
ERK signaling pathway
Extracellular regulated protein kinases (ERK) are important members of the mitogen-activated protein kinase (MAPK) family that control many cellular and physiological processes such as cell growth, development and death [49]. The very core of ERK pathway is the reaction chain composed of three protein kinases (MAPKKK, MAPKK and MAPK), i.e., upstream activating protein ! MAPKKK ! MAPKK ! MAPK. In the ERK pathway, Ras serves as the upstream activating protein, the MAPKKK is Raf, the MAPKK is mitogen and extracellular kinase (MEK) and MAPK is ERK, i.e., Ras-Raf-MEK-ERK. Activated ERK enters the nucleus through transposition and activates the expression of downstream genes mainly including some early reaction genes encoding transcription factors (c-fos, c-myc, c-jun, and Erg-1) [50]. Cytokines, such as epidermal growth factor (EGF), fibroblast growth factor-10 (FGF-10) and hepatocyte growth factor (HGF), can activate the ERK signaling pathway, and activation by EGF has been verified as the typical pathway in which EGF activates Ras to induce the cascade reaction. During embryonic development, the expression of EGF increased gradually in developing sweat gland buds and in extracellular stroma
Fig. 2 – Possible mechanisms of sweat gland regeneration with stem cells. Possible mechanisms include ERK signaling, EDAA1/EDAR signaling, NF-kB signaling and Wnt/b-catenin signaling. Different cytokines can activate the same signaling pathway, whereas one cytokine can activate different signal pathways. There is complicated crosstalk among different signal pathways. Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005
JBUR-4625; No. of Pages 8 burns xxx (2015) xxx–xxx
surrounding the buds [25]. In adults, EGF expression was strongly positive in the myoepithelial cells and secretory cells of eccrine sweat glands and also positive myoepithelial cells of apocrine sweat glands [51]. Blecher et al. [52] reported that EGF induced development of dermal ridges and functional sweat glands in Ta/Y hemizygotes. So we conclude that EGF is actively involved in the morphogenesis and homeostasis of skin and sweat glands. Furthermore, in a study of reprogramming of MSCs into SGL cells, EGF significantly enhanced the efficiency of reprogramming, whereas the ERK pathway blocker PD98059 partially blocked the reprogramming of MSCs into SGL cells [40]. These results suggest that ERK pathway play an important role in such reprogramming process.
5.2. Ectodysplasin-A1 (EDA-A1)/Ectodysplasin-A1 receptor (EDAR) signaling pathway The EDA gene is one of the functional genes that regulate the development of sweat glands. In mouse, sweat buds are initiated by EDAR-mediated signaling [53,54]. Mutation of the EDA gene can result in hypohidrotic ectodermal dysplasia (HED) that mainly displays developmental defects in sweat glands, hair and teeth [55]. EDA-A1 and EDA-A2 are the two functional molecules encoded by the EDA gene. The receptor for EDA-A1 is EDAR, whereas the receptor for EDA-A2 is Xlinked EDAR. EDA-A1 is directly associated with HED and can, through hydrolysis, release the functional domain. The functional domain binds to EDAR for activation of a series of downstream signals such as receptor adaptor EDARADD (EDAR-associated death domain) and nuclear factor (NF)-kB to promote the occurrence and development of cutaneous appendages [56]. The Tabby mouse is the model of human HED and demonstrates the development of sweat glands and hair follicles after transduction of EDA-A1 cDNA by transgenic techniques [57]. Normal mice exhibit larger sweat glands with enhanced function after overexpression of EDA-A1 [58,54]. Gaide et al. [59] found that intravenous injection of EDA-A1 fused with an IgG Fc fragment into pregnant Tabby mice almost completely rescued the phenotypic defect of Tabby mice during the embryonic stage by forming normal sweat glands that continue to the adult stage. High expression of the EDA gene in BM-MSCs successfully induces BM-MSCs to reprogram into SGL cells [60]. Xu et al. [48] also noted increased expression of EDA-A1 and EDAR genes during the reprogramming of UC-MSCs into SGL cells. These results indicate that EDA-A1/EDAR are not only associated with the development of sweat glands, but also play an important role in reprogramming of stem cells into SGL cells.
5.3.
NF-kB signaling pathway
The dimer of NF-kB (p50/p65) is a kind of transcription factor and the non-activated form is a trimer formed with IkB (p50p60-IkB). Phosphorylation of IkB kinase (IKK) by a stimulator results in phosphorylation and degradation of IkB, which releases p50/p60 from the trimer to form the activated state. It has been established that the EDA pathway, mediated by EDA, EDAR and EDARADD, specifically activates NF-kB transcription factors through the IKK pathway for development of skin appendage [56]. In addition, MEKK1 is involved in the
5
activation of IKK. Activated NF-kB enters the nucleus and promotes the expression of genes such as Shh, cyclin D1, Dkk4, Fox family genes and keratin 79 [56,61,62]. These genes are required at different stages in sweat gland development [61]. Also, FoxA1 was shown to be important for sweat secretion and was dark cell specific [63].
5.4.
Wnt/b-catenin signaling pathway
b-catenin is the key molecule of the Wnt signaling pathway which plays important roles in cell proliferation and differentiation. When the Wnt signaling pathway is activated by cytokines, b-catenin-adenomatous polyposis coli-glycogen synthase kinase 3b compound synthesis is inhibited, and free b-catenin in cytoplasm increases and is transferred into cell nuclei to drive the downstream signaling pathway. Lei et al. [64] reported that the proliferation of human eccrine sweat gland epithelial cells promoted by HGF was relative to bcatenin. Another study indicated that a downstream transcription factor of b-catenin signaling, Lef1, enhanced activation of the EDA promoter and promoted expression of the EDA gene during ectoderm development [65]. But whether there is a specific link between these two pathways during the reprogramming of stem cells remains unclear.
6.
Conclusions and future issues
Studies of skin regeneration have solved the problem of repairing large-area skin defects and saved the lives of many patients. To improve the life quality of patients, scientists have performed functional studies of skin regeneration, including the function of perspiration. In theory, the repair and regeneration of sweat glands can be performed by two methods, namely proliferation and differentiation of sweat gland stem cells in situ [20] and reconstruction of sweat glands by transplanting SGL stem cells [42]. Because of the objective reasons, regeneration in situ is hard to be achieved, and transplantation of stem cells has become the best alternative for regeneration. The plasticity of MSCs offers the new hope for sweat gland regeneration after severe burn. However, the sweat gland regeneration by stem cells is still in a primitive stage and has many problems that remain to be solved. First, a stable and efficient induction method has not been developed. If such a method is established, the study of sweat gland regeneration with MSCs will become easier and stem cell manipulation will be more efficient. Although we have established a method to obtain SGL cells by mimicking the microenvironment of sweat gland development [48], the components in the microenvironment are complicated and the conditions are not easily controlled. Second, scientists have always been intrigued by the mechanism of reprogramming of MSCs into SGL cells. It has been indicated that some cytokines and signaling pathways play important regulatory roles [60], but there are still some questions that remain to be answered. First, are the regulatory pathways of reprogramming of different MSC types the same? Second, what kind of crosstalk is there between the signaling pathways modulating the reprogramming of stem cells?
Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005
JBUR-4625; No. of Pages 8
6
burns xxx (2015) xxx–xxx
Third, what genes are involved in downstream of the signaling pathways guiding the reprogramming of MSCs? Finally, the regeneration of sweat glands by MSCs will solve the lack of perspiration in severe burn patients, but the technique requires improved clinical translation and application. First, the surgical indications for transplantation therapy should be established. Second, the opportunity for transplantation and the quantity of cells should be accurately controlled. Third, it is necessary to establish evaluation standards for repair and regeneration of sweat glands. Previously, we transplanted SGL cells differentiated from BM-MSCs into skin wounds after scar removal and evaluated the effect of sweat gland repair and regeneration after one year. The results indicated that the perspiration function in the transplantation area was partially recovered. Histological examination indicated that the transplanted cells failed to form obvious ductal and secretory parts but formed a cell cluster with the phenotype of sweat gland cells [42]. Therefore, our overall aim is to control the local microenvironment and induce SGL cells to develop into a complete sweat gland structure at the transplantation site for successful sweat gland regeneration.
Conflict of interest The authors have no conflicts of interest to disclose.
Ethics statement The informed consent was obtained for experimentation with human subjects. The protocol was approved by the national ethics committee in China.
Acknowledgments This study was supported in part by the National Nature Science Foundation of China (81171798, 81421064, 81230041), Beijing Municipal Natural Science Foundation (Grant No. 7142124) and the National Basic Science and Development Programme (973 Program, 2012CB518105).
references
[1] Brunt KR, Weisel RD, Li RK. Stem cells and regenerative medicine – future perspectives. Can J Physiol Pharmacol 2012;90:327–35. [2] Thompson CM, Hocking AM, Honari S, Muffley LA, Ga M, Gibran NS. Genetic risk factors for hypertrophic scar development. J Burn Care Res 2013;34:477–82. [3] Chuong CM, Randall VA, Widelitz RB, Wu P, Jiang TX. Physiological regeneration of skin appendages and implications for regenerative medicine. Physiology 2012;27:61–72. [4] Okano H. Stem cell research and regenerative medicine in 2014: first year of regenerative medicine in Japan. Stem Cells Dev 2014;23:2127–8.
[5] Sachlos E, Kerstetter-Fogle A. Highlights from the latest articles in regenerative medicine. Regen Med 2014;9:423–5. [6] Rasch AC. World Conference on Regenerative Medicine. Regen Med 2014;9:149–52. [7] Detamore MS. Human umbilical cord mesenchymal stromal cells in regenerative medicine. Stem Cell Res Ther 2013;4:142. [8] Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418:41–9. [9] Jackson L, Jones DR, Scotting P, Sottile V. Adult mesenchymal stem cells: differentiation potential and therapeutic applications. J Postgrad Med 2007;53:121–7. [10] de Villiers JA, Houreld N, Abrahamse H. Adipose derived stem cells and smooth muscle cells: implications for regenerative medicine. Stem Cell Rev 2009;5:256–65. [11] Fan C, Zhang Q, Zhou J. Therapeutic potentials of mesenchymal stem cells derived from human umbilical cord. Stem Cell Rev 2011;7:195–207. [12] Peng J, Wang Y, Zhang L, Zhao B, Zhao Z, Chen J, et al. Human umbilical cord Wharton’s jelly-derived mesenchymal stem cells differentiate into a Schwann-cell phenotype and promote neurite outgrowth in vitro. Brain Res Bull 2011;84:235–43. [13] Zhu H, Yang A, Du J, Li D, Liu M, Ding F, et al. Basic fibroblast growth factor is a key factor that induces bone marrow mesenchymal stem cells towards cells with Schwann cell phenotype. Neurosci Lett 2014;559:82–7. [14] Penolazzi L, Vecchiatini R, Bignardi S, Lambertini E, Torreggiani E, Canella A, et al. Influence of obstetric factors on osteogenic potential of umbilical cord-derived mesenchymal stem cells. Reprod Biol Endocrinol 2009;7:106. [15] Shang J, Liu H, Li J, Zhou Y. Roles of hypoxia during the chondrogenic differentiation of mesenchymal stem cells. Curr Stem Cell Res Ther 2014;9:141–7. [16] Deng B, Wen J, Ding Y, Peng J, Jiang S. Different regulation role of myostatin in differentiating pig ADSCs and MSCs into adipocytes. Cell Biochem Funct 2012;30:145–50. [17] Thanabalasundaram G, Arumalla N, Tailor HD, Khan WS. Regulation of differentiation of mesenchymal stem cells into musculoskeletal cells. Curr Stem Cell Res Ther 2012;7:95–102. [18] Oswald J, Boxberger S, Jørgensen B, Feldmann S, Ehninger G, Bornha¨user M, et al. Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 2004;22:377–84. [19] Fu X, Li J, Sun X, Sun T, Sheng Z. Epidermal stem cells are the source of sweat glands in human fetal skin: evidence of synergetic development of stem cells, sweat glands, growth factors, and matrix metalloproteinases. Wound Repair Regen 2005;13:102–8. [20] Lu CP, Polak L, Rocha AS, Pasolli HA, Chen SC, Sharma N, et al. Identification of stem cell populations in sweat glands and ducts reveals roles in homeostasis and wound repair. Cell 2012;150:136–50. [21] Leung Y, Kandyba E, Chen YB, Ruffins S, Kobielak K. Label retaining cells (LRCs) with myoepithelial characteristic from the proximal acinar region define stem cells in the sweat gland. PLOS ONE 2013;8:e74174. [22] Nagel S, Rohr F, Weber C, Kier J, Siemers F, Kruse C, et al. Multipotent nestin-positive stem cells reside in the stroma of human eccrine and apocrine sweat glands and can be propagated robustly in vitro. PLOS ONE 2013;8:e78365. [23] Chen L, Zhang M, Li H, Tang S, Fu X. Distribution of BrdU label-retaining cells in eccrine sweat glands and comparison of the percentage of BrdU-positive cells in
Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005
JBUR-4625; No. of Pages 8 burns xxx (2015) xxx–xxx
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
eccrine sweat glands and in epidermis in rats. Arch Dermatol Res 2014;306:157–62. Sun X, Fu X, Sheng Z. Cutaneous stem cells: something new and something borrowed. Wound Repair Regen 2007;15:775–85. Li J, Fu X, Sun X, Sun T, Sheng Z. The interaction between epidermal growth factor and matrix metalloproteinases induces the development of sweat glands in human fetal skin. J Surg Res 2002;106:258–63. Biedermann T, Pontiggia L, Bo¨ttcher-Haberzeth S, Tharakan S, Braziulis E, Schiestl C, et al. Human eccrine sweat gland cells can reconstitute a stratified epidermis. J Invest Dermatol 2010;130:1996–2009. Fu XB, Sun TZ, Li XK, Sheng ZY. Morphological and distribution characteristics of sweat glands in hypertrophic scar and their possible effects on sweat gland regeneration. Chin Med J 2005;118:186–91. Li D, Chai J, Shen C, Han Y, Sun T. Human umbilical cordderived mesenchymal stem cells differentiate into epidermal-like cells using a novel co-culture technique. Cytotechnology 2014;66:699–708. Fu X, Fang L, Li X, Cheng B, Sheng Z. Enhanced woundhealing quality with bone marrow mesenchymal stem cells autografting after skin injury. Wound Repair Regen 2006;14:325–35. Badiavas EV, Abedi M, Butmarc J, Falanga V, Quesenberry P. Participation of bone marrow derived cells in cutaneous wound healing. J Cell Physiol 2003;196:245–50. Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells 2007;25:2648–59. Herrmann JL, Weil BR, Abarbanell AM, Wang Y, Poynter JA, Manukyan MC, et al. IL-6 and TGF-a costimulate mesenchymal stem cell vascular endothelial growth factor production by ERK-, JNK-, and PI3K-mediated mechanisms. Shock 2011;35:512–6. Wu Y, Huang S, Enhe J, Ma K, Yang S, Sun T, et al. Bone marrow-derived mesenchymal stem cell attenuates skin fibrosis development in mice. Int Wound J 2013. http:// dx.doi.org/10.1111/iwj.12034. Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 2005;105:2214–9. Fu X, Qu Z, Sheng Z. Potentiality of mesenchymal stem cells in regeneration of sweat glands. J Surg Res 2006;136:204–8. Liu H, Zhang J, Liu CY, Hayashi Y, Kao WW. Bone marrow mesenchymal stem cells can differentiate and assume corneal keratocyte phenotype. J Cell Mol Med 2012;16: 1114–24. Wang J, Liao L, Wang S, Tan J. Cell therapy with autologous mesenchymal stem cells-how the disease process impacts clinical considerations. Cytotherapy 2013;15:893–904. Han CM, Wang SY, Lai PP, Cen HH. Human bone marrowderived mesenchymal stem cells differentiate into epidermal-like cells in vitro. Differentiation 2007;75:292–8. Ma K, Laco F, Ramakrishna S, Liao S, Chan CK. Differentiation of bone marrow-derived mesenchymal stem cells into multi-layered epidermis-like cells in 3D organotypic coculture. Biomaterials 2009;30:3251–8. Li H, Fu X, Ouyang Y, Cai C, Wang J, Sun T. Adult bonemarrow-derived mesenchymal stem cells contribute to wound healing of skin appendages. Cell Tissue Res 2006;326:725–36. Martin G, Swannell S, Mill J, Mott J, Evans J, Frederiksen N, et al. Spray on skin improves psychosocial functioning in pediatric burns patients: a randomized controlled trial. Burns 2008;34:498–504.
[42] Sheng Z, Fu X, Cai S, Lei Y, Sun T, Bai X, et al. Regeneration of functional sweat gland-like structures by transplanted differentiated bone marrow mesenchymal stem cells. Wound Repair Regen 2009;17:427–35. [43] Kamolz LP, Kolbus A, Wick N, Mazal PR, Eisenbock B, Burjak S, et al. Cultured human epithelium: human umbilical cord blood stem cells differentiate into keratinocytes under in vitro conditions. Burns 2006;32:16–9. [44] Dai Y, Li J, Li J, Dai G, Mu H, Wu Q, et al. Skin epithelial cells in mice from umbilical cord blood mesenchymal stem cells. Burns 2007;33:418–28. [45] Karahuseyinoglu S, Kocaefe C, Balci D, Erdemli E, Can A. Functional structure of adipocytes differentiated from human umbilical cord stroma-derived stem cells. Stem Cells 2008;26:682–91. [46] Kocaefe C, Balci D, Hayta BB, Can A. Reprogramming of human umbilical cord stromal mesenchymal stem cells for myogenic differentiation and muscle repair. Stem Cell Rev 2010;6:512–22. [47] Wu KH, Zhou B, Lu SH, Feng B, Yang SG, Du WT, et al. In vitro and in vivo differentiation of human umbilical cord derived stem cells into endothelial cells. J Cell Biochem 2007;100:608–16. [48] Xu Y, Huang S, Ma K, Fu X, Han W, Sheng Z. Promising new potential for mesenchymal stem cells derived from human umbilical cord Wharton’s jelly: sweat gland cell-like differentiative capacity. J Tissue Eng Regen Med 2012;6:645–54. [49] Cagnol S, Chambard JC. ERK and cell death: mechanisms of ERK-induced cell death – apoptosis, autophagy and senescence. FEBS J 2010;277:2–21. [50] Kim N, Kim H, Youm JB, Park WS, Warda M, Ko JH, et al. Site specific differential activation of ras/raf/ERK signaling in rabbit isoproterenol-induced left ventricular hypertrophy. Biochim Biophys Acta 2006;1763:1067–75. [51] Saga K, Takahashi M. Immunoelectron microscopic localization of epidermal growth factor in the eccrine and apocrine sweat glands. J Histochem Cytochem 1992; 40:241–9. [52] Blecher SR, Kapalanga J, Lalonde D. Induction of sweat glands by epidermal growth factor in murine X-linked anhidrotic ectodermal dysplasia. Nature 1990;345:542–4. [53] Cui CY, Schlessinger D. EDA signaling and skin appendage development. Cell Cycle 2006;5:2477–83. [54] Mustonen T, Ilmonen M, Pummila M, Kangas AT, Laurikkala J, Jaatinen R, et al. Ectodysplasin A1 promotes placodal cell fate during early morphogenesis of ectodermal appendages. Development 2004;131:4907–19. [55] Mikkola ML. Molecular aspects of hypohidrotic ectodermal dysplasia. Am J Med Genet A 2009;149A:2031–6. [56] Schmidt-Ullrich R, Tobin DJ, Lenhard D, Schneider P, Paus R, Scheidereit C. NF-kappaB transmits Eda A1/EdaR signalling to activate Shh and cyclin D1 expression, and controls post-initiation hair placode down growth. Development 2006;133:1045–57. [57] Srivastava AK, Durmowicz MC, Hartung AJ, Hudson J, Ouzts LV, Donovan DM, et al. Ectodysplasin-A1 is sufficient to rescue both hair growth and sweat glands in Tabby mice. Hum Mol Genet 2001;10:2973–81. [58] Mustonen T, Pispa J, Mikkola ML, Pummila M, Kangas AT, Pakkasja¨rvi L, et al. Stimulation of ectodermal organ development by Ectodysplasin-A1. Dev Biol 2003;259: 123–36. [59] Gaide O, Schneider P. Permanent correction of an inherited ectodermal dysplasia with recombinant EDA. Nat Med 2003;9:614–8. [60] Cai S, Pan Y, Han B, Sun T, Sheng Z, Fu X. Transplantation of human bone marrow-derived mesenchymal stem cells transfected with ectodysplasin for regeneration of sweat glands. Chin Med J 2011;124:2260–8.
Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005
7
JBUR-4625; No. of Pages 8
8
burns xxx (2015) xxx–xxx
[61] Kunisada M, Cui HY, Piao Y, Minoru SH, Schlessinger D. Requirement for Shh and Fox family genes at different stages in sweat gland development. Hum Mol Genet 2009;18:1769–78. [62] Fliniaux I, Mikkola ML, Lefebvre S, Thesleff I. Identification of dkk4 as a target of Eda-A1/Edar pathway reveals an unexpected role of ectodysplasin as inhibitor of Wnt signalling in ectodermal placodes. Dev Biol 2008;320:60–71. [63] Cui CY, Childress V, Piao Y, Michel M, Johnson AA, Kunisada M, et al. Forkhead transcription factor FoxA1
regulates sweat secretion through Bestrophin 2 anion channel and Na-K-Cl cotransporter 1. Proc Natl Acad Sci U S A 2012;109:1199–203. [64] Lei X, Wu J, Liu B, Lu Y. Hepatocyte growth factor promoting the proliferation of human eccrine sweat gland epithelial cells is relative to AKT signal channel and bcatenin. Arch Dermatol Res 2012;304:23–9. [65] Durmowicz MC, Cui CY, Schlessinger D. The EDA gene is a target of, but does not regulate Wnt signaling. Gene 2002;285:203–11.
Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/burns
Review
Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality Kui Ma a,1, Zhijun Tan b,1, Cuiping Zhang a,*, Xiaobing Fu a a
Key Research Laboratory of Tissue Repair and Regeneration of PLA, and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, PR China b Tianjin Medical University, Tianjin, PR China
article info
abstract
Article history:
Sweat glands play important roles in homeostasis maintenance and body temperature
Received 3 November 2014
regulation. In patients with deep burns, the injury can reach the muscle tissues and damage
Received in revised form
sweat glands. However, the plasticity of mesenchymal stem cells (MSCs) may offer the
18 February 2015
possibility to regenerate sweat glands after severe burn. In particular, recent studies have
Accepted 17 April 2015
changed the possibility to reality. Here, we analyze the barriers of sweat gland regeneration
Available online xxx
in situ after deep burns, propose the possibilities of MSCs in regeneration of sweat glands, summarize the recent researches into sweat gland regeneration with MSCs, and sum up the
Keywords:
possible mechanisms during this process. In addition, the advantage and disadvantage of
Mesenchymal stem cells
sweat gland regeneration with MSCs from different tissues have been discussed. So this
Burns
review will provide meaningful guidance in the clinic for sweat gland regeneration with
Transdifferentiation
MSCs. # 2015 Elsevier Ltd and ISBI. All rights reserved.
Sweat glands Regenerative medicine
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regeneration barriers of sweat glands after deep burns Possibility of MSCs in regeneration of sweat glands. . . . Regeneration of sweat glands with MSCs . . . . . . . . . . . . 4.1. BM-MSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. MSCs from umbilical cord . . . . . . . . . . . . . . . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
000 000 000 000 000 000
* Corresponding author at: Wounds Repair and Tissue Regeneration Laboratory, Burn Institution, The First Affiliated Hospital, General Hospital of PLA, 51 Fu Cheng Road, Beijing 100048, PR China. Tel.: +86 10 68210077x867396; fax: +86 10 68989955. E-mail address: [email protected] (C. Zhang). 1
These authors contributed equally to this work. Abbreviations: SGL, sweat-gland-like; BM-MSCs, bone marrow mesenchymal stem cells; UCB, umbilical cord blood; WJ, Wharton’s jelly; ERK, extracellular regulated protein kinase; MAPK, mitogen-activated protein kinase; EGF, epidermal growth factor; FGF-10, fibroblast growth factor-10; HGF, hepatocyte growth factor; EDAR, Ectodysplasin-A1 receptor; HED, hypohidrotic ectodermal dysplasia; EDARADD, EDAR-associated death domain; NF, nuclear factor; IKK, IkB kinase. http://dx.doi.org/10.1016/j.burns.2015.04.005 0305-4179/# 2015 Elsevier Ltd and ISBI. All rights reserved.
Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005
JBUR-4625; No. of Pages 8
2
burns xxx (2015) xxx–xxx
5.
6.
1.
Mechanism of sweat gland regeneration by MSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. ERK signaling pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Ectodysplasin-A1 (EDA-A1)/Ectodysplasin-A1 receptor (EDAR) signaling pathway 5.3. NF-kB signaling pathway. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Wnt/b-catenin signaling pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and future issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
Recently, the regeneration of cutaneous appendages during the repair of damaged skin has become an important direction in the field of stem cells and regenerative medicine [1]. Sweat gland is a kind of important appendage of the skin, which plays some key roles in homeostasis maintenance and body temperature regulation. The skin of patients with an extensive deep burn is repaired by a hypertrophic scar [2] without regeneration of sweat glands, and therefore loses the function of perspiration. Burns survivors feel the heat very much and have to rest at home in summer, which affects their quality of life. Therefore, regeneration of sweat glands in the skin has become a focus of modern medical study [3]. Meanwhile, the recent progress in stem cell research in regenerative medicine is remarkable [4–6]. Cell therapy with MSCs holds enormous promise for the treatment of damaged organs using regenerative technology [7]. MSCs can be obtained from adult tissue such as bone marrow [8,9], adipose tissue [10], umbilical cord [11] and others. Under suitable conditions, MSCs can differentiate into various types of cells such as neural cells [12,13], osteocytes [14,15], adipose cells [16], muscle cells [17] and vascular endothelial cells [18]. The unique property of MSCs highlights the potential for sweat gland regeneration. In this review, we focus on the barriers of sweat gland regeneration after deep burns and the possibilities, recent researches and possible mechanisms of MSCs in regeneration of sweat glands after deep burns.
2. Regeneration barriers of sweat glands after deep burns The sweat glands develop from the cells in epidermis during embryonic development [19]. Recent studies indicated that mature sweat glands still contain stem cells or progenitor cells [20–23]. However, in most cases of deep burns, above stem cells in the injured sweat glands cannot achieve the regeneration of sweat glands. Furthermore, after scar healing, the new epidermal stem cells also fail to differentiate into sweat gland cells, which results in the loss of sweating function in the wound healed with scarring. Therefore, understanding the effects of scar healing on sweat gland regeneration by epidermal stem cells will be helpful to guide the study of sweat gland regeneration. The microenvironment surrounding the stem cells is called the stem cell niche [24]. Modulation of proliferation and differentiation of epidermal stem cells by the stem cell niche mainly involves cell–cell and cell–extracellular matrix interactions. In addition, cytokines play important roles in
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
000 000 000 000 000 000 000 000
transmitting information between cells and the extracellular matrix [25]. Regeneration of sweat gland cells is also regulated by the above factors because the sweat gland cells are homologous with the basal epidermal stem cells [26]. However, under the condition of scar formation after deep burns, the internal and external environments for self-renewal of the stem cells have changed. First, the cell quantity and types in the scar are different from those in normal skin. Second, the extracellular matrix metabolism related to sweat gland development is disordered. Third, the basal membrane of scar tissues loses the normal structure and function. All these factors will affect sweat gland regeneration by endogenous stem cells in scars. After wound healing by scarring, the absence of perspiration in healed areas does not necessarily indicate that there is no sweat gland tissue in the scar. A previous study indicated that there were expressions of carcinoembryonic antigen and cytokeratin 8, which are thought to be markers of sweat gland cells, in the scar tissue [27]. Therefore, it has been proposed that there is a biological basis and potential for sweat gland regeneration in the wound after burns. The reason for the lack of re-construction of sweat glands in proliferative scars is related to the excessive speed of scar repairing over sweat gland regeneration. The proliferative scar then forms a barrier that prevents sweat gland regeneration. To solve the difficulty of perspiration in deep burn patients, scar needs to be removed, followed by transplantation of sweat gland cells or tissue-engineered skin containing sweat gland cells. However, the sweat gland cells in patients are very few and seriously damaged, therefore, researchers are trying to obtain sweat gland cells from mesenchymal stem cells.
3. Possibility of MSCs in regeneration of sweat glands MSCs have proved to be an attractive cell type for various cell therapies due to their ability to differentiate into various cell lineages, multiple donor tissue types, and relative resilience in ex vivo expansion, as well as immunomodulatory effects during transplants. Recent findings of both experimental studies and clinical trials demonstrated that MSCs were able to repair skin. First, MSCs can differentiate into epidermal-like cells [28] and enhance the reepithelialization during wound repair. Animal autografting experiments with MSCs showed the increased number of epidermal ridges and thickness of the regenerated epidermis [29]. It is interesting to find in one animal experiment that GFP-labeled marrow stem cells were noted in hair follicle, epidermis, and sebaceous glands [30]. Second, MSCs can promote revascularization of the wound
Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005
JBUR-4625; No. of Pages 8 burns xxx (2015) xxx–xxx
bed. There is evidence that MSCs can differentiate into endothelial cells to yield new vessels [31]. In addition, MSCs naturally produce a variety of pro-angiogenic factors that stimulate endothelial cell proliferation and tube formation in the wound bed [32]. Third, MSCs have several effects on fibrotic phenotypes in the wound, and thus play a major role in reducing scar formation following wound healing [33]. Fourth, mesenchymal stem cells have recently been shown to hold a variety of immunomodulatory effects on host immune cells in both wound healing and transplant biology contexts. For example, donor MSCs are able to suppress host T cell proliferation, a key activity in reducing wound bed inflammation [34]. The participation of MSCs in cutaneous repair implies that MSCs may have the potentiality to regenerate sweat glands [35].
4.
Regeneration of sweat glands with MSCs
4.1.
BM-MSCs
BM-MSCs are non- hematopoietic stem cells in the bone marrow and are derived from the mesoderm. Under suitable conditions, BM-MSCs can differentiate into ectoderm-derived tissue [36]. Cell therapy with BM-MSCs holds enormous promise for the treatment of a large number of diseases [37]. In the field of sweat gland regeneration, BM-MSCs are the most studied and widely used stem cells. The advantages of BM-MSCs include lower immunogenicity and less graft-versushost reactions. In addition, BM-MSCs exist in the bone marrow that receives less direct damage from large areas of trauma and burns. Therefore, BM-MSCs have significant theoretical and practical value for the repair of skin and sweat gland regeneration [35]. The potential of BM-MSCs to differentiate into epidermal keratinocytes has been described [38,39]. In theory, epidermal cells derived from BM-MSCs can differentiate into SGL cells. Fortunately, BM-MSCs have been induced successfully to differentiate directly into SGL cells bypassing an intermediate state of epidermal stem cells. Li et al. [40]
3
found that direct co-culture of BM-MSCs with heat-shocked sweat gland cells resulted in differentiation of BM-MSCs into SGL cells. The SGL cells were then transplanted into the wounds of nude mice and significantly promoted the repair and regeneration of damaged sweat glands. Recently, the theory and technique of sweat gland regeneration by stem cells have been partially translated and applied in the clinic (Fig. 1). The major steps include removal of the scar, placement of SGL cells on the wound, and transplantation of a micro-skin autograft [41] or allogeneic skin to cover the wound. These treatments allow the sweat glands to grow in the center of the scar and solve the problem of the lack of perspiration in deep burn patients. Sheng et al. [42] reported that a SGL structure grew in the wound of a patient after transplantation of SGL cells reprogrammed from autologous MSCs. Further investigation showed that the SGL structure performed perspiration that continued during the 3 year follow-up period. Although there are obvious advantages in using BM-MSCs for sweat gland regeneration, there are still issues that need to be considered. First, BM-MSCs are isolated from the bone marrow of patients, which increases their physical and mental stress. Second, in vitro differentiation requires a long time, which makes it difficult to obtain enough SGL cells from stem cells in a timely manner. Finally, the long-term effect of induction remains to be studied. Therefore, whether this method can be directly and effectively used for sweat gland regeneration in burn patients remains to be further studied in the clinic.
4.2.
MSCs from umbilical cord
During the late 1980s, scientists found that the umbilical cord, which is discarded after birth, contains a high concentration of stem cells. MSCs can be derived from umbilical cord blood (UCB) or Wharton’s jelly (WJ). It has been indicated that UCBMSCs can differentiate into skin cells [43,44]. However, there are a limited number of UCB-MSCs which are difficult to be isolated and cultured in vitro. Therefore, scientists have performed extensive studies of WJ-MSCs. Compared with BM-MSCs, WJ-MSCs are more primitive, express similar
Fig. 1 – Sweat gland regeneration after implantation of SGL cells derived from MSCs in a patient recovered from burn. Three months after the surgery, we performed an iodine/starch-based sweat test on burn areas with patient’s informed consent after scar removal and cell transplantation. This procedure detects sweat, reflective of a functional gland. Iodine-starch test was negative on control area (A), but treated area responded to the assay by displaying indigo-black dots (black arrow), indicative of sweat production (B). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005
JBUR-4625; No. of Pages 8
4
burns xxx (2015) xxx–xxx
surface markers, are easier to be obtained, have lower immunogenicity, and therefore are more suitable for allogeneic transplantation [11]. Recent studies indicate that WJMSCs can differentiate into neural cells, osteocytes, adipose cells, muscle cells and vascular endothelial cells [12,14,45–47]. But whether WJ-MSCs have the potential to differentiate into epidermal cells and SGL cells remains to be verified. Xu et al. [48] co-cultured WJ-MSCs with heat-shocked sweat gland cells to induce the differentiation of WJ-MSCs into SGL cells. After one week, immunohistochemical and flow cytometric examinations verified that the SGL cells showed the phenotype of sweat gland cells, suggesting that the heat-shocked microenvironment of sweat glands can induce WJ-MSCs to reprogram into SGL cells. The SGL cells obtained by the above method can be used for sweat gland regeneration at the early stages of burns, but the detailed biological characteristics, safety, and possibility of growing to form sweat gland tissues after transplantation remain to be further studied.
5. Mechanism of sweat gland regeneration by MSCs Although the mechanism of sweat gland regeneration by MSCs remains unclear, there are many indications suggesting that the various cytokines and signaling pathways involved in the regeneration and development of sweat glands play important regulatory roles. In addition, different cytokines
can activate the same signaling pathway, whereas one cytokine can activate different signal pathways and there is complicated crosstalk among different signal pathways (Fig. 2).
5.1.
ERK signaling pathway
Extracellular regulated protein kinases (ERK) are important members of the mitogen-activated protein kinase (MAPK) family that control many cellular and physiological processes such as cell growth, development and death [49]. The very core of ERK pathway is the reaction chain composed of three protein kinases (MAPKKK, MAPKK and MAPK), i.e., upstream activating protein ! MAPKKK ! MAPKK ! MAPK. In the ERK pathway, Ras serves as the upstream activating protein, the MAPKKK is Raf, the MAPKK is mitogen and extracellular kinase (MEK) and MAPK is ERK, i.e., Ras-Raf-MEK-ERK. Activated ERK enters the nucleus through transposition and activates the expression of downstream genes mainly including some early reaction genes encoding transcription factors (c-fos, c-myc, c-jun, and Erg-1) [50]. Cytokines, such as epidermal growth factor (EGF), fibroblast growth factor-10 (FGF-10) and hepatocyte growth factor (HGF), can activate the ERK signaling pathway, and activation by EGF has been verified as the typical pathway in which EGF activates Ras to induce the cascade reaction. During embryonic development, the expression of EGF increased gradually in developing sweat gland buds and in extracellular stroma
Fig. 2 – Possible mechanisms of sweat gland regeneration with stem cells. Possible mechanisms include ERK signaling, EDAA1/EDAR signaling, NF-kB signaling and Wnt/b-catenin signaling. Different cytokines can activate the same signaling pathway, whereas one cytokine can activate different signal pathways. There is complicated crosstalk among different signal pathways. Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005
JBUR-4625; No. of Pages 8 burns xxx (2015) xxx–xxx
surrounding the buds [25]. In adults, EGF expression was strongly positive in the myoepithelial cells and secretory cells of eccrine sweat glands and also positive myoepithelial cells of apocrine sweat glands [51]. Blecher et al. [52] reported that EGF induced development of dermal ridges and functional sweat glands in Ta/Y hemizygotes. So we conclude that EGF is actively involved in the morphogenesis and homeostasis of skin and sweat glands. Furthermore, in a study of reprogramming of MSCs into SGL cells, EGF significantly enhanced the efficiency of reprogramming, whereas the ERK pathway blocker PD98059 partially blocked the reprogramming of MSCs into SGL cells [40]. These results suggest that ERK pathway play an important role in such reprogramming process.
5.2. Ectodysplasin-A1 (EDA-A1)/Ectodysplasin-A1 receptor (EDAR) signaling pathway The EDA gene is one of the functional genes that regulate the development of sweat glands. In mouse, sweat buds are initiated by EDAR-mediated signaling [53,54]. Mutation of the EDA gene can result in hypohidrotic ectodermal dysplasia (HED) that mainly displays developmental defects in sweat glands, hair and teeth [55]. EDA-A1 and EDA-A2 are the two functional molecules encoded by the EDA gene. The receptor for EDA-A1 is EDAR, whereas the receptor for EDA-A2 is Xlinked EDAR. EDA-A1 is directly associated with HED and can, through hydrolysis, release the functional domain. The functional domain binds to EDAR for activation of a series of downstream signals such as receptor adaptor EDARADD (EDAR-associated death domain) and nuclear factor (NF)-kB to promote the occurrence and development of cutaneous appendages [56]. The Tabby mouse is the model of human HED and demonstrates the development of sweat glands and hair follicles after transduction of EDA-A1 cDNA by transgenic techniques [57]. Normal mice exhibit larger sweat glands with enhanced function after overexpression of EDA-A1 [58,54]. Gaide et al. [59] found that intravenous injection of EDA-A1 fused with an IgG Fc fragment into pregnant Tabby mice almost completely rescued the phenotypic defect of Tabby mice during the embryonic stage by forming normal sweat glands that continue to the adult stage. High expression of the EDA gene in BM-MSCs successfully induces BM-MSCs to reprogram into SGL cells [60]. Xu et al. [48] also noted increased expression of EDA-A1 and EDAR genes during the reprogramming of UC-MSCs into SGL cells. These results indicate that EDA-A1/EDAR are not only associated with the development of sweat glands, but also play an important role in reprogramming of stem cells into SGL cells.
5.3.
NF-kB signaling pathway
The dimer of NF-kB (p50/p65) is a kind of transcription factor and the non-activated form is a trimer formed with IkB (p50p60-IkB). Phosphorylation of IkB kinase (IKK) by a stimulator results in phosphorylation and degradation of IkB, which releases p50/p60 from the trimer to form the activated state. It has been established that the EDA pathway, mediated by EDA, EDAR and EDARADD, specifically activates NF-kB transcription factors through the IKK pathway for development of skin appendage [56]. In addition, MEKK1 is involved in the
5
activation of IKK. Activated NF-kB enters the nucleus and promotes the expression of genes such as Shh, cyclin D1, Dkk4, Fox family genes and keratin 79 [56,61,62]. These genes are required at different stages in sweat gland development [61]. Also, FoxA1 was shown to be important for sweat secretion and was dark cell specific [63].
5.4.
Wnt/b-catenin signaling pathway
b-catenin is the key molecule of the Wnt signaling pathway which plays important roles in cell proliferation and differentiation. When the Wnt signaling pathway is activated by cytokines, b-catenin-adenomatous polyposis coli-glycogen synthase kinase 3b compound synthesis is inhibited, and free b-catenin in cytoplasm increases and is transferred into cell nuclei to drive the downstream signaling pathway. Lei et al. [64] reported that the proliferation of human eccrine sweat gland epithelial cells promoted by HGF was relative to bcatenin. Another study indicated that a downstream transcription factor of b-catenin signaling, Lef1, enhanced activation of the EDA promoter and promoted expression of the EDA gene during ectoderm development [65]. But whether there is a specific link between these two pathways during the reprogramming of stem cells remains unclear.
6.
Conclusions and future issues
Studies of skin regeneration have solved the problem of repairing large-area skin defects and saved the lives of many patients. To improve the life quality of patients, scientists have performed functional studies of skin regeneration, including the function of perspiration. In theory, the repair and regeneration of sweat glands can be performed by two methods, namely proliferation and differentiation of sweat gland stem cells in situ [20] and reconstruction of sweat glands by transplanting SGL stem cells [42]. Because of the objective reasons, regeneration in situ is hard to be achieved, and transplantation of stem cells has become the best alternative for regeneration. The plasticity of MSCs offers the new hope for sweat gland regeneration after severe burn. However, the sweat gland regeneration by stem cells is still in a primitive stage and has many problems that remain to be solved. First, a stable and efficient induction method has not been developed. If such a method is established, the study of sweat gland regeneration with MSCs will become easier and stem cell manipulation will be more efficient. Although we have established a method to obtain SGL cells by mimicking the microenvironment of sweat gland development [48], the components in the microenvironment are complicated and the conditions are not easily controlled. Second, scientists have always been intrigued by the mechanism of reprogramming of MSCs into SGL cells. It has been indicated that some cytokines and signaling pathways play important regulatory roles [60], but there are still some questions that remain to be answered. First, are the regulatory pathways of reprogramming of different MSC types the same? Second, what kind of crosstalk is there between the signaling pathways modulating the reprogramming of stem cells?
Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005
JBUR-4625; No. of Pages 8
6
burns xxx (2015) xxx–xxx
Third, what genes are involved in downstream of the signaling pathways guiding the reprogramming of MSCs? Finally, the regeneration of sweat glands by MSCs will solve the lack of perspiration in severe burn patients, but the technique requires improved clinical translation and application. First, the surgical indications for transplantation therapy should be established. Second, the opportunity for transplantation and the quantity of cells should be accurately controlled. Third, it is necessary to establish evaluation standards for repair and regeneration of sweat glands. Previously, we transplanted SGL cells differentiated from BM-MSCs into skin wounds after scar removal and evaluated the effect of sweat gland repair and regeneration after one year. The results indicated that the perspiration function in the transplantation area was partially recovered. Histological examination indicated that the transplanted cells failed to form obvious ductal and secretory parts but formed a cell cluster with the phenotype of sweat gland cells [42]. Therefore, our overall aim is to control the local microenvironment and induce SGL cells to develop into a complete sweat gland structure at the transplantation site for successful sweat gland regeneration.
Conflict of interest The authors have no conflicts of interest to disclose.
Ethics statement The informed consent was obtained for experimentation with human subjects. The protocol was approved by the national ethics committee in China.
Acknowledgments This study was supported in part by the National Nature Science Foundation of China (81171798, 81421064, 81230041), Beijing Municipal Natural Science Foundation (Grant No. 7142124) and the National Basic Science and Development Programme (973 Program, 2012CB518105).
references
[1] Brunt KR, Weisel RD, Li RK. Stem cells and regenerative medicine – future perspectives. Can J Physiol Pharmacol 2012;90:327–35. [2] Thompson CM, Hocking AM, Honari S, Muffley LA, Ga M, Gibran NS. Genetic risk factors for hypertrophic scar development. J Burn Care Res 2013;34:477–82. [3] Chuong CM, Randall VA, Widelitz RB, Wu P, Jiang TX. Physiological regeneration of skin appendages and implications for regenerative medicine. Physiology 2012;27:61–72. [4] Okano H. Stem cell research and regenerative medicine in 2014: first year of regenerative medicine in Japan. Stem Cells Dev 2014;23:2127–8.
[5] Sachlos E, Kerstetter-Fogle A. Highlights from the latest articles in regenerative medicine. Regen Med 2014;9:423–5. [6] Rasch AC. World Conference on Regenerative Medicine. Regen Med 2014;9:149–52. [7] Detamore MS. Human umbilical cord mesenchymal stromal cells in regenerative medicine. Stem Cell Res Ther 2013;4:142. [8] Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418:41–9. [9] Jackson L, Jones DR, Scotting P, Sottile V. Adult mesenchymal stem cells: differentiation potential and therapeutic applications. J Postgrad Med 2007;53:121–7. [10] de Villiers JA, Houreld N, Abrahamse H. Adipose derived stem cells and smooth muscle cells: implications for regenerative medicine. Stem Cell Rev 2009;5:256–65. [11] Fan C, Zhang Q, Zhou J. Therapeutic potentials of mesenchymal stem cells derived from human umbilical cord. Stem Cell Rev 2011;7:195–207. [12] Peng J, Wang Y, Zhang L, Zhao B, Zhao Z, Chen J, et al. Human umbilical cord Wharton’s jelly-derived mesenchymal stem cells differentiate into a Schwann-cell phenotype and promote neurite outgrowth in vitro. Brain Res Bull 2011;84:235–43. [13] Zhu H, Yang A, Du J, Li D, Liu M, Ding F, et al. Basic fibroblast growth factor is a key factor that induces bone marrow mesenchymal stem cells towards cells with Schwann cell phenotype. Neurosci Lett 2014;559:82–7. [14] Penolazzi L, Vecchiatini R, Bignardi S, Lambertini E, Torreggiani E, Canella A, et al. Influence of obstetric factors on osteogenic potential of umbilical cord-derived mesenchymal stem cells. Reprod Biol Endocrinol 2009;7:106. [15] Shang J, Liu H, Li J, Zhou Y. Roles of hypoxia during the chondrogenic differentiation of mesenchymal stem cells. Curr Stem Cell Res Ther 2014;9:141–7. [16] Deng B, Wen J, Ding Y, Peng J, Jiang S. Different regulation role of myostatin in differentiating pig ADSCs and MSCs into adipocytes. Cell Biochem Funct 2012;30:145–50. [17] Thanabalasundaram G, Arumalla N, Tailor HD, Khan WS. Regulation of differentiation of mesenchymal stem cells into musculoskeletal cells. Curr Stem Cell Res Ther 2012;7:95–102. [18] Oswald J, Boxberger S, Jørgensen B, Feldmann S, Ehninger G, Bornha¨user M, et al. Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 2004;22:377–84. [19] Fu X, Li J, Sun X, Sun T, Sheng Z. Epidermal stem cells are the source of sweat glands in human fetal skin: evidence of synergetic development of stem cells, sweat glands, growth factors, and matrix metalloproteinases. Wound Repair Regen 2005;13:102–8. [20] Lu CP, Polak L, Rocha AS, Pasolli HA, Chen SC, Sharma N, et al. Identification of stem cell populations in sweat glands and ducts reveals roles in homeostasis and wound repair. Cell 2012;150:136–50. [21] Leung Y, Kandyba E, Chen YB, Ruffins S, Kobielak K. Label retaining cells (LRCs) with myoepithelial characteristic from the proximal acinar region define stem cells in the sweat gland. PLOS ONE 2013;8:e74174. [22] Nagel S, Rohr F, Weber C, Kier J, Siemers F, Kruse C, et al. Multipotent nestin-positive stem cells reside in the stroma of human eccrine and apocrine sweat glands and can be propagated robustly in vitro. PLOS ONE 2013;8:e78365. [23] Chen L, Zhang M, Li H, Tang S, Fu X. Distribution of BrdU label-retaining cells in eccrine sweat glands and comparison of the percentage of BrdU-positive cells in
Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005
JBUR-4625; No. of Pages 8 burns xxx (2015) xxx–xxx
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
eccrine sweat glands and in epidermis in rats. Arch Dermatol Res 2014;306:157–62. Sun X, Fu X, Sheng Z. Cutaneous stem cells: something new and something borrowed. Wound Repair Regen 2007;15:775–85. Li J, Fu X, Sun X, Sun T, Sheng Z. The interaction between epidermal growth factor and matrix metalloproteinases induces the development of sweat glands in human fetal skin. J Surg Res 2002;106:258–63. Biedermann T, Pontiggia L, Bo¨ttcher-Haberzeth S, Tharakan S, Braziulis E, Schiestl C, et al. Human eccrine sweat gland cells can reconstitute a stratified epidermis. J Invest Dermatol 2010;130:1996–2009. Fu XB, Sun TZ, Li XK, Sheng ZY. Morphological and distribution characteristics of sweat glands in hypertrophic scar and their possible effects on sweat gland regeneration. Chin Med J 2005;118:186–91. Li D, Chai J, Shen C, Han Y, Sun T. Human umbilical cordderived mesenchymal stem cells differentiate into epidermal-like cells using a novel co-culture technique. Cytotechnology 2014;66:699–708. Fu X, Fang L, Li X, Cheng B, Sheng Z. Enhanced woundhealing quality with bone marrow mesenchymal stem cells autografting after skin injury. Wound Repair Regen 2006;14:325–35. Badiavas EV, Abedi M, Butmarc J, Falanga V, Quesenberry P. Participation of bone marrow derived cells in cutaneous wound healing. J Cell Physiol 2003;196:245–50. Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells 2007;25:2648–59. Herrmann JL, Weil BR, Abarbanell AM, Wang Y, Poynter JA, Manukyan MC, et al. IL-6 and TGF-a costimulate mesenchymal stem cell vascular endothelial growth factor production by ERK-, JNK-, and PI3K-mediated mechanisms. Shock 2011;35:512–6. Wu Y, Huang S, Enhe J, Ma K, Yang S, Sun T, et al. Bone marrow-derived mesenchymal stem cell attenuates skin fibrosis development in mice. Int Wound J 2013. http:// dx.doi.org/10.1111/iwj.12034. Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 2005;105:2214–9. Fu X, Qu Z, Sheng Z. Potentiality of mesenchymal stem cells in regeneration of sweat glands. J Surg Res 2006;136:204–8. Liu H, Zhang J, Liu CY, Hayashi Y, Kao WW. Bone marrow mesenchymal stem cells can differentiate and assume corneal keratocyte phenotype. J Cell Mol Med 2012;16: 1114–24. Wang J, Liao L, Wang S, Tan J. Cell therapy with autologous mesenchymal stem cells-how the disease process impacts clinical considerations. Cytotherapy 2013;15:893–904. Han CM, Wang SY, Lai PP, Cen HH. Human bone marrowderived mesenchymal stem cells differentiate into epidermal-like cells in vitro. Differentiation 2007;75:292–8. Ma K, Laco F, Ramakrishna S, Liao S, Chan CK. Differentiation of bone marrow-derived mesenchymal stem cells into multi-layered epidermis-like cells in 3D organotypic coculture. Biomaterials 2009;30:3251–8. Li H, Fu X, Ouyang Y, Cai C, Wang J, Sun T. Adult bonemarrow-derived mesenchymal stem cells contribute to wound healing of skin appendages. Cell Tissue Res 2006;326:725–36. Martin G, Swannell S, Mill J, Mott J, Evans J, Frederiksen N, et al. Spray on skin improves psychosocial functioning in pediatric burns patients: a randomized controlled trial. Burns 2008;34:498–504.
[42] Sheng Z, Fu X, Cai S, Lei Y, Sun T, Bai X, et al. Regeneration of functional sweat gland-like structures by transplanted differentiated bone marrow mesenchymal stem cells. Wound Repair Regen 2009;17:427–35. [43] Kamolz LP, Kolbus A, Wick N, Mazal PR, Eisenbock B, Burjak S, et al. Cultured human epithelium: human umbilical cord blood stem cells differentiate into keratinocytes under in vitro conditions. Burns 2006;32:16–9. [44] Dai Y, Li J, Li J, Dai G, Mu H, Wu Q, et al. Skin epithelial cells in mice from umbilical cord blood mesenchymal stem cells. Burns 2007;33:418–28. [45] Karahuseyinoglu S, Kocaefe C, Balci D, Erdemli E, Can A. Functional structure of adipocytes differentiated from human umbilical cord stroma-derived stem cells. Stem Cells 2008;26:682–91. [46] Kocaefe C, Balci D, Hayta BB, Can A. Reprogramming of human umbilical cord stromal mesenchymal stem cells for myogenic differentiation and muscle repair. Stem Cell Rev 2010;6:512–22. [47] Wu KH, Zhou B, Lu SH, Feng B, Yang SG, Du WT, et al. In vitro and in vivo differentiation of human umbilical cord derived stem cells into endothelial cells. J Cell Biochem 2007;100:608–16. [48] Xu Y, Huang S, Ma K, Fu X, Han W, Sheng Z. Promising new potential for mesenchymal stem cells derived from human umbilical cord Wharton’s jelly: sweat gland cell-like differentiative capacity. J Tissue Eng Regen Med 2012;6:645–54. [49] Cagnol S, Chambard JC. ERK and cell death: mechanisms of ERK-induced cell death – apoptosis, autophagy and senescence. FEBS J 2010;277:2–21. [50] Kim N, Kim H, Youm JB, Park WS, Warda M, Ko JH, et al. Site specific differential activation of ras/raf/ERK signaling in rabbit isoproterenol-induced left ventricular hypertrophy. Biochim Biophys Acta 2006;1763:1067–75. [51] Saga K, Takahashi M. Immunoelectron microscopic localization of epidermal growth factor in the eccrine and apocrine sweat glands. J Histochem Cytochem 1992; 40:241–9. [52] Blecher SR, Kapalanga J, Lalonde D. Induction of sweat glands by epidermal growth factor in murine X-linked anhidrotic ectodermal dysplasia. Nature 1990;345:542–4. [53] Cui CY, Schlessinger D. EDA signaling and skin appendage development. Cell Cycle 2006;5:2477–83. [54] Mustonen T, Ilmonen M, Pummila M, Kangas AT, Laurikkala J, Jaatinen R, et al. Ectodysplasin A1 promotes placodal cell fate during early morphogenesis of ectodermal appendages. Development 2004;131:4907–19. [55] Mikkola ML. Molecular aspects of hypohidrotic ectodermal dysplasia. Am J Med Genet A 2009;149A:2031–6. [56] Schmidt-Ullrich R, Tobin DJ, Lenhard D, Schneider P, Paus R, Scheidereit C. NF-kappaB transmits Eda A1/EdaR signalling to activate Shh and cyclin D1 expression, and controls post-initiation hair placode down growth. Development 2006;133:1045–57. [57] Srivastava AK, Durmowicz MC, Hartung AJ, Hudson J, Ouzts LV, Donovan DM, et al. Ectodysplasin-A1 is sufficient to rescue both hair growth and sweat glands in Tabby mice. Hum Mol Genet 2001;10:2973–81. [58] Mustonen T, Pispa J, Mikkola ML, Pummila M, Kangas AT, Pakkasja¨rvi L, et al. Stimulation of ectodermal organ development by Ectodysplasin-A1. Dev Biol 2003;259: 123–36. [59] Gaide O, Schneider P. Permanent correction of an inherited ectodermal dysplasia with recombinant EDA. Nat Med 2003;9:614–8. [60] Cai S, Pan Y, Han B, Sun T, Sheng Z, Fu X. Transplantation of human bone marrow-derived mesenchymal stem cells transfected with ectodysplasin for regeneration of sweat glands. Chin Med J 2011;124:2260–8.
Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005
7
JBUR-4625; No. of Pages 8
8
burns xxx (2015) xxx–xxx
[61] Kunisada M, Cui HY, Piao Y, Minoru SH, Schlessinger D. Requirement for Shh and Fox family genes at different stages in sweat gland development. Hum Mol Genet 2009;18:1769–78. [62] Fliniaux I, Mikkola ML, Lefebvre S, Thesleff I. Identification of dkk4 as a target of Eda-A1/Edar pathway reveals an unexpected role of ectodysplasin as inhibitor of Wnt signalling in ectodermal placodes. Dev Biol 2008;320:60–71. [63] Cui CY, Childress V, Piao Y, Michel M, Johnson AA, Kunisada M, et al. Forkhead transcription factor FoxA1
regulates sweat secretion through Bestrophin 2 anion channel and Na-K-Cl cotransporter 1. Proc Natl Acad Sci U S A 2012;109:1199–203. [64] Lei X, Wu J, Liu B, Lu Y. Hepatocyte growth factor promoting the proliferation of human eccrine sweat gland epithelial cells is relative to AKT signal channel and bcatenin. Arch Dermatol Res 2012;304:23–9. [65] Durmowicz MC, Cui CY, Schlessinger D. The EDA gene is a target of, but does not regulate Wnt signaling. Gene 2002;285:203–11.
Please cite this article in press as: Ma K, et al. Mesenchymal stem cells for sweat gland regeneration after burns: From possibility to reality. Burns (2015), http://dx.doi.org/10.1016/j.burns.2015.04.005