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Amniotic Mesenchymal Stem Cells Enhance Wound Healing in Diabetic NOD/SCID Mice through High Angiogenic and Engraftment Capabilities  [PDF]
Sung-Whan Kim, Hong-Zhe Zhang, Longzhe Guo, Jong-Min Kim, Moo Hyun Kim
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041105
Abstract: Although human amniotic mesenchymal stem cells (AMMs) have been recognised as a promising stem cell resource, their therapeutic potential for wound healing has not been widely investigated. In this study, we evaluated the therapeutic potential of AMMs using a diabetic mouse wound model. Quantitative real-time PCR and ELISA results revealed that the angiogenic factors, IGF-1, EGF and IL-8 were markedly upregulated in AMMs when compared with adipose-derived mesenchymal stem cells (ADMs) and dermal fibroblasts. In vitro scratch wound assays also showed that AMM-derived conditioned media (CM) significantly accelerated wound closure. Diabetic mice were generated using streptozotocin and wounds were created by skin excision, followed by AMM transplantation. AMM transplantation significantly promoted wound healing and increased re-epithelialization and cellularity. Notably, transplanted AMMs exhibited high engraftment rates and expressed keratinocyte-specific proteins and cytokeratin in the wound area, indicating a direct contribution to cutaneous closure. Taken together, these data suggest that AMMs possess considerable therapeutic potential for chronic wounds through the secretion of angiogenic factors and enhanced engraftment/differentiation capabilities.
Dopamine Regulates Mobilization of Mesenchymal Stem Cells during Wound Angiogenesis  [PDF]
Saurav Shome, Partha Sarathi Dasgupta, Sujit Basu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031682
Abstract: Angiogenesis is an important step in the complex biological and molecular events leading to successful healing of dermal wounds. Among the different cellular effectors of wound angiogenesis, the role of mesenchymal stem cells (MSCs) is of current interest due to their transdifferentiation and proangiogenic potentials. Skin is richly innervated by sympathetic nerves which secrete dopamine (DA) and we have recently shown that concentration of DA present in synaptic cleft can significantly inhibit wound tissue neovascularization. As recent reports indicate that MSCs by mobilizing into wound bed play an important role in promoting wound angiogenesis, we therefore investigated the effect of DA on the migration of MSCs in wound tissues. DA acted through its D2 receptors present in the MSCs to inhibit their mobilization to the wound beds by suppressing Akt phosphorylation and actin polymerization. In contrast, this inhibitory effect of DA was reversed after treatment with specific DA D2 receptor antagonist. Increased mobilization of MSCs was demonstrated in the wound site following blockade of DA D2 receptor mediated actions, and this in turn was associated with significantly more angiogenesis in wound tissues. This study is of translational value and indicates use of DA D2 receptor antagonists to stimulate mobilization of these stem cells for faster regeneration of damaged tissues.
Dopamine Regulates Angiogenesis in Normal Dermal Wound Tissues  [PDF]
Saurav Shome, Tapasi Rana, Subhalakshmi Ganguly, Biswarup Basu, Sandipan Chaki Choudhury, Chandrani Sarkar, Debanjan Chakroborty, Partha Sarathi Dasgupta, Sujit Basu
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025215
Abstract: Cutaneous wound healing is a normal physiological process and comprises different phases. Among these phases, angiogenesis or new blood vessel formation in wound tissue plays an important role. Skin is richly supplied by sympathetic nerves and evidences indicate the significant role of the sympathetic nervous system in cutaneous wound healing. Dopamine (DA) is an important catecholamine neurotransmitter released by the sympathetic nerve endings and recent studies have demonstrated the potent anti-angiogenic action of DA, which is mediated through its D2 DA receptors. We therefore postulate that this endogenous catecholamine neurotransmitter may have a role in the neovascularization of dermal wound tissues and subsequently in the process of wound healing. In the present study, the therapeutic efficacy of D2 DA receptor antagonist has been investigated for faster wound healing in a murine model of full thickness dermal wound. Our results indicate that treatment with specific D2 DA receptor antagonist significantly expedites the process of full thickness normal dermal wound healing in mice by inducing angiogenesis in wound tissues. The underlined mechanisms have been attributed to the up-regulation of homeobox transcription factor HoxD3 and its target α5β1 integrin, which play a pivotal role in wound angiogenesis. Since D2 DA receptor antagonists are already in clinical use for other disorders, these results have significant translational value from the bench to the bedside for efficient wound management along with other conventional treatment modalities.
Paracrine Factors of Mesenchymal Stem Cells Recruit Macrophages and Endothelial Lineage Cells and Enhance Wound Healing  [PDF]
Liwen Chen, Edward E. Tredget, Philip Y. G. Wu, Yaojiong Wu
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001886
Abstract: Bone marrow derived mesenchymal stem cells (BM-MSCs) have been shown to enhance wound healing; however, the mechanisms involved are barely understood. In this study, we examined paracrine factors released by BM-MSCs and their effects on the cells participating in wound healing compared to those released by dermal fibroblasts. Analyses of BM-MSCs with Real-Time PCR and of BM-MSC-conditioned medium by antibody-based protein array and ELISA indicated that BM-MSCs secreted distinctively different cytokines and chemokines, such as greater amounts of VEGF-α, IGF-1, EGF, keratinocyte growth factor, angiopoietin-1, stromal derived factor-1, macrophage inflammatory protein-1alpha and beta and erythropoietin, compared to dermal fibroblasts. These molecules are known to be important in normal wound healing. BM-MSC-conditioned medium significantly enhanced migration of macrophages, keratinocytes and endothelial cells and proliferation of keratinocytes and endothelial cells compared to fibroblast-conditioned medium. Moreover, in a mouse model of excisional wound healing, where concentrated BM-MSC-conditioned medium was applied, accelerated wound healing occurred compared to administration of pre-conditioned or fibroblast-conditioned medium. Analysis of cell suspensions derived from the wound by FACS showed that wounds treated with BM-MSC-conditioned medium had increased proportions of CD4/80-postive macrophages and Flk-1-, CD34- or c-kit-positive endothelial (progenitor) cells compared to wounds treated with pre-conditioned medium or fibroblast-conditioned medium. Consistent with the above findings, immunohistochemical analysis of wound sections showed that wounds treated with BM-MSC-conditioned medium had increased abundance of macrophages. Our results suggest that factors released by BM-MSCs recruit macrophages and endothelial lineage cells into the wound thus enhancing wound healing.
Transplantation of Bone Marrow-Derived Mesenchymal Stem Cells Promotes Delayed Wound Healing in Diabetic Rats  [PDF]
Jiangbo Wan,Liulu Xia,Wenjia Liang,Yi Liu,Qian Cai
Journal of Diabetes Research , 2013, DOI: 10.1155/2013/647107
Abstract: In this paper, we established a delayed wound healing model on diabetic rat to mimic the pathophysiology of clinical patients who suffered from diabetic foot ulcers. We also evaluated if transplantation of allogeneic bone marrow-derived mesenchymal stem cells could promote the delayed wound healing and investigated the possible underlying biological mechanisms and stem cell behavior involved in this process. The results showed that bone marrow-derived mesenchymal stem cells had a positive effect on delayed wound healing in diabetic rats. Intramuscular transplantation demonstrated the best efficacy. This effect is associated with granulation tissue formation, angiogenesis, cellular proliferation, and high vascular endothelial growth factor expression in wound tissues. In addition, bone marrow-derived mesenchymal stem cells have been shown to mobilize and find home for ischemic and wounded tissues to participate in the process of wound healing. Intramuscular transplantation of exogenous isogeneic stem cells may be suitable for clinical application in the treatment of diabetic foot ulcers although the safety of this therapy should be considered. 1. Introduction The incidence of diabetes mellitus is growing and reaching epidemic proportions worldwide [1]. The total number of diabetics is estimated to rise from 171 million in 2000 to 366 million in 2030 [2]. Diabetic foot ulcers (DFUs) are one of the most serious complications of diabetes. The lifetime risk of developing foot ulceration in persons with diabetes is as high as 25% [3]. Over 14–24% of these patients will have progressive disease that eventually leads to amputation [4]. In fact, complications of DFUs are the number one cause of nontraumatic lower extremity amputations [5], which is also associated with a high rate of morbidity and mortality with a 5-year survival rate as low as 31% for major limb amputees [6]. Wound healing is a complex process, which includes four overlapping phases: coagulation, inflammation, migration-proliferation, and remodeling [7]. Poor wound healing is a major issue in patients who suffer from DFUs. Peripheral vascular disease, trauma, infection, and neuropathy complicate the treatment of these wounds and thus necessitate a multidisciplinary approach [8]. Appropriate wound management varies mainly according to the cause of the wound, such as aggressive debridement, adequate pressure offloading, treatment of infection, hyperbaric oxygen therapy, bypass surgery for revascularization, and local dressings [9]. However, those concomitant or sequential therapeutic approaches
Cell-free derivatives from mesenchymal stem cells are effective in wound therapy  [cached]
Pravin J Mishra,Prasun J Mishra,Debabrata Banerjee
World Journal of Stem Cells , 2012, DOI: 10.4252/wjsc.v4.i5.35
Abstract: AIM: To compare the efficacy of cell-free derivatives from Bone marrow derived human mesenchymal stem cells (hMSCs) in wound therapy. METHODS: hMSCs have been shown to play an important role in wound therapy. The present study sought to compare efficacy of hMSCs and cell-free derivatives of hMSCs, which may be clinically more relevant as they are easier to prepare, formulate and transport. hMSCs were isolated from human bone marrow and cultured. Multi lineage differentiation of hMSCs was performed to confirm their identity. The ability of hMSCs to migrate was evaluated using in vitro and in vivo migration assays. Cell lysates and conditioned medium concentrate was prepared from hMSCs (see Methods for details). Wounds were induced in mice and wound areas were measure before and after cell and cell-free derivative treatment. RNA and proteins were extracted from the skin and cytokine levels were measured. RESULTS: Co-culture of hMSCs with keratinocytes resulted in increased expression of CXCL-12 (SDF1) and ENA78 (CXCL-5) in the conditioned media indicating that the hMSCs can respond to signals from keratinocytes. Accelerated wound closure was observed when hMSCs were injected near the site of excisional wounds in athymic as well as NOD/SCID mice. Interestingly, cell-free lysates prepared from hMSCs were also effective in inducing accelerated wound closure and increased expression of SDF1 and CXCL-5 at the wound bed. Additionally, concentrated media from hMSCs as well as an emulsion containing lysates prepared from hMSCs was also found to be more effective in rapid re-epithelialization than fibroblasts or vehicle-alone control. Use of cell-free derivatives may help replace expensive wound care approaches including use of growth factors, epidermal/dermal substitutes, synthetic membranes, cytokines, and matrix components, and most importantly avoid transmission of pathogens from human and animal products. CONCLUSION: These results encourage development of derivatives of hMSCs for wound care and re-epithelialization applications.
Human Umbilical Cord Mesenchymal Stem Cells Transplantation Promotes Cutaneous Wound Healing of Severe Burned Rats  [PDF]
Lingying Liu, Yonghui Yu, Yusen Hou, Jiake Chai, Hongjie Duan, Wanli Chu, Haijun Zhang, Quan Hu, Jundong Du
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088348
Abstract: Background Severe burns are a common and highly lethal trauma. The key step for severe burn therapy is to promote the wound healing as early as possible, and reports indicate that mesenchymal stem cell (MSC) therapy contributes to facilitate wound healing. In this study, we investigated effect of human umbilical cord MSCs (hUC-MSCs) could on wound healing in a rat model of severe burn and its potential mechanism. Methods Adult male Wistar rats were randomly divided into sham, burn, and burn transplanted hUC-MSCs. GFP labeled hUC-MSCs or PBS was intravenous injected into respective groups. The rate of wound closure was evaluated by Image Pro Plus. GFP-labeled hUC-MSCs were tracked by in vivo bioluminescence imaging (BLI), and human-specific DNA expression in wounds was detected by PCR. Inflammatory cells, neutrophils, macrophages, capillaries and collagen types I/III in wounds were evaluated by histochemical staining. Wound blood flow was evaluated by laser Doppler blood flow meter. The levels of proinflammatory and anti-inflammatory factors, VEGF, collagen types I/III in wounds were analyzed using an ELISA. Results We found that wound healing was significantly accelerated in the hUC-MSC therapy group. The hUC-MSCs migrated into wound and remarkably decreased the quantity of infiltrated inflammatory cells and levels of IL-1, IL-6, TNF-α and increased levels of IL-10 and TSG-6 in wounds. Additionally, the neovascularization and levels of VEGF in wounds in the hUC-MSC therapy group were markedly higher than those in other control groups. The ratio of collagen types I and III in the hUC-MSC therapy group were markedly higher than that in the burn group at indicated time after transplantation. Conclusion The study suggests that hUC-MSCs transplantation can effectively improve wound healing in severe burned rat model. Moreover, these data might provide the theoretical foundation for the further clinical application of hUC-MSC in burn areas.
Differentiation of Human Dermal Mesenchymal Stem Cells into Cardiomyocytes by Treatment with 5-Azacytidine: Concept for Regenerative Therapy in Myocardial Infarction  [PDF]
Pravin D. Potdar,Preeti Prasannan
ISRN Stem Cells , 2013, DOI: 10.1155/2013/687282
Abstract: Myocardial infarction (MI) is the leading cause of death worldwide. Stem cells regenerative medicine offers a promising approach to cure such degenerative disorders. Mesenchymal stem cells are thought to be one of the important types of stem cells which can differentiate into various lineages such as neuron, hepatocytes, and cardiomyocytes. In the present study, human dermal mesenchymal stem cells (hDMSCs) have been developed from human scalp punch biopsy and characterized for their mesenchymal phenotype so that these cells can be useful for differentiating into cardiomyocytes. 5-Azacytidine induces cardiomyocyte differentiation in vitro and therefore it has been used to differentiate hDMSCs cells into cardiomyocytes. It was observed that hDMSCs differentiated into cardiomyocyte within a period of 4 days to 15 days after treatment with 10?μM and 20?μM of 5-azacytidine. The cardiomyocyte phenotype was confirmed by studying expression of α-cardiac actin, β-myosin heavy chain, and cardiac troponin T. Thus, this paper describes the differentiation of hDMSCs into cardiomyocytes which can be further be used for treatment of MI. This type of cell-based cardiac therapy will offer a new hope for millions of patients worldwide who are suffering from heart disease. 1. Introduction Myocardial Infarction (MI) is most commonly known as heart attack. It is one of the leading causes of mortality all over the world mainly due to constant change in lifestyle with ever increasing stress. MI is not only seen among the 50–60-year-age group but presently has also become a common reason for death in the younger generation. MI is caused due to shortage of blood supply to a part of the heart which reduces the oxygen supply to the affected area leading to necrosis of the tissue (scar formation) and there is no complete recovery after such damage in adult humans [1]. For several decades, heart transplantation has been an option for therapy, but due to complications arising from host-graft rejection reaction and shortage of healthy donors, there is an immediate need to come up with other feasible options for the therapy of MI. Recent development in stem cell research therapy and cell transplantation delivers great promise for the treatment of cardiovascular disorders [2, 3]. Stem cells show immense promise for their application in medical field due to their unique ability to self-renew along with the potential to differentiate into different cell types. Such remarkable properties of stem cells show great promise in the field of regenerative medicine [4]. Mesenchymal stem cells are
Pericytes, Mesenchymal Stem Cells and the Wound Healing Process  [PDF]
Stuart J. Mills,Allison J. Cowin,Pritinder Kaur
Cells , 2013, DOI: 10.3390/cells2030621
Abstract: Pericytes are cells that reside on the wall of the blood vessels and their primary function is to maintain the vessel integrity. Recently, it has been realized that pericytes have a much greater role than just the maintenance of vessel integrity essential for the development and formation of a vascular network. Pericytes also have stem cell-like properties and are seemingly able to differentiate into adipocytes, chondrocytes, osteoblasts and granulocytes, leading them to be identified as mesenchymal stem cells (MSCs). More recently it has been suggested that pericytes play a key role in wound healing, whereas the beneficial effects of MSCs in accelerating the wound healing response has been recognized for some time. In this review, we collate the most recent data on pericytes, particularly their role in vessel formation and how they can affect the wound healing process.
Loss of PPARγ expression by fibroblasts enhances dermal wound closure
Wei Sha, Katherine Thompson, Jennifer South, Murray Baron, Andrew Leask
Fibrogenesis & Tissue Repair , 2012, DOI: 10.1186/1755-1536-5-5
Abstract: Mice deleted for PPARγ in skin fibroblasts show an enhanced rate of dermal wound closure, concomitant with elevated phosphorylation of Smad3, Akt and ERK, and increased expression of proliferating cell nuclear antigen (PCNA), collagen, α-smooth muscle actin (α-SMA) and CCN2. Conversely, dermal homeostasis was not appreciably affected by loss of PPARγ expression.PPARγ expression by fibroblasts suppresses cutaneous tissue repair. In the future, direct PPARγ antagonists and agonists might be of clinical benefit in controlling chronic wounds or scarring, respectively.If the dermis is injured, specialized fibroblasts called myofibroblasts repopulate the wound and synthesize and remodel new connective tissue [1]. Wound repair is very complex and dynamic, involving the interactions of multiple cell types and growth factors/cytokines; dysregulation of this process results in chronic wounds or fibrosis [2]. Thus, understanding the molecular mechanisms controlling the normal tissue repair program is likely to be of clinical relevance.Expression of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-γ is reduced in dermal fibroblasts isolated from fibrotic lesions of patients with the autoimmune connective tissue disease scleroderma (systemic sclerosis, SSc); moreover, the PPARγ agonist rosiglitazone reverses the persistent fibrotic phenotype of this cell type [3]. Normally, PPAR-γ is bound to the retinoid X receptor (RXR) and co-repressors, preventing its binding to DNA; however, upon receptor ligation, the co-repressors are displaced from the PPAR-γ/RXR complex allowing PPAR-γ to bind PPAR-γ response elements in the promoters of target genes [4]. The PPAR/RXR transcriptional complex plays a critical role in maintaining energy balance, which is dysregulated in conditions such as obesity, diabetes, and atherosclerosis [4].An increasing body of evidence also suggests that PPAR-γ plays a key role in connective tissue turnover, a key process involved with tissu
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