Efficacy assessment of mesenchymal stem cell transplantation for burn wounds in animals: a systematic review.
ABSTRACT: BACKGROUND:Clinically, severe burns remain one of the most challenging issues, but an ideal treatment is yet absent. Our purpose is to compare the efficacy of stem cell therapy in a preclinical model of burn wound healing. METHODS:Research reports on mesenchymal stem cells (MSCs) for burn wound healing were retrieved from 5 databases: PubMed, Embase, MEDLINE, Web of Science, and the Cochrane Library. The primary outcomes reported in this article include the un-healing rate of the wound area, the closure rate, and the wound area. Secondary outcomes included CD-31, vascular density, interleukin (IL)-10, thickness of eschar tissue, vascular endothelial growth factor (VEGF), and white blood cell count. Finally, a subgroup analysis was conducted to explore heterogeneity that potentially impacted the primary outcomes. A fixed-effects model with a 95% confidence interval (CI) was performed when no significant heterogeneity existed. Otherwise, a random-effects model was used. All data analysis was conducted by using Engauge Digitizer 10.8 and R software. RESULTS:Twenty eligible articles were finally included in the analysis. Stem cell therapy greatly improved the closure rate (2.00, 95% CI 0.52 to 3.48, p?=?0.008) and compromised the wound area (-?2.36; 95% CI -?4.90 to 0.18; p?=?0.069) rather than the un-healing rate of the wound area (-?11.10, 95% CI -?32.97 to 10.78, p?=?0.320). Though p was 0.069, there was a trend toward shrinkage of the burn wound area after stem cell therapy. Vascular density (4.69; 95% CI 0.06 to 9.31; p?=?0.047) and thickness of eschar tissue (6.56, 95% CI 1.15 to 11.98, p?=?0.017) were also discovered to be significantly improved in the burn site of stem cell-treated animals. Moreover, we observed that animals in the stem cell group had an increased white blood cell count (0.84, 95% CI 0.01 to 1.66, p?=?0.047) 5?days post treatment. Other indicators, such as VEGF (p?=?0.381), CD-31 (p?=?0.335) and IL-10 (p?=?0.567), were not significantly impacted. CONCLUSIONS:Despite limited data from preclinical trials, this meta-analysis suggests that stem cell therapy is curative in decreasing the burn wound area and provides some insights into future clinical studies of stem cell therapy for burns.
Project description:Pericytes are cells that reside adjacent to microvasculature and regulate vascular function. Pericytes gained great interest in the field of wound healing and regenerative medicine due to their multipotential fate and ability to enhance angiogenesis. In burn wounds, scarring and scar contractures are the major pathologic feature and cause loss of mobility. The present study investigated the influence of burn wound environment on pericytes during wound healing. Pericytes isolated from normal skin and tangentially excised burn eschar tissues were analyzed for differences in gene and protein expression using RNA-seq., immunocytochemistry, and ELISA analyses. RNA-seq identified 443 differentially expressed genes between normal- and burn eschar-derived pericytes. Whereas, comparing normal skin pericytes to normal skin fibroblasts identified 1021 distinct genes and comparing burn eschar pericytes to normal skin fibroblasts identified 2449 differential genes. Altogether, forkhead box E1 (FOXE1), a transcription factor, was identified as a unique marker for skin pericytes. Interestingly, FOXE1 levels were significantly elevated in burn eschar pericytes compared to normal. Additionally, burn wound pericytes showed increased expression of profibrotic genes periostin, fibronectin, and endosialin and a gain in contractile function, suggesting a contribution to scarring and fibrosis. Our findings suggest that the burn wound environment promotes pericytes to differentiate into a myofibroblast-like phenotype promoting scar formation and fibrosis.
Project description:The majority of full-thickness burn wounds heal with hypertrophic scar formation. Burn eschar most probably influences early burn wound healing, since granulation tissue only forms after escharotomy. In order to investigate the effect of burn eschar on delayed granulation tissue formation, burn wound extract (BWE) was isolated from the interface between non-viable eschar and viable tissue. The influence of BWE on the activity of endothelial cells derived from dermis and adipose tissue, dermal fibroblasts and adipose tissue-derived mesenchymal stromal cells (ASC) was determined. It was found that BWE stimulated endothelial cell inflammatory cytokine (CXCL8, IL-6 and CCL2) secretion and migration. However, BWE had no effect on endothelial cell proliferation or angiogenic sprouting. Indeed, BWE inhibited basic Fibroblast Growth Factor (bFGF) induced endothelial cell proliferation and sprouting. In contrast, BWE stimulated fibroblast and ASC proliferation and migration. No difference was observed between cells isolated from dermis or adipose tissue. The inhibitory effect of BWE on bFGF-induced endothelial proliferation and sprouting would explain why excessive granulation tissue formation is prevented in full-thickness burn wounds as long as the eschar is still present. Identifying the eschar factors responsible for this might give indications for therapeutic targets aimed at reducing hypertrophic scar formation which is initiated by excessive granulation tissue formation once eschar is removed.
Project description:Background:Researchers have explored the use of adipose-derived stem cells (ASCs) as a cell-based therapy to cover wounds in burn patients; however, underlying mechanistic aspects are not completely understood. We hypothesized that ASCs would improve post-burn wound healing after eschar excision and grafting by increasing wound blood flow via induction of angiogenesis-related pathways. Methods:To test the hypothesis, we used an ovine burn model. A 5 cm2 full thickness burn wound was induced on each side of the dorsum. After 24 hours, the burned skin was excised and a 2 cm2 patch of autologous donor skin was grafted. The wound sites were randomly allocated to either topical application of 7 million allogeneic ASCs or placebo treatment (phosphate-buffered saline [PBS]). Effects of ASCs culture media was also compared to those of PBS. Wound healing was assessed at one and two weeks following the application of ASCs. Allogeneic ASCs were isolated, cultured and characterized from non-injured healthy sheep. The identity of the ASCs was confirmed by flow cytometry analysis, differentiation into multiple lineages and gene expression via real-time polymerase chain reaction. Wound blood flow, epithelialization, graft size and take and the expression of vascular endothelial growth factor (VEGF) were determined via enzyme-linked immunosorbent assay and Western blot. Results:Treatment with ASCs accelerated the patch graft growth compared to the control (p <?0.05). Topical application of ASCs significantly increased wound blood flow (p <?0.05). Expression of VEGF was significantly higher in the wounds treated with ASCs compared to control (p <?0.05). Conclusions:ASCs accelerated grafted skin growth possibly by increasing the blood flow via angiogenesis induced by a VEGF-dependent pathway.
Project description:Burns in the elderly continue to be a challenge despite advances in burn wound care management. Elderly burn patients continue to have poor outcomes compared to the younger population. This is secondary to changes in the quality of the aged skin, leading to impaired wound healing, aggravated immunologic and inflammatory responses, and age-related comorbidities. Considering the fast-growing elderly population, it is imperative to understand the anatomic, physiologic, and molecular changes of the aging skin and the mechanisms involved in their wound healing process to prevent complications associated with burn wounds. Various studies have shown that stem cell-based therapies improve the rate and quality of wound healing and skin regeneration; however, the focus is on the younger population. In this paper, we start with an anatomical, physiological and molecular dissection of the elderly skin to understand why wound healing is delayed. We then review the potential use of stem cells in elderly burn wounds, as well as the mechanisms by which mesenchymal stem cell (MSCs)-based therapies may impact burn wound healing in the elderly. MSCs improve burn wound healing by stimulating and augmenting growth factor secretion and cell proliferation, and by modulating the impaired elderly immune response. MSCs can be used to expedite healing in superficial partial thickness burns and donor site wounds, improve graft take and prevent graft breakdown.
Project description:Local transplantation of epidermal stem cells (ESCs) exerts a therapeutic effect on burn wounds. However, cell viability can impede their clinical application. HOX antisense intergenic RNA (HOTAIR) is involved in regulating adult tissue stem cells, as well as in developmental patterning and pluripotency. However, little is known about its role in regulating ESCs. The present study was performed to investigate the effects of HOTAIR in the modulation of ESCs and wound repair. Firstly, reverse transcription?quantitative PCR was used to detect the relative expression of HOTAIR during burn wound healing in mice to determine whether HOTAIR is associated with wound healing. Subsequently, ESCs derived from mouse skin were transfected with a lentiviral vector to overexpress or knockdown HOTAIR. The effects of HOTAIR on cell proliferation and differentiation were measured by 5?bromodeoxyuridine and MTT assays, and by assessing NANOG mRNA expression. Lastly, mice with burns were administered a subcutaneous injection of HOTAIR?overexpressing ESCs. Images were captured and histological analyses were performed to evaluate wound healing. The results revealed that the expression of HOTAIR gradually increased and peaked at day 7 post?burn and maintained at relatively high levels until day 14 post?burn during wound healing. Furthermore, overexpression of HOTAIR promoted ESC proliferation and maintained the stem cell state in vitro. By contrast, suppression of HOTAIR inhibited cell proliferation and cell stemness. It was also identified that HOTIR?overexpressing ESCs accelerated re?epithelialization and facilitated burn wound repair. In conclusion, the present findings confirmed an essential role of HOTAIR in the regulation of ESC proliferation and stemness. Therefore, targeting HOTAIR in ESCs may be a potentially promising therapy for burn wound healing.
Project description:Adipose-derived stem cells (ADSCs) transplant has been reported to be a potential treatment for burn wounds. However, the effects of autogenicity and allogenicity of ADSCs on burn wound healing have not been investigated and the method for using ADSCs still needs to be established. This study compared the healing effects of autologous and allogenic ADSCs and determined an optimal method of using ADSCs to treat acute burn wounds. Experiments were performed in 20 male Wistar rats (weight, 176-250 g; age, 6-7 weeks). Two identical full-thickness burn wounds (radius, 4 mm) were created in each rat. ADSCs harvested from inguinal area and characterized by their high multipotency were injected into burn wounds in the original donor rats (autologous ADSCs group) or in other rats (allogenic ADSCs group). The injection site was either the wound center or the four corners 0.5 cm from the wound edge. The reduction of burn surface areas in the two experimental groups and in control group were evaluated with Image J software for 15 days post-wounding to determine the wound healing rates. Wound healing was significantly faster in the autologous ADSCs group compared to both the allogenic ADSCs group (p<0.05) and control group (p<0.05). Wound healing in the allogenic ADSC group did not significantly differ from that in control group. Notably, ADSC injections 0.5cm from the wound edge showed significantly improved healing compared to ADSCs injections in the wound center (p<0.05). This study demonstrated the therapeutic efficacy of ADSCs in treating acute burn wounds in rats. However, only autologous ADSCs improved healing in acute burn wounds; allogenic ADSCs did not. This study further determined a superior location of using ADSCs injections to treat burn wounds including the injection site. Future studies will replicate the experiment in a larger and long-term scale burn wounds in higher mammalian models to facilitate ADSCs therapy in burn wound clinical practice.
Project description:Eschar formation is a potential sequela of burn injuries. Definitive management may include escharectomy and eschar debridement. After eschar removal, the wound can be covered with a skin graft or reepithelialization. For prolonged refractory eschar on the fingertips, topical use of rb-bFGF after debridement can achieve an optimal outcome.
Project description:According to the latest report from the World Health Organization, an estimated 265,000 deaths still occur every year as a direct result of burn injuries. A widespread range of these deaths induced by burn wound happens in low- and middle-income countries, where survivors face a lifetime of morbidity. Most of the deaths occur due to infections when a high percentage of the external regions of the body area is affected. Microbial nutrient availability, skin barrier disruption, and vascular supply destruction in burn injuries as well as systemic immunosuppression are important parameters that cause burns to be susceptible to infections. Topical antimicrobials and dressings are generally employed to inhibit burn infections followed by a burn wound therapy, because systemic antibiotics have problems in reaching the infected site, coupled with increasing microbial drug resistance. Nanotechnology has provided a range of molecular designed nanostructures (NS) that can be used in both therapeutic and diagnostic applications in burns. These NSs can be divided into organic and non-organic (such as polymeric nanoparticles (NPs) and silver NPs, respectively), and many have been designed to display multifunctional activity. The present review covers the physiology of skin, burn classification, burn wound pathogenesis, animal models of burn wound infection, and various topical therapeutic approaches designed to combat infection and stimulate healing. These include biological based approaches (e.g. immune-based antimicrobial molecules, therapeutic microorganisms, antimicrobial agents, etc.), antimicrobial photo- and ultrasound-therapy, as well as nanotechnology-based wound healing approaches as a revolutionizing area. Thus, we focus on organic and non-organic NSs designed to deliver growth factors to burned skin, and scaffolds, dressings, etc. for exogenous stem cells to aid skin regeneration. Eventually, recent breakthroughs and technologies with substantial potentials in tissue regeneration and skin wound therapy (that are as the basis of burn wound therapies) are briefly taken into consideration including 3D-printing, cell-imprinted substrates, nano-architectured surfaces, and novel gene-editing tools such as CRISPR-Cas.
Project description:Burn injuries are a leading cause of morbidity including prolonged hospitalization, disfigurement, and disability. Currently there is no Food and Drug Administration-approved burn therapeutics. A clinical distinction of burn injuries from other acute wounds is the event of the so-called secondary burn wound progression within the first week of the injury, in which a burn expands horizontally and vertically from its initial boundary to a larger area. Therefore, an effective therapeutics for burns should show dual abilities to prevent the burn wound progression and thereafter promote burn wound healing. Herein we report that topically applied F-5 fragment of heat shock protein-90? is a dual functional agent to promote burn wound healing in pigs. First, F-5 prevents burn wound progression by protecting the surrounding cells from undergoing heat-induced caspase 3 activation and apoptosis with increased Akt activation. Accordingly, F-5-treated burn and excision wounds show a marked decline in inflammation. Thereafter, F-5 accelerates burn wound healing by stimulating the keratinocyte migration-led reepithelialization, leading to wound closure. This study addresses a topical agent that is capable of preventing burn wound progression and accelerating burn wound healing.
Project description:Cell therapy has emerged as an important component of life-saving procedures in treating burns. Over past decades, advances in stem cells and regenerative medicine have offered exciting opportunities of developing cell-based alternatives and demonstrated the potential and feasibility of various stem cells for burn wound healing. However, there are still scientific and technical issues that should be resolved to facilitate the full potential of the cellular devices. More evidence from large, randomly controlled trials is also needed to understand the clinical impact of cell therapy in burns. This article aims to provide an up-to-date review of the research development and clinical applications of cell therapies in burn wound healing and skin regeneration.