Sha Huang

Bone marrow-derived mesenchymal stem cell attenuates skin fibrosis development in mice.

Recent studies showed that mesenchymal stem cell (MSC) transplantation significantly alleviated tissue fibrosis; however, little is known about the efficacy on attenuating cutaneous scar formation. In this study, we established a dermal fibrosis model induced by bleomycin and evaluated the benefit of bone marrow‐derived mesenchymal stem cells (BM‐MSCs) on skin fibrosis development. Tracing assay of green fluorescent protein (GFP+)BM‐MSCs showed that the cells disappeared gradually within 24 hours upon administration, which hinted the action of BM‐MSCs in vivo was exerted in the initial phase of repair in this model. Therefore, we repeatedly transplanted syngeneic BM‐MSCs in the process of skin fibrosis formation. After 3 weeks, it was found that BM‐MSC‐treated lesional skin demonstrated a unanimous basket‐weave organisation of collagen arrangement similar to normal skin, with few inflammatory cells. In addition, lesional skin with BM‐MSC treatment exhibited a significant down‐regulation of transforming growth factor‐β1 (TGF‐β1), type I collagen and heat‐shock protein 47 (HSP47), with higher expression of matrix metalloproteinases (MMPs)‐2, ‐9 and ‐13. Further experiments showed that α‐smooth muscle actin (α‐SMA) positive cells, the most reliable marker of myofibroblasts, apparently decreased after BM‐MSC transplantation, which revealed that BM‐MSCs could attenuate myofibroblast proliferation and differentiation as well as matrix production. Taken together, these findings suggested that BM‐MSCs can inhibit the formation process of bleomycin‐induced skin fibrosis, alleviate inflammation and favour the remodelling of extracellular matrix.

3D bioprinted extracellular matrix mimics facilitate directed differentiation of epithelial progenitors for sweat gland regeneration.

UNLABELLED Sweat glands perform a vital thermoregulatory function in mammals. Like other skin appendages, they originate from epidermal progenitors. However, they have low regenerative potential in response to injury, and whether adult epidermal progenitors could be specified to differentiate to a sweat gland cell lineage remains largely unexplored. We used bioprinting technology to create a functional in vitro cell-laden 3D extracellular matrix mimics (3D-ECM) with composite hydrogels based on gelatin and sodium alginate because of chemical and structural similarity to ECM components. To achieve specific cell differentiation, mouse plantar dermis and epidermal growth factor were synchronously incorporated into the 3D-ECM mimics to create an inductive niche for epidermal progenitor cells obtained from mice. The biological 3D construct could maintain cell viability, thereby facilitating cell spreading and matrix formation. In vitro data by immunofluorescence and gene expression assay of key cell-surface markers demonstrated that the bioprinted 3D-ECM could effectively create a restrictive niche for epidermal progenitors that ensures unilateral differentiation into sweat gland cells. Furthermore, direct delivery of bioprinted 3D-ECM into burned paws of mice resulted in functional restoration of sweat glands. This study represents the rational design to enhance the specific differentiation of epidermal lineages using 3D bioprinting and may have clinical and translational implications in regenerating sweat glands. STATEMENT OF SIGNIFICANCE Sweat gland regeneration after injury is of clinical importance but remains largely unsolved because of low regenerative potential and lack of a definite niche. Some studies have shown sweat gland regeneration with gene-based interventions or cell-based induction via embryonic components, but translation to clinic is challenging. The novelty and significance of the work lies in the fact that we design a 3D bioprinted extracellular matrix that provides the spatial inductive cues for enhancing specific differentiation of epidermal lineages to regenerate sweat glands, which is critical for treating deep burns or other wounds. Our studies are encouraging given the overwhelming advantages of our designed 3D bioprinting construct over other cell delivery technology in maintaining high cell proliferation; another interesting finding is that adult tissue components retain a gland lineage-inductive power as embryonic tissue, which can facilitate translation.

Platelet rich plasma clot releasate preconditioning induced PI3K/AKT/NFκB signaling enhances survival and regenerative function of rat bone marrow mesenchymal stem cells in hostile microenvironments.

Mesenchymal stem cells (MSCs) have been optimal targets in the development of cell based therapies, but their limited availability and high death rate after transplantation remains a concern in clinical applications. This study describes novel effects of platelet rich clot releasate (PRCR) on rat bone marrow-derived MSCs (BM-MSCs), with the former driving a gene program, which can reduce apoptosis and promote the regenerative function of the latter in hostile microenvironments through enhancement of paracrine/autocrine factors. By using reverse transcription-polymerase chain reaction, immunofluorescence and western blot analyses, we showed that PRCR preconditioning could alleviate the apoptosis of BM-MSCs under stress conditions induced by hydrogen peroxide (H2O2) and serum deprivation by enhancing expression of vascular endothelial growth factor and platelet-derived growth factor (PDGF) via stimulation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT/NF-κB signaling pathways. Furthermore, the effects of PRCR preconditioned GFP-BM-MSCs subcutaneously transplanted into rats 6 h after wound surgery were examined by histological and other tests from days 0-22 after transplantation. Engraftment of the PRCR preconditioned BM-MSCs not only significantly attenuated apoptosis and wound size but also improved epithelization and blood vessel regeneration of skin via regulation of the wound microenvironment. Thus, preconditioning with PRCR, which reprograms BM-MSCs to tolerate hostile microenvironments and enhance regenerative function by increasing levels of paracrine factors through PDGFR-α/PI3K/AKT/NF-κB signaling pathways would be a safe method for boosting the effectiveness of transplantation therapy in the clinic.

Umbilical cord-derived mesenchymal stem cells: strategies, challenges, and potential for cutaneous regeneration

Umbilical cord mesenchymal stem cells (MSCs) are a unique, accessible, and non-controversial source of early stem cells that can be readily manipulated. As the most common pluripotent cell, bone marrow-derived MSCs display limitations with the progress of stem cell therapy. By contrast, umbilical cord-derived cells, which have plentiful resources, are more accessible. However, several uncertain aspects, such as the effect of donor selection or culture conditions, long-term therapeutic effects, product consistency, and potential tumorigenicity, are the bottleneck in this clinical therapy. MSCs are predicted to undergo an unprecedented development in clinical treatment when a generally acknowledged criterion emerges. In the current paper, we highlight the application of umbilical cord-derived MSCs in skin therapies based on our previous studies, as well as the achievements of our peers in this field. This paper focuses on the strategies, challenges, and potential of this novel therapy.

Insights into bone marrow-derived mesenchymal stem cells safety for cutaneous repair and regeneration

Wound healing involves the orchestration of a complex process of interactions between numerous types of cell, components of extracellular matrix and signalling molecules following injury, which is usually a highly successful biological course to reconstruct the integrity of the skin. Nevertheless, when skin is severely damaged, the injured skin is limited in its ability to repair itself and possibly results in the hypertrophic scars or so‐called keloids, and non healing wound or ulcer. Bone marrow‐derived mesenchymal stem cells (BM‐MSCs) are being clinically explored as a promising therapy in the field of tissue repair and regeneration. However, potential risks associated with these cell‐based therapies remain uncertain. The aim of this review is to summarise the safety issues accompanying the administration of BM‐MSCs for acute or chronic skin repair and regeneration. More importantly, this review highlights the requirement for fundamental research to improve future clinical application of these strategies, as well as for regulatory authorities to establish clinical criteria to identify the qualitative requirements for the manufacture process of cells products, which will ensure the manufacture process of the best benefit‐to‐risk ratio of cell‐based therapy for the patients.

Paracrine action of mesenchymal stromal cells delivered by microspheres contributes to cutaneous wound healing and prevents scar formation in mice.

BACKGROUND AIMS Accumulating evidence suggests that mesenchymal stromal cells (MSCs) participate in wound healing to favor tissue regeneration and inhibit fibrotic tissue formation. However, the evidence of MSCs to suppress cutaneous scar is extremely rare, and the mechanism remains unidentified. This study aimed to demonstrate whether MSCs-as the result of their paracrine actions on damaged tissues-would accelerate wound healing and prevent cutaneous fibrosis. METHODS For efficient delivery of MSCs to skin wounds, microspheres were used to maintain MSC potency. Whether MSCs can accelerate wound healing and alleviate cutaneous fibrosis through paracrine action was investigated with the use of a Transwell co-culture system in vitro and a murine model in vivo. RESULTS MSCs cultured on gelatin microspheres fully retained their cell surface marker expression profile, proliferation, differentiation and paracrine potential. Co-cultures of MSCs and fibroblasts indicated that the benefits of MSCs on suppressing fibroblast proliferation and its fibrotic behavior induced by inflammatory cytokines probably were caused by paracrine actions. Importantly, microspheres successfully delivered MSCs into wound margins and significantly accelerated wound healing and concomitantly reduced the fibrotic activities of cells within the wounds and excessive accumulation of extracellular matrix as well as the transforming growth factor-β1/transforming growth factor-β3 ratio. CONCLUSIONS This study provides insight into what we believe to be a previously undescribed, multifaceted role of MSC-released protein in reducing cutaneous fibrotic formation. Paracrine action of MSCs delivered by microspheres may thus qualify as a promising strategy to enhance tissue repair and to prevent excessive fibrosis during cutaneous wound healing.

Angiogenic Effect of Mesenchymal Stem Cells as a Therapeutic Target for Enhancing Diabetic Wound Healing

Impaired wound-healing activity in diabetes could result from several factors, including severely damaged angiogenic responses, which can affect wound healing process to cause delayed wound repair. Mesenchymal stem cells (MSCs) have been shown to enhance wound healing via multiple effects, including promoting angiogenesis both in vitro and in vivo; however, the mechanisms involved in enhancing diabetic wound healing are barely understood. This article reviews the recent literatures on MSCs treatment for promoting angiogenesis or vascularization in diabetic wounds and the potential mechanisms involved, with an emphasis on the role of paracrine soluble factors. Meanwhile, the potential benefits and related risks associated with the therapeutic use of MSCs have been presented and may lead to better understanding of the influence of MSCs without increasing potential risks. Further investigation will be required to determine the molecular basis of paracrine mechanisms and regulated angiogenesis of MSCs for its rational manipulation for impaired angiogenesis repair and diabetic wound healing.

Age-associated changes in regenerative capabilities of mesenchymal stem cell: impact on chronic wounds repair

Mesenchymal stem cells (MSCs) represent an ideal source of autologous cell‐based therapy for chronic wounds. Functional characteristics of MSCs may benefit wound healing by exerting their multi‐regenerative potential. However, cell ageing resulting from chronic degenerative diseases or donor age could cause inevitable effects on the regenerative abilities of MSCs. A variety of studies have shown the relationship between MSC ageing and age‐related dysfunction, but few associate these age‐related impacts on MSCs with their ability of repairing chronic wounds, which are common in the elderly population. Here, we discuss the age‐associated changes of MSCs and describe the potential impacts on MSC‐based therapy for chronic wounds. Furthermore, critical evaluation of the current literatures is necessary for understanding the underlying mechanisms of MSC ageing and raising the corresponding concerns on considering their possible use for chronic wound repair.

Paracrine factors from mesenchymal stem cells: a proposed therapeutic tool for acute lung injury and acute respiratory distress syndrome

Despite extensive researches in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), current pharmacological therapies and respiratory support are still the main methods to treat patients with ALI and ARDS and the effects remain limited. Hence, innovative therapies are needed to decrease the morbidity and mortality. Because of the proven therapeutic effects in other fields, mesenchymal stem cells (MSCs) might be considered as a promising alternative to treat ALI and ARDS. Numerous documents demonstrate that MSCs can exert multiple functions, such as engraftment, differentiation and immunoregulation, but now the key researches are concentrated on paracrine factors secreted by MSCs that can mediate endothelial and epithelial permeability, increase alveolar fluid clearance and other potential mechanisms. This review aimed to review the current researches in terms of the effects of MSCs on ALI and ARDS and to analyse these paracrine factors, as well as to predict the potential directions and challenges of the application in this field.

Dissimilar characteristics of umbilical cord mesenchymal stem cells from donors of different ages.

Increasing attention is being placed on the use of adult stem cells due to their potential therapeutic applications for unmet medical needs. Among all adult stem cell types, umbilical cord mesenchymal stem cells (UCMSCs) can be collected easily and does not harm newborns and the mothers. The excellent pluripotency and proliferation potential of UCMSCs has been previously demonstrated by many groups. However, little is known about the different characteristics of these cells due to diversity of donors (e.g., the mothers’ age). Regarding this, we examined the effect of mothers’ age-related variation on the basic properties (proliferation, colony forming and differentiation potential) of UCMSCs in vitro. The data evidenced that elder mother results in reduction of both proliferative and colony forming capacity of UCMSCs, and impacts proliferative potential more significantly. Data also evidenced that a decline in osteogenic potential, but an increase in adipogenic potential of UCMSCs from the elder donors. Additionally, no phenotypic differences were observed by flow cytometry analysis using a panel of 6 main surface antigen markers. We observed no differences in karyotyping and both UCMSCs populations exhibited diploid cells without chromosomal aberrations. The results of our study are the basis for banking UCMSCs, which may be labeled with donors’ information for different experiments, and the mother age-related differences in characteristics of UCMSCs should be taken into account when these cells are considered for further practical applications.