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The skin regeneration potential of a pro-angiogenic secretome from human skin-derived multipotent stromal cells.

ABSTRACT: Multipotent stromal cells stimulate skin regeneration after acute or chronic injuries. However, many stem cell therapy protocols are limited by the elevated number of cells required and poor cell survival after transplantation. Considering that the beneficial effects of multipotent stromal cells on wound healing are typically mediated by paracrine mechanisms, we examined whether the conditioned medium from skin-derived multipotent stromal cells would be beneficial for restoring the skin structure of mice after wounding. A proteomic characterization of skin-derived multipotent stromal cell-conditioned medium was performed, and the angiogenic function of this secretome was investigated in vitro using an endothelial cell tube formation assay. We then applied the skin-derived multipotent stromal cell-conditioned medium directly to full-thickness excisional wounds or embedded it into carrageenan or poly(vinyl alcohol) hydrogels to monitor tissue regeneration in mice. Biological processes related to wound healing and angiogenesis were highlighted by the analysis of the skin-derived multipotent stromal cell secretome, and a pro-angiogenic capacity for promoting tubule-like structures was first confirmed in vitro. Skin wounds treated with skin-derived multipotent stromal cell-conditioned medium also displayed increased angiogenesis, independently of the association of the conditioned medium with hydrogels. However, improvements in wound closure and epidermis or decreased inflammatory cell presence were not observed. Hence, the use of the secretome obtained from human skin-derived multipotent stromal cells may be a potential strategy to aid the natural skin repair of full-thickness lesions mainly based on its pro-angiogenic properties.

SUBMITTER: Robert AW

PROVIDER: S-EPMC6415469 | biostudies-literature | 2019 Jan-Dec

REPOSITORIES: biostudies-literature

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The skin regeneration potential of a pro-angiogenic secretome from human skin-derived multipotent stromal cells.

Robert Anny Waloski AW Azevedo Gomes Felipe F Rode Michele Patricia MP Marques da Silva Maiara M Veleirinho Maria Beatriz da Rocha MBDR Maraschin Marcelo M Hayashi Leila L Wosgrau Calloni Giordano G Stimamiglio Marco Augusto MA

Journal of tissue engineering 20190101

Multipotent stromal cells stimulate skin regeneration after acute or chronic injuries. However, many stem cell therapy protocols are limited by the elevated number of cells required and poor cell survival after transplantation. Considering that the beneficial effects of multipotent stromal cells on wound healing are typically mediated by paracrine mechanisms, we examined whether the conditioned medium from skin-derived multipotent stromal cells would be beneficial for restoring the skin structur ...[more]

PMID: 30886688

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Project description:BackgroundMultipotent stem cells have been successfully isolated from various tissues and are currently utilized for tissue-engineering and cell-based therapies. Among the many sources, skin has recently emerged as an attractive source for multipotent cells because of its abundance. Recent literature showed that skin stromal cells (SSCs) possess mesoderm lineage differentiation potential; however, the endothelial differentiation and angiogenic potential of SSC remains elusive. In our study, SSCs were isolated from human neonatal foreskin (hNFSSCs) and adult dermal skin (hADSSCs) using explants cultures and were compared with bone marrow (hMSC-TERT) and adipose tissue-derived mesenchymal stem cells (hADMSCs) for their potential differentiation into osteoblasts, adipocytes, and endothelial cells.ResultsConcordant with previous studies, both MSCs and SSCs showed similar morphology, surface protein expression, and were able to differentiate into osteoblasts and adipocytes. Using an endothelial induction culture system combined with an in vitro matrigel angiogenesis assay, hNFSSCs and hADSSCs exhibited the highest tube-forming capability, which was similar to those formed by human umbilical vein endothelial cells (HUVEC), with hNFSSCs forming the most tightly packed, longest, and largest diameter tubules among the three cell types. CD146 was highly expressed on hNFSSCs and HUVEC followed by hADSSCs, and hMSC-TERT, while its expression was almost absent on hADMSCs. Similarly, higher vascular density (based on the expression of CD31, CD34, vWF, CD146 and SMA) was observed in neonatal skin, followed by adult dermal skin and adipose tissue. Thus, our preliminary data indicated a plausible relationship between vascular densities, and the expression of CD146 on multipotent cells derived from those tissues.ConclusionsOur data is the first to demonstrate that human dermal skin stromal cells can be differentiated into endothelial lineage. Hence, SSCs represents a novel source of stem/stromal cells for tissue regeneration and the vascularization of engineered tissues. Moreover, the CD146 investigations suggested that the microenvironmental niche might contribute to direct stromal cells multipotency toward certain lineages, which warrants further investigation.

Project description:BackgroundHuman multipotent progenitor cells (hiMPCs) created from induced pluripotent stem cells (iPSCs) represent a new cell source for cartilage regeneration. In most studies, bone morphogenetic proteins (BMPs) are needed to enhance transforming growth factor-β (TGFβ)-induced hiMPC chondrogenesis. In contrast, TGFβ alone is sufficient to result in robust chondrogenesis of human primary mesenchymal stromal cells (hMSCs). Currently, the mechanism underlying this difference between hiMPCs and hMSCs has not been fully understood.MethodsIn this study, we first tested different growth factors alone or in combination in stimulating hiMPC chondrogenesis, with a special focus on chondrocytic hypertrophy. The reparative capacity of hiMPCs-derived cartilage was assessed in an osteochondral defect model created in rats. hMSCs isolated from bone marrow were included in all studies as the control. Lastly, a mechanistic study was conducted to understand why hiMPCs and hMSCs behave differently in responding to TGFβ.ResultsChondrogenic medium supplemented with TGFβ3 and BMP6 led to robust in vitro cartilage formation from hiMPCs with minimal hypertrophy. Cartilage tissue generated from this new method was resistant to osteogenic transition upon subcutaneous implantation and resulted in a hyaline cartilage-like regeneration in osteochondral defects in rats. Interestingly, TGFβ3 induced phosphorylation of both Smad2/3 and Smad1/5 in hMSCs, but only activated Smad2/3 in hiMPCs. Supplementing BMP6 activated Smad1/5 and significantly enhanced TGFβ's compacity in inducing hiMPC chondrogenesis. The chondro-promoting function of BMP6 was abolished by the treatment of a BMP pathway inhibitor.ConclusionsThis study describes a robust method to generate chondrocytes from hiMPCs with low hypertrophy for hyaline cartilage repair, as well as elucidates the difference between hMSCs and hiMPCs in response to TGFβ. Our results also indicated the importance of activating both Smad2/3 and Smad1/5 in the initiation of chondrogenesis.

Dataset Information

The skin regeneration potential of a pro-angiogenic secretome from human skin-derived multipotent stromal cells.

Publications

The skin regeneration potential of a pro-angiogenic secretome from human skin-derived multipotent stromal cells.

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