Adipose-Derived Stem Cell-Seeded Hydrogels Increase Endogenous Progenitor Cell Recruitment and Neovascularization in Wounds

Abstract

Adipose-derived mesenchymal stem cells (ASCs) are appealing for cell-based wound therapies because of their accessibility and ease of harvest, but their utility is limited by poor cell survival within the harsh wound microenvironment. In prior work, our laboratory has demonstrated that seeding ASCs within a soft pullulancollagen hydrogel enhances ASC survival and improves wound healing. To more fully understand the mechanism of this therapy, we examined whether ASC-seeded hydrogels were able to modulate the recruitment and/ or functionality of endogenous progenitor cells. Employing a parabiosis model and fluorescence-activated cell sorting analysis, we demonstrate that application of ASC-seeded hydrogels to wounds, when compared with injected ASCs or a noncell control, increased the recruitment of provascular circulating bone marrow-derived mesenchymal progenitor cells (BM-MPCs). BM-MPCs comprised 23.0% of recruited circulating progenitor cells in wounds treated with ASC-seeded hydrogels versus 8.4% and 2.1% in those treated with controls, p < 0.05. Exploring the potential for functional modulation of BM-MPCs, we demonstrate a statistically significant increase in BM-MPC migration, proliferation, and tubulization when exposed to hydrogel-seeded ASCconditioned medium versus control ASC-conditioned medium (73.8% vs. 51.4% scratch assay closure; 9.1% vs. 1.4% proliferation rate; 10.2 vs. 5.5 tubules/HPF; p < 0.05 for all assays). BM-MPC expression of genes related to cell stemness and angiogenesis was also significantly increased following exposure to hydrogel-seeded ASCconditioned medium ( p < 0.05). These data suggest that ASC-seeded hydrogels improve both progenitor cell recruitment and functionality to effect greater neovascularization.

Analysis of Cell-seeded, Collagen-rich Hydrogel for Wound Healing

“…Previous studies have shown the ability of ADSCs to enhance wound healing when seeded into hydrogels, with increased angiogenesis and proliferation compared with nonseeded scaffolds. 18 , 19 Our histologic and immunohistochemical analyses of cHG show similar results. cHG-treated wounds had significantly decreased wound length, increased collagen production, enhanced angiogenesis, and accelerated cell proliferation compared with control.…”

Precise Intradermal Injection of Nanofat-Derived Stromal Cells Combined with Platelet-Rich Fibrin Improves the Efficacy of Facial Skin Rejuvenation

“…ASCs have outstanding self-renewal potential, paracrine function, and the capacity to differentiate into multiple phenotypes. Some data have suggested the application of ASCs in lesions induces healing because of the role of ASCs in stimulating angiogenesis, which is attributed to their endothelial differentiation and release of several cytokines under specific conditions [21-24]. …”

Black, White, and Gray: Macrophages in Skin Repair and Disease

“…Use of topical stem cell therapies that can release growth factors and modulate macrophage responses is one strategy 98 . In addition to modulating the immune response, stem cell-based therapies are associated with a myriad of benefits including improvement of neovascularization by influencing endothelial cells, promoting ECM deposition by influencing fibroblasts and increasing recruitment of progenitor cells into wounds 99,100 .…”