Adipose Stromal Cells Repair Pressure Ulcers in Both Young and Elderly Mice: Potential Role of Adipogenesis in Skin Repair

Abstract

More than 2.5 million patients in the U.S. require treatment for pressure ulcers annually, and the elderly are at particularly high risk for pressure ulcer development. Current therapy for pressure ulcers consists of conservative medical management for shallow lesions and aggressive debridement and surgery for deeper lesions. The current study uses a murine model to address the hypothesis that adipose-derived stromal/stem cell (ASC) treatment would accelerate and enhance pressure ulcer repair. The dorsal skin of both young (2 months old [mo]) and old (20 mo) C57BL/6J female mice was sandwiched between external magnets for 12 hours over 2 consecutive days to initiate a pressure ulcer. One day following the induction, mice were injected with ASCs isolated from congenic mice transgenic for the green fluorescent protein under a ubiquitous promoter. Relative to phosphatebuffered saline-treated controls, ASC-treated mice displayed a cell concentration-dependent acceleration of wound closure, improved epidermal/dermal architecture, increased adipogenesis, and reduced inflammatory cell infiltration. The ASC-induced improvements occurred in both young and elderly recipients, although the expression profile of angiogenic, immunomodulatory, and reparative mRNAs differed as a function of age. The results are consistent with clinical reports that fat grafting improved skin architecture in thermal injuries; the authors of this published study have invoked ASC-based mechanisms to account for their clinical outcomes. Thus, the current proof-of-principle study sets the stage for clinical translation of autologous and/or allogeneic ASC treatment of pressure ulcers. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:632-642 SIGNIFICANCE Adipose-derived stromal/stem cells (ASCs) promote the healing of pressure ulcer wounds in both young and old mice. ASCs enhance wound healing rates through adipogenic differentiation and regeneration of the underlying architecture of the skin.

Fibrin‐based stem cell containing scaffold improves the dynamics of burn wound healing

“…We performed immunohistochemical analysis of burn wounds 7 days after initial injury to quantify the number of blood vessels (≥ 20 μm in diameter) in the regenerating tissue (Figure ). Consistent with existing literature on cutaneous ASCs therapies and our previous findings, ASCs delivery within P‐fibrin scaffold leads to enhanced local angiogenesis of the regenerating burn wound. This finding is not surprising, given the ability of ASCs to persist in the wound area for up to two weeks and their pro‐angiogenic/granulation tissue promoting secretory profile after culture in P‐fibrin gel (Supporting Information Figure 2) and in response to cytokines in burn wound exudates …”

“…To quantify infiltrating mononuclear cells we have used color deconvolution followed by quantification of the dark purple stain. 17 According to our data, P-fibrin treated groups exhibited significant increases in wound cellularity at 7 days post injury. These data are consistent with the known ability of thrombin and fibrinogenderived peptides to recruit monocytes and macrophages.…”

“…Histological analysis of regenerating burn wounds on day 7 showed a significant increase in wound thickness after P‐fibrin wound treatment, independent of ASCs presence (Figure A). To quantify infiltrating mononuclear cells we have used color deconvolution followed by quantification of the dark purple stain . According to our data, P‐fibrin treated groups exhibited significant increases in wound cellularity at 7 days post injury.…”

Human Adipose-Derived Hydrogel Characterization Based on In Vitro ASC Biocompatibility and Differentiation

“…Thereafter, they were cultured in adipogenic media (AdipoQual™; LaCell LLC; New Orleans, LA; n = 3), and osteogenic media (10 nM dexamethasone, 20 mM β-glycerophosphate, and 50 μM L-ascorbic acid; n = 3) for 28 days, with the media being replaced every 2-3 days. Adipogenic and osteogenic differentiations were assessed by Oil Red O and Alizarin Red staining, respectively, according to previously described methods [31,32].…”

Stem Cells and Tissue Engineering

“…The application of ASCs in wound repair and tissue regeneration has been shown in a number of experimental models both in vitro and in vivo (62). Application of ASCs significantly accelerated the re-epithelialization of cutaneous wounds by promoting human dermal fibroblast proliferation through direct cell-cell contact or through paracrine secretion of a variety of growth factors including bFGF and TGF-β (63, 64). Furthermore, these ASCs differentiate into adipocytes to provide a supportive architecture for dermal regeneration and re-epithelialization (65).…”