Transplantation of BMSCs expressing hPDGF-A/hBD2 promotes wound healing in rats with combined radiation-wound injury.


The aim of this study was to test the efficacy of transplantation of ...
The aim of this study was to test the efficacy of transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) expressing human platelet-derived growth factor A (hPDGF-A) and human beta-defensin2 (hBD2) in accelerating wound healing of combined radiation-wound injury. Recombinant adenovirus vector simultaneously expressing hPDGF-A and hBD2 was constructed and packaged into virus particles that were used to infect rat BMSCs. The expressions of the exogenous in BMSCs were determined by reverse transcriptase (RT)-PCR and western -blot, whereas the functions were determined by cell counting kit (CCK), wound-healing assay on monolayer cells and Kleihauer-Betke (K-B) test. The recombinant adenovirus-infected BMSCs (1 x 10(7)) were subcutaneously transplanted into the wound bed and wound healing was observed for the indicated duration. Rats with combined total body ionizing radiation (6 Gy) and full-thickness skin excision (2% of total body surface area) wound injury were treated with normal BMSCs (group N), BMSCs infected with recombinant adenovirus expressing hPDGF-A and hBD2 (group T) or phosphate-buffered saline (PBS) (group S). The mean wound healing time, percentage of residual wound area (n=8), blind pathological observation (n=3 per time point for each group) and the amount of bacteria under the scar (the same sample was used in the pathological study, n=3) were used for evaluating wound healing. Collagen was visualized by Sirius red staining. Exogenous hPDGF-A and hBD2 were expressed in BMSCs as indicated by RT-PCR and western blot. Faster wound healing of scratched monolayer cells was demonstrated in hPDGF-A/hBD2 gene-modified BMSCs (T-MSCs) when compared with the corresponding control (P<0.01), and conditioned culture medium from T-MSCs showed stimulative effect on BMSC proliferation and in vitro antibiotic effect in the presence of trypsin. Neutralizing antibody interfering in vitro demonstrated that secreted hPDGF-A was the main factor stimulating cell proliferation. In an in vivo test, the radiation-wound combined injury exhibited shorter healing time (21 days). Histologically, there was better granulation formation/maturation and skin-dependent regeneration, as well as more collagen deposition (P<0.01) in rats of group T than in other groups. The deposition and remodeling of collagen in wounds were ranked in the following order: group T>group N>group S. Significantly less bacterial colony formation in the cultured under-scar samples in the rats of group T was observed (P<0.01) at day 7 and thereafter when compared with control. After transplantation, the BMSCs expressed exogenous genes in the wound for at least 2 weeks, as indicated by the reporter gene. Topical transplantation of gene-modified BMSCs promoted wound healing, which may be the benefit of the secretion of antibacterial hBD2 and mitogenic hPDGF-A, resulting in better granulation formation/maturation and skin appendage regeneration in wound. These data demonstrated the potential application of this combination of cell therapy and gene therapy on refractory wound healing.




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