Background: Transplantation of mesenchymal stem cells (MSC) has been proposed to improve wound healing. However,\nas these cells only transiently survive in the implantation site, the mechanisms underlying this beneficial healing response\nare associated with restorative paracrine effects of MSC matricellular factors on resident stromal cells. However, this requires\nthat the recipient has a robust reservoir of viable cells. Here, we examine the influence of MSCs on the behavior\nof cotransplanted fibroblasts, in a manner to provide augmented cellular reserve to debilitated individuals, specifically\nfocusing on matrix remodeling following in-vivo wounding.\nMethods: Using a Hylan-A dermal filler hydrogel containing collagen I and tenascin-C for delivery and increased survival\nof transplanted cells, we find that cotransplantation of MSCs with fibroblasts reduces scarring.\nResults: Transplanted xenogeneic MSCs augmented fibroblast proliferation, migration, and extracellular matrix deposition\ncritical for wound closure, and reduced inflammation following wounding. MSCs also corrected matrix remodeling by\nCXCR3-deficient fibroblasts which otherwise led to hypertrophic scarring. This effect was superior to MSC or fibroblast\ntransplantation alone.\nConclusions: Taken together, these data suggest that MSCs, even if eventually rejected, transplanted with fibroblasts\nnormalize matrix regeneration during healing. The current study provides insight into cellular therapies as a viable\nmethod for antifibrotic treatment and demonstrates that even transiently engrafted cells can have a long-term impact\nvia matrix modulation and education of other tissue cells.
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