Abstract
BackgroundTransplantation of mesenchymal stem cells (MSC) has been proposed to improve wound healing. However, as these cells only transiently survive in the implantation site, the mechanisms underlying this beneficial healing response are associated with restorative paracrine effects of MSC matricellular factors on resident stromal cells. However, this requires that the recipient has a robust reservoir of viable cells. Here, we examine the influence of MSCs on the behavior of cotransplanted fibroblasts, in a manner to provide augmented cellular reserve to debilitated individuals, specifically focusing on matrix remodeling following in-vivo wounding.MethodsUsing a Hylan-A dermal filler hydrogel containing collagen I and tenascin-C for delivery and increased survival of transplanted cells, we find that cotransplantation of MSCs with fibroblasts reduces scarring.ResultsTransplanted xenogeneic MSCs augmented fibroblast proliferation, migration, and extracellular matrix deposition critical for wound closure, and reduced inflammation following wounding. MSCs also corrected matrix remodeling by CXCR3-deficient fibroblasts which otherwise led to hypertrophic scarring. This effect was superior to MSC or fibroblast transplantation alone.ConclusionsTaken together, these data suggest that MSCs, even if eventually rejected, transplanted with fibroblasts normalize matrix regeneration during healing. The current study provides insight into cellular therapies as a viable method for antifibrotic treatment and demonstrates that even transiently engrafted cells can have a long-term impact via matrix modulation and education of other tissue cells.
Highlights
Transplantation of mesenchymal stem cells (MSC) has been proposed to improve wound healing
We evaluated in vitro the MSC + fibroblast coculture cell morphology, viability, proliferation, and migration in response to growth factor and chemokine stimulation
A transwell coculture wound assay [19, 27] was used in which MSCs in the collagen–tenascin-C incorporated hydrogel matrix system were seeded in the top insert and stimulated with CXCR3 ligand IP-9, and fibroblasts were seeded in the bottom wells
Summary
Transplantation of mesenchymal stem cells (MSC) has been proposed to improve wound healing As these cells only transiently survive in the implantation site, the mechanisms underlying this beneficial healing response are associated with restorative paracrine effects of MSC matricellular factors on resident stromal cells. Preclinical studies aiming for tissue generation have been thwarted by very low homing efficacy, poor long-term engraftment, and a limited capacity for differentiation of MSCs once transplanted in vivo [13, 14] This has led to the focus of MSC therapy shifting from replacement to the trophic (‘cytokine factories’), and possibly immunological effects of these cells [15, 16]. The effectiveness of transplanting either of these cell types on wound healing has been less than anticipated due in part to the limited persistence in the wound bed and intrinsic functioning that is dysregulated from the orchestrated progression of physiologic healing
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