Improved Transplanted Stem Cell Survival in a Polymer Gel Supplemented with Tenascin C Accelerates Healing and Reduces Scarring of Murine Skin Wounds

Abstract

Mesenchymal stem cells remain of great interest in regenerative medicine due to their ability to home to sites of injury, differentiate into a variety of relevant lineages, and modulate inflammation and angiogenesis through paracrine activity. Many studies have found that despite the great promise of MSC therapy, cell survival upon implant is highly limited and greatly reduces the therapeutic utility of MSCs. The matrikine Tenascin C, a protein expressed often at the edges of a healing wound, contains unique EGF-like repeats that are able to bind EGFR at low affinity and induce downstream pro-survival signaling without inducing receptor internalization. In this study, we utilized Tenascin C in a collagen/GAG-based polymer (Tpolymer) for skin wound healing, incorporating human MSCs into the polymer prior to application to mouse punch biopsy wound beds. We found that the TPolymer was able to promote MSC survival out to 21 days in vivo, leading to associated improvements in wound healing such as dermal maturation and collagen content. This was most marked in a model of hypertrophic scarring, in which the scar formation was limited. This approach also reduced the inflammatory response in the wound bed, limiting CD3e+ cell invasion by approximately 50% in the early wound healing process, while increasing the numbers of endothelial cells during the first week of wound healing as well. Ultimately, this matrikine-based approach to improving MSC survival may be of great use across a variety of cell therapies utilizing matrices as delivery vehicles for cells.

Connexin 43 Hemichannels Regulate the Expression of Wound Healing-Associated Genes in Human Gingival Fibroblasts

“…Thus, in cultures of human GFBLs where the cells possess functional Cx43 GJs and HCs, the blocking of Cx43 HC function and ATP signaling by Cx43 mimetic peptides causes a robust ERK1/2-dependent change in the expression of a set of wound healing-associated genes. These changes include significant upregulation of MMPs (MMP-1, -3, and -10) that modulate inflammation and tissue remodeling 66 , 67 , TN-C that regulates cell migration and suppresses fibrosis 68 , and VEGF-A that promotes angiogenesis 69 , and downregulation of Collagen type I, α-SMA and NMMIIB that are associated with fibrosis 70 . Thus, the inhibition of Cx43 HC-dependent ATP signaling by Cx43 HC-specific blocking peptides may be used to promote a gene expression response that may be beneficial for fast and scarless wound healing.…”

PF-127 hydrogel plus sodium ascorbyl phosphate improves Wharton’s jelly mesenchymal stem cell-mediated skin wound healing in mice

“…Tissue engineering-based strategy demonstrates that the utilization of biomaterial-based scaffolds as stem cell delivery and retention platforms can enhance the therapeutic efficiency of stem cells on wound regeneration [14][15][16]. Pluronic F-127 (PF-127, also known as poloxamer 407), a FDA-approved synthetic copolymer made of poly (ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide), is injectable, biodegradable, and thermo-reversible [17,18].…”

Precise cell behaviors manipulation through light-responsive nano-regulators: recent advance and perspective

“…In the human body, extracellular matrix (ECM) and several cues modulate cell-cell communication and the interactions of the cell with the surrounding fluids, which in turn monitor stem cell fates consisting of viability, proliferation and differentiation. Thus, scaffolds that mimic nature topography-related cues with similar chemical and physical properties including size, morphology, surface roughness represent noticeably powerful platforms for tissue engineering and regenerative medicine 125, 126. With respect to this direction, various scaffolds and nanomaterials have been constructed to act as either stem cell culture matrixes or biophysical cues for stem cell differentiation in diverse lineages which possibly produce promising clinical implications for organ (e.g., liver, kidney, lung, etc.)…”