Transplanted Fibroblasts Prevents Dysfunctional Repair in a Murine CXCR3-Deficient Scarring Model

Abstract

In skin, the regeneration of the ontogenically distinct mesenchymal and epithelial compartments must proceed in a coordinated manner orchestrated by extracellular signaling networks. We have recently found that the switch from regeneration to remodeling during repair is modulated by chemokines that bind CXCR3 receptor. If this signaling is disrupted, wounds continue to be active resulting in a chronic hypercellular and hypertrophic state characterized by an immature matrix composition. As healing is masterminded in large part by fibroblasts and their synthesis of the extracellular matrix, the question arose as to whether this onoging scarring can be modulated by transplanted fibroblasts. We examined wounds in the CXCR3−/− mouse scarring model. These wounds exhibited a significant delay in healing in all areas compared to young and aged wild-type mice. Full-thickness wounds were transplanted with fibroblasts derived from newborn CXCR3−/− or wild-type mice. The transplanted fibroblasts were labeled with fluorescent dye (CM-DiI) and suspended in hyaluronic-acid gel; by 30 days, these transplanted cells comprised some 30% of the dermal stromal cells regardless of the host or source of transplanted cells. Wild-type fibroblasts transplanted into CXCR3−/−mice wounds reversed the delay and dysfunction previously seen in CXCR3−/−wounds; this correction was not noted with transplanted CXCR3−/−fibroblasts. Additionally, transplant of CXCR3−/− cells into wounds in wild-type animals did not adversely affect those wounds. The transplanted fibroblasts exhibited strong survival and migration patterns and led to an increase in tensile-strength. Expression of matrix proteins and collagen in CXCR3−/− wounds transplanted with wild-type fibroblasts resembled normal wild-type healing, and the wound matrix in wild-type mice transplanted with CXCR3−/− cells also presented a mature matrix. These suggest that the major determinant of healing versus scarring lies with the nature of the matrix. These finding have intriguing implications for rational cellular interventions aimed at promoting wound healing via cell-therapy.

The Matrikine Tenascin-C Protects Multipotential Stromal Cells/Mesenchymal Stem Cells from Death Cytokines Such as FasL

“…30 We previously reported that EGF in its soluble form (sEGF) does not promote MSC survival due to the short duration of signaling. 13,15 However, sustained, surface-restricted EGFR signaling by a tEGF construct protects MSCs from FasL induced cell death.…”

Chemokines and Their Receptors Are Key Players in the Orchestra That Regulates Wound Healing

“…These wounds contained the ECM that resembled that of the wild-type mice and healed normally. 176 It has also been shown that CXCL12 is elevated in HTS, and that interactions with its receptor, CXCR4, result in signaling pathways that are involved in the development of HTS by promoting migration of the CD14 + and CXCR4 + cells from the blood circulation into the wound tissue. These cells differentiate into fibrocytes and myofibroblasts, leading to development of HTS.…”

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring

“…Not only did these normal fibroblasts survive within the wound milieu, they had a positive effect on healing, including matrix remodeling, improved collagen alignment, and increased tensile strength. 155 This raises the possibility of using transplanted fibroblasts as cellular therapies to stimulate more functional and regenerative healing responses. 155 Hypertrophic scars are hypercellular due to increased numbers of fibroblasts and recruitment of peripheral nonhematopoietic cells.…”

“…155 This raises the possibility of using transplanted fibroblasts as cellular therapies to stimulate more functional and regenerative healing responses. 155 Hypertrophic scars are hypercellular due to increased numbers of fibroblasts and recruitment of peripheral nonhematopoietic cells. Once again, the recruitment of cells hints at the possible role of chemokines during hypertrophic scar development.…”