Matricellular protein Tenascin-C enhances mesenchymal stem cell angiogenic and wound healing efficacy under ischemic conditions.

Human mesenchymal stem cells/multipotent stromal cells (MSCs) hold great promise in aiding wound healing through their ability to modulate all phases of repair and regeneration, most notably their secretion of pro-regenerative paracrine factors. However, MSC clinical utility is hindered by poor survival rates post-transplantation due to the harsh microenvironment in injured tissue. Previous work has shown that the matricellular protein Tenascin-C (TNC) provides survival signaling to MSCs via the epidermal growth factor receptor by restricting its activation at the plasma membrane, resulting in enhanced prosurvival signals. Herein, we investigate how TNC influences MSC survival and MSC-mediated promotion of the wound healing process. This study examined the survival and angiogenic potential of MSCs cultured on TNC-coated surfaces under ischemic duress in vitro. We also assessed the angiogenic and wound healing outcomes of MSC + TNC in vivo using a CXCR3-/- mouse model that exhibits a delayed healing phenotype within the tissue replacement phase of repair. We found that MSCs in the presence of TNC exhibit higher levels of angiogenic-promoting processes, collagen maturation, and an overall better wound healing outcome than MSCs administered alone. This was seen in vitro in terms of enhanced tube formation. In vivo, the MSCs in the presence of TNC stabilized with a coacervate delivery system resulted in more regenerative wounds with accelerated maturation of the dermis. These findings suggest the coupling of TNC to MSCs as a promising tool for future MSC-ECM combinatorial therapies for wound healing applications.

The matricellular protein decorin delivered intradermally with coacervate improves wound resolution in the CXCR3-deficient mouse model of hypertrophic scarring.

Cutaneous wound healing is an intricate orchestration of three overlapping phases of repair that encompass numerous cell types, signalling cascades, and microenvironment modifications to reach a successful resolution. Disruption of any of these steps will create an abnormal healing response resulting in either ulceration or excessive scarring. It has become evident that the extracellular matrix and its associated components are key orchestrators during this process. One of these essential matrix proteins is decorin, a small leucine-rich proteoglycan (SLRP) that acts as a regulator of collagen fibrillogenesis and a non-competitive inhibitor of multiple growth factors signalling cascades. Decorin is a necessary shut-off switch for the pro-reparative mechanism of the tissue replacement phase and limits the occurrence of hypertrophic scarring by preventing excessive repair. We investigated the use of decorin as a therapeutic by administering the matrix protein anchored in a slow-release coacervate in a hypertrophic scarring mouse model. The results show that early wound healing phase measurements exhibit little difference in performance compared to our coacervate-only baseline or HB-EGF-treated control mice. However, during the resolution phase of wound healing, the decorin-treatment significantly reduces cutaneous thickness, enhances collagen alignment, and improves overall wound scoring in the mice. Thus, mice treated with decorin display better healing outcomes and could limit the hypertrophic scarring phenotype in the coacervate only, and HB-EGF controls. These results suggest that decorin may be a promising tool and alternative therapy for patients who suffer from over-exuberant matrix deposition during wound healing.