Mesenchymal Stem Cell/Multipotent Stromal Cell Augmentation of Wound Healing: Lessons from the Physiology of Matrix and Hypoxia Support

Cutaneous wounds requiring tissue replacement are often challenging to treat and result in substantial economic burden. Many of the challenges inherent to therapy-mediated healing are due to comorbidities of disease and aging that render many wounds as chronic or nonhealing. Repeated failure to resolve chronic wounds compromises the reserve or functioning of localized reparative cells. Transplantation of mesenchymal stem cells/multipotent stromal cells (MSCs) has been proposed to augment the reparative capacity of resident cells within the wound bed to overcome stalled wound healing. However, MSCs face a variety of challenges within the wound micro-environment that curtail their survival after transplantation. MSCs are naturally pro-angiogenic and proreparative, and thus numerous techniques have been attempted to improve their survival and efficacy after transplantation, many with little impact. These setbacks have prompted researchers to re-examine the normal wound bed physiology, resulting in new approaches to MSC transplantation using extracellular matrix proteins and hypoxia preconditioning. These studies have also led to new insights on associated intracellular mechanisms, particularly autophagy, which play key roles in further regulating MSC survival and paracrine signaling. This review provides a brief overview of cutaneous wound healing with discussion on how extracellular matrix proteins and hypoxia can be utilized to improve MSC retention and therapeutic outcome.