Grant: Operating Grant

After severe skin injury such as burns, our body rapidly but imperfectly repairs the damage, leaving behind a stiff scar. Scarring is a clinical burden because skin is losing vital functions. During normal repair, local fibroblasts are activated into myofibroblasts (MFs) to secrete and organize large amounts of fibrous collagen by exerting strong pulling forces. This action is beneficial since it prevents our tissues from breaking but it leads to scarring when the repair demands of our body exceed its regenerative potential. To support healing and to regenerate damaged organs, adult mesenchymal stromal/stem cells (MSCs) have entered clinical trials. MSCs retain the capability to differentiate into different specialized cells (e.g., skin, cartilage, bone) and truly regenerate organs. MSCs can be obtained from bone marrow biopsies, expanded in cell culture and re-transplanted to the same patient. Pivotal cell culture expansion activates MSCs into MFs. It is unclear whether MF-MSCs are beneficial or detrimental for skin repair and regeneration. We hypothesize that becoming MF will influence the capacity of MSCs to regenerate the dermis of injured skin. We will induce and suppress MF activation to test the effect on MSC pluripotency and to assess whether the MF is a terminal or transient state of the MSC. We will use innovative soft culture substrates to suppress MF activation of MSCs. We will analyze genetic changes (epigenetics) resulting from soft substrate culture to decipher the mechanism of this mechanical memory. In mouse experimental models, mechanically primed MSCs will be transplanted into normally healing and fibrotic wounds to test their impact on the repair process. In co-cultures with fibroblasts, we will reveal the mechanistic cross-talk between primed and fibrotic MSCs and the local repair cells of the body. Understanding and controlling the mechanisms of MSC fibrogenesis will augment the success rate of tissue regeneration therapies using MSCs.