Grant: DRA: Canada Impact+ Research Training Awards - Doctoral

"Severe hypertrophic skin scarring, e.g., resulting from large area burns, reduces patients' quality of life. Scarring can be lessened with adult donor-derived therapeutic MSCs, which avoid immune rejection and regenerate connective tissues. Current therapies must expand biopsied MSCs on rigid culture plastic surfaces, e.g., bioreactor beads. Culture on rigid surfaces activates MSCs into myofibroblasts (MFs), which produce excess scar collagen. Transplanting MF-MSCs risks exacerbating rather than reducing scarring. By pre-culturing MSCs on silicone substrates with the softness of normal skin, the Hinz lab suppressed MF activation. Soft-grown MSCs improved skin healing in a rodent model of hypertrophic scarring. Using RNA sequencing, they identified the transcription factor Sall1 specifically upregulated in soft-grown MSCs. Sall1 knockdown increased MSC-to-MF activation on soft surfaces, while Sall1 overexpression (OE) suppressed MF activation on stiff surfaces. Searching for anti-fibrotic effectors produced by Sall1-OE MSCs identified the B-type natriuretic peptide (BNP). Secreted BNP has anti-scarring effects in the heart, but it is unstable, and its role in the skin is unknown. We hypothesize that delivery of BNP via soft-grown and/or Sall1-OE MSCs will reduce skin scarring. We aim to: (1) identify the downstream mechanisms of BNP resulting in skin scar suppression, (2) determine mechanisms enhancing BNP expression through Sall1, and (3) compare the potential of BNP-overexpressing MSCs with recombinant BNP in reducing hypertrophic skin scarring in wounded animals. We propose that the continued supply of BNP by MSCs, together with their known regenerative functions, will be superior in supporting scarless healing compared with the delivery of rapidly degraded BNP alone."