Disrupting mechanotransduction decreases fibrosis and contracture in split-thickness skin grafting

• Published in: Science translational medicine 2022-05, Vol.14 (645), p.eabj9152-eabj9152
• Main Authors: Chen, Kellen, Henn, Dominic, Januszyk, Michael, Barrera, Janos A, Noishiki, Chikage, Bonham, Clark A, Griffin, Michelle, Tevlin, Ruth, Carlomagno, Theresa, Shannon, Tara, Fehlmann, Tobias, Trotsyuk, Artem A, Padmanabhan, Jagannath, Sivaraj, Dharshan, Perrault, David P, Zamaleeva, Alsu I, Mays, Chyna J, Greco, Autumn H, Kwon, Sun Hyung, Leeolou, Melissa C, Huskins, Savana L, Steele, Sydney R, Fischer, Katharina S, Kussie, Hudson C, Mittal, Smiti, Mermin-Bunnell, Alana M, Diaz Deleon, Nestor M, Lavin, Christopher, Keller, Andreas, Longaker, Michael T, Gurtner, Geoffrey C
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Autografts; Biomechanics; Burns - pathology; Cicatrix - pathology; Collagen; Contracture - pathology; CXCL10 protein; Enzyme inhibitors; Fibroblasts; Fibrosis; Focal adhesion kinase; Inflammation; Mechanical properties; Mechanotransduction; Mechanotransduction, Cellular; Mesenchyme; Pigmentation; Skin; Skin & tissue grafts; Skin - pathology; Skin Transplantation - methods; Swine; Transplantation
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.abj9152

Burns and other traumatic injuries represent a substantial biomedical burden. The current standard of care for deep injuries is autologous split-thickness skin grafting (STSG), which frequently results in contractures, abnormal pigmentation, and loss of biomechanical function. Currently, there are no effective therapies that can prevent fibrosis and contracture after STSG. Here, we have developed a clinically relevant porcine model of STSG and comprehensively characterized porcine cell populations involved in healing with single-cell resolution. We identified an up-regulation of proinflammatory and mechanotransduction signaling pathways in standard STSGs. Blocking mechanotransduction with a small-molecule focal adhesion kinase (FAK) inhibitor promoted healing, reduced contracture, mitigated scar formation, restored collagen architecture, and ultimately improved graft biomechanical properties. Acute mechanotransduction blockade up-regulated myeloid CXCL10-mediated anti-inflammation with decreased CXCL14-mediated myeloid and fibroblast recruitment. At later time points, mechanical signaling shifted fibroblasts toward profibrotic differentiation fates, and disruption of mechanotransduction modulated mesenchymal fibroblast differentiation states to block those responses, instead driving fibroblasts toward proregenerative, adipogenic states similar to unwounded skin. We then confirmed these two diverging fibroblast transcriptional trajectories in human skin, human scar, and a three-dimensional organotypic model of human skin. Together, pharmacological blockade of mechanotransduction markedly improved large animal healing after STSG by promoting both early, anti-inflammatory and late, regenerative transcriptional programs, resulting in healed tissue similar to unwounded skin. FAK inhibition could therefore supplement the current standard of care for traumatic and burn injuries.