Disrupting mechanotransduction decreases fibrosis and contracture in split-thickness skin grafting. Chen, K., Henn, D., Januszyk, M., Barrera, J. A., Noishiki, C., Bonham, C. A., Griffin, M., Tevlin, R., Carlomagno, T., Shannon, T., Fehlmann, T., Trotsyuk, A. A., Padmanabhan, J., Sivaraj, D., Perrault, D. P., Zamaleeva, A. I., Mays, C. J., Greco, A. H., Kwon, S. H., Leeolou, M. C., Huskins, S. L., Steele, S. R., Fischer, K. S., Kussie, H. C., Mittal, S., Mermin-Bunnell, A. M., Deleon, N. M. D., Lavin, C., Keller, A., Longaker, M. T., & Gurtner, G. C. Science Translational Medicine, 14(645):eabj9152, 05, 2022.
Disrupting mechanotransduction decreases fibrosis and contracture in split-thickness skin grafting [link]Paper  doi  abstract   bibtex   1 download  
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. Use of a FAK inhibitor to target mechanotransduction pathways reduces scarring and promotes healing after traumatic injuries requiring skin grafting. Split-thickness skin grafting (STSG) is used to treat deep burns and other traumatic skin injuries. However, STSG is complicated by hypertrophic scar formation, contractures, and potentially loss of biomechanical function. Here, Chen and colleagues developed a porcine model of STSG and, through single-cell RNA sequencing, identified up-regulation of mechanotransduction signaling pathways in the healing grafts. Applying a hydrogel containing a focal adhesion kinase (FAK) inhibitor to the grafts to disrupt mechanotransduction improved healing and reduced contracture and scar formation, with anti-inflammatory effects in the acute setting and proregenerative effects at later time points. These findings suggest that FAK inhibition could be beneficial for treatment of injuries requiring STSG.
@article{scitranslmed.abj9152,
	doi = {10.1126/scitranslmed.abj9152},
	author = {Chen,  Kellen and Henn, Dominic and Januszyk, Michael and Barrera, Janos A. and Noishiki, Chikage and Bonham, Clark A. and Griffin, Michelle and Tevlin, Ruth and Carlomagno, Theresa and Shannon, Tara and Fehlmann, Tobias and Trotsyuk, Artem A. and Padmanabhan, Jagannath and Sivaraj, Dharshan and Perrault, David P. and Zamaleeva, Alsu I. and Mays, Chyna J. and Greco, Autumn H. and Kwon, Sun Hyung and Leeolou, Melissa C. and Huskins, Savana L. and Steele, Sydney R. and Fischer, Katharina S. and Kussie, Hudson C. and Mittal, Smiti and Mermin-Bunnell, Alana M. and Deleon, Nestor M. Diaz and Lavin, Christopher and Keller, Andreas and Longaker, Michael T. and Gurtner, Geoffrey C.},
	title = {Disrupting mechanotransduction decreases fibrosis and contracture in split-thickness skin grafting},
	journal = {Science Translational Medicine},
	volume = {14},
	number = {645},
	pages = {eabj9152},
	month = {05},
	year = {2022},
	doi = {10.1126/scitranslmed.abj9152},
	URL = {https://www.science.org/doi/abs/10.1126/scitranslmed.abj9152},
	eprint = {https://www.science.org/doi/pdf/10.1126/scitranslmed.abj9152},
	abstract = {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. Use of a FAK inhibitor to target mechanotransduction pathways reduces scarring and promotes healing after traumatic injuries requiring skin grafting. Split-thickness skin grafting (STSG) is used to treat deep burns and other traumatic skin injuries. However, STSG is complicated by hypertrophic scar formation, contractures, and potentially loss of biomechanical function. Here, Chen and colleagues developed a porcine model of STSG and, through single-cell RNA sequencing, identified up-regulation of mechanotransduction signaling pathways in the healing grafts. Applying a hydrogel containing a focal adhesion kinase (FAK) inhibitor to the grafts to disrupt mechanotransduction improved healing and reduced contracture and scar formation, with anti-inflammatory effects in the acute setting and proregenerative effects at later time points. These findings suggest that FAK inhibition could be beneficial for treatment of injuries requiring STSG.}
}
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