Disrupting mechanotransduction decreases fibrosis and contracture in split-thickness skin grafting.
Kellen ChenDominic HennMichael JanuszykJanos A BarreraChikage NoishikiClark A BonhamMichelle F GriffinRuth TevlinTheresa CarlomagnoTara ShannonTobias FehlmannArtem A TrotsyukJagannath PadmanabhanDharshan SivarajDavid P PerraultAlsu I ZamaleevaChyna J MaysAutumn H GrecoSun Hyung KwonMelissa C LeeolouSavana L HuskinsSydney R SteeleKatharina S FischerHudson C KussieSmiti MittalAlana M Mermin-BunnellNestor M Diaz DeleonChristopher LavinAndreas KellerMichael T LongakerGeoffrey C GurtnerPublished in: Science translational medicine (2022)
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.
Keyphrases
- wound healing
- single cell
- bone marrow
- small molecule
- stem cells
- cell therapy
- spinal cord injury
- soft tissue
- healthcare
- transcription factor
- palliative care
- gene expression
- anti inflammatory
- signaling pathway
- endothelial cells
- quality improvement
- acute myeloid leukemia
- liver failure
- mesenchymal stem cells
- dendritic cells
- depressive symptoms
- public health
- rna seq
- staphylococcus aureus
- pain management
- cystic fibrosis
- epithelial mesenchymal transition
- drug induced
- extracellular matrix
- cell proliferation
- liver fibrosis
- pi k akt
- breast reconstruction
- pseudomonas aeruginosa
- protein kinase
- endoplasmic reticulum stress
- pluripotent stem cells
- heat stress