Richardson, W. J. | Search bioRxiv

bioRxiv2020

The Connexin 43 Carboxyl Terminal Mimetic Peptide alphaCT1 Prompts Differentiation of a Collagen Scar Matrix Resembling Unwounded Skin

Phase II clinical trials have reported that acute treatment of surgical skin wounds with the therapeutic peptide αCT1 improves cutaneous scar appearance by 47% 9-months post-surgery – though mode-of-action remains unknown. Scar matrix structure in biopsies 2 to 6 weeks post-wounding treated topically with αCT1 or control treatments from human subjects, Sprague-Dawley rats, and IAF hairless guinea pigs were compared. The sole effect on scar structure in humans was that αCT1-treated scars had less alignment of collagen fibers relative to control wounds, a state that resembles unwounded skin. This more random alignment was recapitulated in both animal models, together with transient increases in collagen density, although the guinea pig was found to more closely replicate the pattern of response to αCT1 in human scars, compared to rat. Fibroblasts treated with αCT1 in vitro showed decreased directionality and an agent-based computational model parameterized with fibroblast motility data predicted collagen alignments in simulated scars consistent with that observed experimentally in human and the animal models. In conclusion, αCT1 prompts decreased directionality of fibroblast movement and the generation of a 3D collagen matrix post-wounding that is similar to unwounded skin – changes that correlate with long-term improvement in scar appearance.Competing Interest StatementGSG is CEO and President of FirstString Research Inc. CLG is Senior Director of Research and Development at FirstString Research Inc. RGG is a non-remunerated member of the Scientific Advisory Board of FirstString Research, which licensed α carboxyl terminus 1 peptide. GSG, RGG, LJJ, and CLG have ownership interests in FirstString Research Inc. The remaining authors have no disclosures to report.View Full Text

cell biology↗

bioRxiv2020

Mechano-Chemo Signaling Interactions Modulate Matrix Production by Cardiac Fibroblasts

Extracellular matrix remodeling after myocardial infarction occurs in a dynamic environment in which local mechanical stresses and biochemical signaling species stimulate the accumulation of collagen-rich scar tissue. It is well-known that cardiac fibroblasts regulate post-infarction matrix turnover by secreting matrix proteins, proteases, and protease inhibitors in response to both biochemical stimuli and mechanical stretch, but how these stimuli act together to dictate cellular responses is still unclear. We developed a screen of cardiac fibroblast-secreted proteins in response to combinations of biochemical agonists and cyclic uniaxial stretch in order to elucidate the relationships between stretch, biochemical signaling, and cardiac matrix turnover. We found that stretch significantly synergized with biochemical agonists to inhibit the secretion of matrix metalloproteinases, with stretch either amplifying protease suppression by individual agonists or antagonizing agonist-driven upregulation of protease expression. Stretch also modulated fibroblast sensitivity towards biochemical agonists by either sensitizing cells towards agonists that suppress protease secretion or de-sensitizing cells towards agonists that upregulate protease secretion. These findings suggest that the mechanical environment can significantly alter fibrosis-related signaling in cardiac fibroblasts, suggesting caution when extrapolating in vitro data to predict effects of fibrosis-related cytokines in situations like myocardial infarction where mechanical stretch occurs.

bioengineering↗