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Phenotypic Differences in Adult and Fetal Dermal Fibroblast Responses to Mechanical Tension

By Umang M. Parikh, Walker D. Short, Natalie Templeman, Alexander Blum, Daniel Colchado, Harrison Strang, Aditya Kaul, Hui Li, Xinyi Wang, Monica M. Fahrenholtz, Swathi Balaji

Posted 01 Oct 2020
bioRxiv DOI: 10.1101/2020.09.30.319749

The regenerative wound healing phenotype observed in the fetal wounds is characterized by a unique hyaluronan rich wound microenvironment. Fetal fibroblasts produce a pericellular matrix which is abundant in high molecular weight HA. In vivo, fetal skin has negligible resting tension and heals regeneratively when small wounds are made. However, critically large fetal wounds heal with increased scar. We hypothesize that higher mechanical tension will differentially alter fibroblast-mediated HA metabolism in adult and fetal fibroblasts, leading to a profibrotic fetal fibroblast phenotype. C57BL/6J fetal (FFB, E14.5) and adult (AFB, 8 wk) dermal fibroblasts were cultured on silicone membranes +/-10% static strain (1, 3, 6, and 12h). Monolayers were analyzed via PCR for HA-synthesis (HAS1-3), HA-remodeling (HYAL1-2, KIAA1199), and HA-receptor (CD44) genes, normalized to static FFB. Total HA was analyzed by gel electrophoresis at 12h. Data is reported as mean+/-SD (n=3), with p-values calculated by two-way ANOVA (post-hoc Tukey’s test). FFB pericellular matrix was reduced after tension conditions, and HA profile shifted from HMW-HA to LMW-HA. Under static conditions, AFB had increased expression of HAS 1 and 2, as well as increased expression of KIA1199, HYAL1 and 2 when compared to FFB. Overall, tension resulted in an increase in HAS1, HAS3, and HYAL1 expression in FFB, and decreased HAS2 but increased HYAL1 for AFB under tension. Staining for cytoskeletal components demonstrates that tension results in organization of F-actin and aSMA in FFB to resemble AFB. Expression of aSMA is increased in AFB with tension, while CD26 expression is increased in FFB with tension. These insights into the intrinsic differences between regenerative FFB and fibrotic AFB may yield targets to attenuate fibrosis. ### Competing Interest Statement The authors have declared no competing interest. * LIST OF ABBREVIATIONS : HA : Hyaluronan EN1 : Engrailed-1 ECM : Extracellular Matrix MW : Molecular Weight LMW-HA : Low Molecular Weight Hyaluronan HMW-HA : High Molecular Weight Hyaluronan HAS : Hyaluronan Synthase HYAL : Hyaluronidase FFB : Fetal Fibroblasts AFB : Adult Fibroblasts

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