Fibroblast activation in response to TGFβ1 is modulated by co-culture with endothelial cells in a vascular organ-on-chip platform.

Autor:	Luu RJ; Bioengineering Division, The Charles Stark Draper Laboratory Inc., Cambridge, MA, United States., Hoefler BC; Bioengineering Division, The Charles Stark Draper Laboratory Inc., Cambridge, MA, United States., Gard AL; Bioengineering Division, The Charles Stark Draper Laboratory Inc., Cambridge, MA, United States., Ritenour CR; Pfizer Inc., Groton, CT, United States., Rogers MT; Bioengineering Division, The Charles Stark Draper Laboratory Inc., Cambridge, MA, United States., Kim ES; Bioengineering Division, The Charles Stark Draper Laboratory Inc., Cambridge, MA, United States., Coppeta JR; Bioengineering Division, The Charles Stark Draper Laboratory Inc., Cambridge, MA, United States., Cain BP; Bioengineering Division, The Charles Stark Draper Laboratory Inc., Cambridge, MA, United States., Isenberg BC; Bioengineering Division, The Charles Stark Draper Laboratory Inc., Cambridge, MA, United States., Azizgolshani H; Bioengineering Division, The Charles Stark Draper Laboratory Inc., Cambridge, MA, United States., Fajardo-Ramirez OR; Laboratory for Systems Mechanobiology, Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States., García-Cardeña G; Laboratory for Systems Mechanobiology, Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States., Lech MP; Pfizer Inc., Cambridge, MA, United States., Tomlinson L; Pfizer Inc., Cambridge, MA, United States., Charest JL; Bioengineering Division, The Charles Stark Draper Laboratory Inc., Cambridge, MA, United States., Williams C; Bioengineering Division, The Charles Stark Draper Laboratory Inc., Cambridge, MA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in molecular biosciences [Front Mol Biosci] 2023 Jul 28; Vol. 10, pp. 1160851. Date of Electronic Publication: 2023 Jul 28 (Print Publication: 2023).
DOI:	10.3389/fmolb.2023.1160851
Abstrakt:	Background: Tissue fibrosis is a major healthcare burden that affects various organs in the body for which no effective treatments exist. An underlying, emerging theme across organs and tissue types at early stages of fibrosis is the activation of pericytes and/or fibroblasts in the perivascular space. In hepatic tissue, it is well known that liver sinusoidal endothelial cells (EC) help maintain the quiescence of stellate cells, but whether this phenomenon holds true for other endothelial and perivascular cell types is not well studied. Methods: The goal of this work was to develop an organ-on-chip microvascular model to study the effect of EC co-culture on the activation of perivascular cells perturbed by the pro-fibrotic factor TGFβ1. A high-throughput microfluidic platform, PREDICT96, that was capable of imparting physiologically relevant fluid shear stress on the cultured endothelium was utilized. Results: We first studied the activation response of several perivascular cell types and selected a cell source, human dermal fibroblasts, that exhibited medium-level activation in response to TGFβ1. We also demonstrated that the PREDICT96 high flow pump triggered changes in select shear-responsive factors in human EC. We then found that the activation response of fibroblasts was significantly blunted in co-culture with EC compared to fibroblast mono-cultures. Subsequent studies with conditioned media demonstrated that EC-secreted factors play at least a partial role in suppressing the activation response. A Luminex panel and single cell RNA-sequencing study provided additional insight into potential EC-derived factors that could influence fibroblast activation. Conclusion: Overall, our findings showed that EC can reduce myofibroblast activation of perivascular cells in response to TGFβ1. Further exploration of EC-derived factors as potential therapeutic targets in fibrosis is warranted. Competing Interests: This study received funding from Pfizer, Inc. The funder was involved in the study design, collection, analysis, interpretation of data, the writing of the article, and the decision to submit it for publication. RL, BH, AH, MR, EK, JC, BC, BI, HA, JC and CW are employed by The Charles Stark Draper Laboratory Inc. CR is employed by Pfizer Inc, Groton. ML and LT are employed by Pfizer Inc, Cambridge. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Luu, Hoefler, Gard, Ritenour, Rogers, Kim, Coppeta, Cain, Isenberg, Azizgolshani, Fajardo-Ramirez, García-Cardeña, Lech, Tomlinson, Charest and Williams.)
Databáze:	MEDLINE
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