Transcriptome and proteome profiling of activated cardiac fibroblasts supports target prioritization in cardiac fibrosis

Maria Raquel Moita; Marta M Silva; Cláudia Diniz; Margarida Serra; René M Hoet; Ana Barbas; Daniel Simão

doi:10.3389/fcvm.2022.1015473

Transcriptome and proteome profiling of activated cardiac fibroblasts supports target prioritization in cardiac fibrosis

Front Cardiovasc Med. 2022 Dec 1:9:1015473. doi: 10.3389/fcvm.2022.1015473. eCollection 2022.

Authors

Maria Raquel Moita^{1

2}, Marta M Silva¹, Cláudia Diniz^{1

2}, Margarida Serra^{1

2}, René M Hoet³, Ana Barbas⁴, Daniel Simão¹

Affiliations

¹ iBET - Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.
² Instituto de Tecnologia Química e Biológica António Xavier, Universidade NOVA de Lisboa, Oeiras, Portugal.
³ Department of Pathology, CARIM - School of Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands.
⁴ Bayer Portugal, Carnaxide, Portugal.

Abstract

Background: Activated cardiac fibroblasts (CF) play a central role in cardiac fibrosis, a condition associated with most cardiovascular diseases. Conversion of quiescent into activated CF sustains heart integrity upon injury. However, permanence of CF in active state inflicts deleterious heart function effects. Mechanisms underlying this cell state conversion are still not fully disclosed, contributing to a limited target space and lack of effective anti-fibrotic therapies.

Materials and methods: To prioritize targets for drug development, we studied CF remodeling upon activation at transcriptomic and proteomic levels, using three different cell sources: primary adult CF (aHCF), primary fetal CF (fHCF), and induced pluripotent stem cells derived CF (hiPSC-CF).

Results: All cell sources showed a convergent response upon activation, with clear morphological and molecular remodeling associated with cell-cell and cell-matrix interactions. Quantitative proteomic analysis identified known cardiac fibrosis markers, such as FN1, CCN2, and Serpine1, but also revealed targets not previously associated with this condition, including MRC2, IGFBP7, and NT5DC2.

Conclusion: Exploring such targets to modulate CF phenotype represents a valuable opportunity for development of anti-fibrotic therapies. Also, we demonstrate that hiPSC-CF is a suitable cell source for preclinical research, displaying significantly lower basal activation level relative to primary cells, while being able to elicit a convergent response upon stimuli.

Keywords: cardiac fibroblast; cardiac fibrosis; myofibroblast; quantitative proteomics; transcriptomic.