Resident Fibroblast MKL1 Is Sufficient to Drive Pro-fibrogenic Response in Mice.

Xianhua Gui,Qianwen Zhao,Shan Huang,Tinghui Shao,Hong Liu,Tianfa Li

doi:10.3389/fcell.2021.812748

Abstract

Fibrosis is an evolutionarily conserved pathophysiological process serving bifurcated purposes. On the one hand, fibrosis is essential for wound healing and contributes to the preservation of organ function. On the other hand, aberrant fibrogenic response may lead to tissue remodeling and precipitate organ failure. Recently lineage tracing studies have shown that resident fibroblasts are the primary mediator of fibrosis taking place in key organs such as the heart, the lungs, and the kidneys. Megakaryocytic leukemia 1 (MKL1) is transcriptional regulator involved in tissue fibrosis. Here we generated resident fibroblast conditional MKL1 knockout (CKO) mice by crossing the Mkl1 f/f mice to the Col1a2-CreERT2 mice. Models of cardiac fibrosis, pulmonary fibrosis, and renal fibrosis were reproduced in the CKO mice and wild type (WT) littermates. Compared to the WT mice, the CKO mice displayed across-the-board attenuation of fibrosis in different models. Our data cement the pivotal role MKL1 plays in tissue fibrosis but point to the cellular origin from which MKL1 exerts its pro-fibrogenic effects.

Highlights

Fibrosis is considered a key part of the wound healing process that safeguards the architectural and functional integrity of the host (Henderson et al, 2020)
We evaluated the effect of Megakaryocytic leukemia 1 (MKL1) deletion in resident fibroblasts on cardiac fibrosis in a classic model in which the left anterior descending artery was permanently ligated to induce myocardial infarction (MI, Figure 2A); significant cardiac fibrosis typically develops within 7 days of the surgical procedure (Cleutjens et al, 1995)
We present data to show that mice harboring resident fibroblast-specific MKL1 deletion display attenuated tissue fibrosis in several different models suggesting that resident fibroblast MKL1 is sufficient to drive a pro-fibrogenic response in vivo

Summary

Introduction

Fibrosis is considered a key part of the wound healing process that safeguards the architectural and functional integrity of the host (Henderson et al, 2020). Fibrotic tissue (scar) helps cover the wound to prevent excessive loss of blood and maintain body fluid homeostasis. On the other hand, accelerated production of extracellular matrix (ECM) proteins contributes to interstitial remodeling and preservation of organ function. Insufficient activation of myofibroblasts in the aging heart triggers defective wound healing and heart failure following myocardial infarction (Bujak et al, 2008). Depletion of excessive myofibroblasts mitigates adverse interstitial remodeling and improves organ function in mice (Kaur et al, 2016; Meng et al, 2016; Xu et al, 2020)

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Conclusion