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

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 Mkl1f/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.

The insulin‐like growth factor binding protein–microfibrillar associated protein–sterol regulatory element binding protein axis regulates fibroblast–myofibroblast transition and cardiac fibrosis

“…In a previous study, we discovered that MKL1 ablation in resident fibroblasts retards the development of cardiac fibrosis (Huang et al, 2022). However, the underlying mechanism remains unclear.…”

An MRTF-A–ZEB1–IRF9 axis contributes to fibroblast–myofibroblast transition and renal fibrosis

“…Mrtfa f/f mice 18 , 19 were crossed with Postn -Cre ERT2 mice 20 to generate myofibroblast-specific MRTF-A knockout mice. Renal fibrosis was induced in 8-week-old male mice by either the unilateral ureteral obstruction (UUO) procedure or the ischemia‒reperfusion procedure as previously described 21 – 23 . To induce diabetic nephropathy, the mice were injected with a single dose of streptozotocin (STZ, 200 mg/kg) followed by feeding with a high-fat diet (HFD) for 14 weeks as previously described 24 – 26 .…”

SRF/MRTF‐A and liver cirrhosis: Pathologic associations

“…34 However, the most important role of the SRF/MRTF-A complex is in the initiation and propagation of fibrotic processes in various tissues, including liver. [35][36][37] Liver fibrosis is a key pathological process elicited by diverse acute and chronic liver diseases. Excessive and prolonged liver fibrosis disturbs liver architecture and function, culminating in liver cirrhosis.…”

“…For instance, angiotensin II‐induced aortic dissection is caused by abrupt local inflammatory response, which is abrogated by MRTF‐A deletion in murine models, 33 since MRTF‐A silencing inhibits the secretion of proinflammatory cytokines in activated macrophages by promoting nuclear factor (NF)‐κB activity, the master regulator of inflammation 34 . However, the most important role of the SRF/MRTF‐A complex is in the initiation and propagation of fibrotic processes in various tissues, including liver 35–37 …”