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MBNL1-mediated Regulation of Differentiation RNAs Promotes Myofibroblast Transformation and the Fibrotic Response

ABSTRACT: The differentiation of fibroblasts into myofibroblasts mediates tissue wound healing and fibrotic remodeling. To better understand this process we performed a genome-wide screen in fibroblasts, which identified the RNA-binding protein muscleblind-like 1 (MBNL1) as a potent regulator of myofibroblast differentiation. MBNL1 promoted transformation of fibroblasts into myofibroblasts, while loss of Mbnl1 abrogated myofibroblast differentiation and impaired the fibrotic phase of wound healing in mouse models of myocardial infarction and dermal injury. Conditional fibroblast-specific MBNL1 transgenic mice showed a fibrotic phenotype in the absence of injury. Mechanistically, MBNL1 directly bound to and regulated the alternative splicing and stability of a network of myofibroblast differentiation specific genes, such as the nodal transcriptional regulator serum response factor (SRF). CRISPR-Cas9 mediated gene editing of the MBNL1 binding site in Srf impaired myofibroblast differentiation. These data establish a new RNA-dependent paradigm through MBNL1 that underlies global myofibroblast differentiation, the fibrotic response, and tissue wound healing.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE74185 | GEO | 2015/10/20

SECONDARY ACCESSION(S): PRJNA299279

REPOSITORIES: GEO

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Project description:Over the past decade, our laboratory developed a cat model of corneal wound healing after photorefractive keratectomy (PRK). Recently, we used this model in a combination of in vivo and in vitro approaches to show that myofibroblasts directly inhibit nerve regeneration in the wounded stroma, sub-basal plexus and epithelium. In vitro, two distinct phases to this inhibition have been observed: (1) initial slowing of neurite elongation via a releasable factor, and (2) neurite contact inhibition by myofibroblasts. For phase 1, transforming growth factor beta 1 (TGF-1) was shown to be the soluble, anti-neuritogenic factor released by myofibroblasts, and the specific signaling cascade it triggered to slow neurite elongation was identified. Ultimately, preventing myofibroblast differentiation suppressed both phase 1 and phase 2 inhibition, and resulted in faster nerve regeneration. However, in most cases of accidental injury, patients present after myofibroblast differentiation/fibrosis have occurred. The issue then is no longer preventing fibrosis, but rather overcoming its effects. We recently discovered that the synthetic PPAR ligand and Thiazolidinedione (TZD) drug, Troglitazone, stimulates myofibroblast de-differentiation in vitro and in vivo through a PPAR independent pathway. We now show that this TDZ’s ability to promote myofibroblast de-differentiation can be mimicked by UK-5099, a compound that spares PPAR, instead inhibiting a recently identified alternative target of TZDs: the mitochondrial pyruvate carrier (MPC). The recent literature and our preliminary results thus form a strong premise for refocusing our efforts on mitochondria, and critically testing the hypothesis that inhibiting the MPC facilitates myofibroblast de-differentiation, which together with metabolic remodeling in regenerating nerves can treat both fibrosis and overcome the blocked reinnervation inherent in its context. Work is ongoing to understand the metabolic changes that underlie the ability of TDZs to facilitate wound healing though mito-centric regulation of both myofibroblasts and corneal nerves. Here, we present the results of an RNA sequencing experiment designed to examine changes to the global transcriptome that occur as a result of TGF-β1-induced activation of corneal fibroblasts, and of TDZ- or UK5099-stimulated myofibroblast de-differentiation.

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MBNL1-mediated Regulation of Differentiation RNAs Promotes Myofibroblast Transformation and the Fibrotic Response

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