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Isolation of Primary Myofibroblasts from Mouse and Human Colon Tissue
Published on: October 12, 2013
Myofibroblast lineage mapping and inhibiting subretinal fibrosis by targeting SMAD3 and MRTF pathways via microRNA-24
Yinga Wu1, Yao Tong1, Katherine G Byrnes1
1Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, 70118, USA.
Abstract:
Subretinal fibrosis underlies the end-stage pathogenesis of retinal diseases including age-related macular degeneration (AMD). It can disrupt retinal structure and eventually lead to legal blindness by generating contractile force, fibrotic scarring, subretinal hemorrhage, and retinal detachment. Myofibroblasts are the predominant cells critically involved in subretinal fibrosis, however, the cellular contribution to myofibroblasts remains unclear. Here we demonstrate that multiple cell lineages, including macrophages, endothelial cells (EC), retinal pigment epithelial (RPE) cells and pericytes, significantly contribute to myofibroblasts in a laser-induced subretinal fibrosis model. We found microRNA miR-24 is significantly downregulated in the plasma of wet AMD patients. Overexpression of miR-24 represses epithelial-mesenchymal transition (EMT), endothelial-mesenchymal transition (EndMT), and the resulting fibrosis by regulating TGF-β/SMAD3 and PAK4/LIMK2/MRTF pathways. Consistently, a combination of SMAD3 and MRTF inhibitors show superior efficacy to individual inhibitors in repressing fibrosis in vitro and laser-induced subretinal fibrosis in vivo. Together, these suggest the contribution of multiple cell-types in myofibroblast transformation in subretinal fibrosis, and repression of miR-24-regulated TGF-β/SMAD3 and PAK4/LIMK2/MRTF pathways in multiple cell types holds therapeutic potential for treating subretinal fibrosis in AMD and other fibrotic disorders.
Insights
Multiple cell types contribute to myofibroblast formation in subretinal fibrosis. MicroRNA miR-24 dysregulation and its targeted pathways present a potential therapeutic strategy for age-related macular degeneration (AMD).
Area of Science:
- Ophthalmology and Molecular Biology
- Cellular Biology and Pathology
Background:
- Subretinal fibrosis is a key pathological process in end-stage retinal diseases like age-related macular degeneration (AMD), leading to vision loss.
- Myofibroblasts drive subretinal fibrosis, but their cellular origins remain incompletely understood.
Purpose of the Study:
- To identify the cellular contributors to myofibroblast formation in subretinal fibrosis.
- To investigate the role of microRNA miR-24 in regulating fibrotic pathways and its therapeutic potential in AMD.
Main Methods:
- Utilized a laser-induced subretinal fibrosis model in mice.
- Analyzed plasma samples from wet AMD patients for miR-24 levels.
- Investigated the effects of miR-24 overexpression and pathway inhibitors (SMAD3, MRTF) on fibrosis in vitro and in vivo.
Main Results:
- Macrophages, endothelial cells (EC), retinal pigment epithelial (RPE) cells, and pericytes were identified as significant contributors to myofibroblasts.
- miR-24 was downregulated in wet AMD patients and its overexpression inhibited epithelial-mesenchymal transition (EMT) and endothelial-mesenchymal transition (EndMT).
- Combined SMAD3 and MRTF inhibition demonstrated superior efficacy in repressing fibrosis compared to individual inhibitors.
Conclusions:
- Subretinal fibrosis involves myofibroblast transformation from multiple cell lineages.
- miR-24, through regulation of TGF-β/SMAD3 and PAK4/LIMK2/MRTF pathways, plays a crucial role in preventing fibrosis.
- Targeting miR-24-regulated pathways offers a promising therapeutic avenue for AMD and other fibrotic conditions.
