Dataset Information

Knock-out of MicroRNA 145 impairs cardiac fibroblast function and wound healing post-myocardial infarction.

ABSTRACT: Prevention of infarct scar thinning and dilatation and stimulation of scar contracture can prevent progressive heart failure. Since microRNA 145 (miR-145) plays an important role in cardiac fibroblast response to wound healing and cardiac repair after an myocardial infarction (MI), using a miR-145 knock-out (KO) mouse model, we evaluated contribution of down-regulation of miR-145 to cardiac fibroblast and myofibroblast function during adverse cardiac remodelling. Cardiac function decreased more and the infarct size was larger in miR-145 KO than that in WT mice after MI and this phenomenon was accompanied by a decrease in cardiac fibroblast-to-myofibroblast differentiation. Quantification of collagen I and ?-SMA protein levels as well as wound contraction revealed that transdifferentiation of cardiac fibroblasts into myofibroblasts was lower in KO than WT mice. In vitro restoration of miR-145 induced more differentiation of fibroblasts to myofibroblasts and this effect involved the target genes Klf4 and myocardin. MiR-145 contributes to infarct scar contraction in the heart and the absence of miR-145 contributes to dysfunction of cardiac fibroblast, resulting in greater infarct thinning and dilatation. Augmentation of miR-145 could be an attractive target to prevent adverse cardiac remodelling after MI by enhancing the phenotypic switch of cardiac fibroblasts to myofibroblasts.

SUBMITTER: Song HF

PROVIDER: S-EPMC7417705 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Knock-out of MicroRNA 145 impairs cardiac fibroblast function and wound healing post-myocardial infarction.

Song Hui-Fang HF He Sheng S Li Shu-Hong SH Wu Jun J Yin Wenjuan W Shao Zhengbo Z Du Guo-Qing GQ Wu Jie J Li Jiao J Weisel Richard D RD Verma Subodh S Xie Jun J Li Ren-Ke RK

Journal of cellular and molecular medicine 20200706 16

Prevention of infarct scar thinning and dilatation and stimulation of scar contracture can prevent progressive heart failure. Since microRNA 145 (miR-145) plays an important role in cardiac fibroblast response to wound healing and cardiac repair after an myocardial infarction (MI), using a miR-145 knock-out (KO) mouse model, we evaluated contribution of down-regulation of miR-145 to cardiac fibroblast and myofibroblast function during adverse cardiac remodelling. Cardiac function decreased more ...[more]

PMID: 32628810

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Project description:Both skin wound healing and the cardiac response to myocardial infarction (MI) progress through similar pathways involving inflammation, resolution, tissue repair, and scar formation. Due to the similarities, we hypothesized that the healing response to skin wounding would predict future response to MI. Mice were given a 3-mm skin wound using a disposable biopsy punch and the skin wound was imaged daily until closure. The same set of animals was given MI by permanent coronary artery ligation 28 days later and followed for 7 days. Cardiac physiology was measured by echocardiography at baseline and MI days 3 and 7. Animals that survived until day 7 were grouped as survivors, and animals that died from MI were grouped as nonsurvivors. Survivors had faster skin wound healing than nonsurvivors. Faster skin wound healing predicted MI survival better than commonly used cardiac functional variables (e.g., infarct size, fractional shortening, and end diastolic dimension). N-glycoproteome profiling of MI day 3 plasma revealed α2-macroglobulin and ELL-associated factor 1 as strong predictors of future MI death and progression to heart failure. A second cohort of MI mice validated these findings. To investigate the clinical relevance of α2-macroglobulin, we mapped the plasma glycoproteome in patients with MI 48 h after admission and in healthy controls. In patients, α2-macroglobulin was increased 48 h after MI. Apolipoprotein D, another plasma glycoprotein, detrimentally regulated both skin and cardiac wound healing in male but not female mice by promoting inflammation. Our results reveal that the skin is a mirror to the heart and common pathways link wound healing across organs.NEW & NOTEWORTHY Faster skin wound healers had more efficient cardiac healing after myocardial infarction (MI). Two plasma proteins at D3 MI, EAF1 and A2M, predicted MI death in 66% of cases. ApoD regulated both skin and cardiac wound healing in male mice by promoting inflammation. The skin was a mirror to the heart and common pathways linked wound healing across organs.

Project description:Wound healing is a well-organized dynamic process involving coordinated consecutive phases: homeostasis, inflammation, proliferation and resolution. Fibroblasts play major roles in skin wound healing such as in wound contraction and release of growth factors which are of importance in angiogenesis and tissue remodeling. Abnormal fibroblast phenotypes have been identified in patients with chronic wounds. In this work, we analyzed scRNA-seq datasets of normal and wounded skin from mice at day 4 post-wound to investigate fibroblast heterogeneity during the proliferative phase of wound healing. Compositional analysis revealed a specific subset of fibroblast (cluster 3) that primarily increased in wounded skin (14%) compared to normal skin (3.9%). This subset was characterized by a gene signature marked by the plasma membrane proteins Sfrp2 + Sfrp4 + Sfrp1 + and the transcription factors Ebf1 + Prrx1 + Maged1 + . Differential gene expression and enrichment analysis identified epithelial to mesenchymal transition (EMT) and angiogenesis to be upregulated in the emerging subset of fibroblasts of the wounded skin. Using two other datasets for murine wounded skin confirmed the increase in cluster 3-like fibroblasts at days 2, 7 and 14 post-wounding with a peak at day 7. By performing a similarity check between the differential gene expression profile between wounded and normal skin for this emerging fibroblast subset with drug signature from the ConnectivityMap database, we identified drugs capable of mimicking the observed gene expression change in fibroblasts during wound healing. TTNPB, verteprofin and nicotinic acid were identified as candidate drugs capable of inducing fibroblast gene expression profile necessary for wound healing. On the other hand, methocarbamol, ifosfamide and penbutolol were recognized to antagonize the identified fibroblast differential expression profile during wound healing which might cause delay in wound healing. Taken together, analysis of murine transcriptomic skin wound healing datasets suggested a subset of fibroblasts capable of inducing EMT and further inferred drugs that might be tested as potential candidates to induce wound closure.

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Knock-out of MicroRNA 145 impairs cardiac fibroblast function and wound healing post-myocardial infarction.

Publications

Knock-out of MicroRNA 145 impairs cardiac fibroblast function and wound healing post-myocardial infarction.

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