Dataset Information

MircroRNA-10b Promotes Human Embryonic Stem Cell-Derived Cardiomyocyte Proliferation via Novel Target Gene LATS1.

ABSTRACT: Adult mammalian cardiomyocytes (CMs) retain a limited proliferative ability, which is insufficient for the repair of CM loss in ischemic cardiac injury. Regulation of the Hippo signaling pathway to promote endogenous CM proliferation has emerged as a promising strategy for heart regeneration. Previous studies have shown that the microRNA cluster miR302-367 negatively regulates the Hippo pathway, promoting CM proliferation. In this study, we identified another microRNA, miR-10b, that regulates the Hippo pathway and promotes cell proliferation in human embryonic stem cell-derived CMs (hESC-CMs). We observed that miR-10b expression was enriched in the early stage of CMs, but its expression was reduced over time. Overexpression of miR-10b promoted CM proliferation, while knockdown of miR-10b suppressed CM proliferation. Moreover, miR-10b protected CMs against apoptosis. miR-10b functions, in part, by directly targeting LATS1, which is a major component of the Hippo pathway. Our study suggests that miR-10b has promising potential for heart regeneration.

SUBMITTER: Xie Y

PROVIDER: S-EPMC6948266 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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MircroRNA-10b Promotes Human Embryonic Stem Cell-Derived Cardiomyocyte Proliferation via Novel Target Gene LATS1.

Xie Yifang Y Wang Qiaozi Q Gao Ning N Wu Fujian F Lan Feng F Zhang Feng F Jin Li L Huang Zheyong Z Ge Junbo J Wang Hongyan H Wang Yongming Y

Molecular therapy. Nucleic acids 20191129

Adult mammalian cardiomyocytes (CMs) retain a limited proliferative ability, which is insufficient for the repair of CM loss in ischemic cardiac injury. Regulation of the Hippo signaling pathway to promote endogenous CM proliferation has emerged as a promising strategy for heart regeneration. Previous studies have shown that the microRNA cluster miR302-367 negatively regulates the Hippo pathway, promoting CM proliferation. In this study, we identified another microRNA, miR-10b, that regulates th ...[more]

PMID: 31902743

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Project description:BackgroundHuman embryonic stem cell-derived cardiomyocytes (hESC-CMs) show tremendous promise for cardiac regeneration, but the successful development of hESC-CM-based therapies requires improved tools to investigate their electrical behavior in recipient hearts. While optical voltage mapping is a powerful technique for studying myocardial electrical activity ex vivo, we have previously shown that intra-cardiac hESC-CM grafts are not labeled by conventional voltage-sensitive fluorescent dyes. We hypothesized that the water-soluble voltage-sensitive dye di-2-ANEPEQ would label engrafted hESC-CMs and thereby facilitate characterization of graft electrical function and integration.MethodsWe developed and validated a novel optical voltage mapping strategy based on the simultaneous imaging of the calcium-sensitive fluorescent protein GCaMP3, a graft-autonomous reporter of graft activation, and optical action potentials (oAPs) derived from di-2-ANEPEQ, which labels both graft and host myocardium. Cardiomyocytes from three different GCaMP3+ hESC lines (H7, RUES2, or ESI-17) were transplanted into guinea pig models of subacute and chronic infarction, followed by optical mapping at 2 weeks post-transplantation.ResultsUse of a water-soluble voltage-sensitive dye revealed pro-arrhythmic properties of GCaMP3+ hESC-CM grafts from all three lines including slow conduction velocity, incomplete host-graft coupling, and spatially heterogeneous patterns of activation that varied beat-to-beat. GCaMP3+ hESC-CMs from the RUES2 and ESI-17 lines both showed prolonged oAP durations both in vitro and in vivo. Although hESC-CMs partially remuscularize the injured hearts, histological evaluation revealed immature graft structure and impaired gap junction expression at this early timepoint.ConclusionSimultaneous imaging of GCaMP3 and di-2-ANEPEQ allowed us to acquire the first unambiguously graft-derived oAPs from hESC-CM-engrafted hearts and yielded critical insights into their arrhythmogenic potential and line-to-line variation.

Project description:BackgroundIschemic heart diseases are still a threat to human health. Human pluripotent stem cell-based transplantation exhibits great promise in cardiovascular disease therapy, including heart ischemia. The purpose of this study was to compare the efficacy of human embryonic stem cell-derived cardiomyocyte (ESC-CM) therapy in two heart ischemia models, namely, permanent ischemia (PI) and myocardial ischemia reperfusion (IR).MethodsHuman embryonic stem cell-derived cardiomyocytes were differentiated from engineered human embryonic stem cells (ESC-Rep) carrying green fluorescent protein (GFP), herpes simplex virus-1 thymidine kinase (HSVtk), and firefly luciferase (Fluc). Two different heart ischemia models were generated by the ligation of the left anterior descending artery (LAD), and ESC-Rep-derived cardiomyocytes (ESC-Rep-CMs) were transplanted into the mouse hearts. Cardiac function was analyzed to evaluate the outcomes of ESC-Rep-CM transplantation. Bioluminescence signal analysis was performed to assess the cell engraftment. Finally, the inflammation response was analyzed by real-time PCR and ELISA.ResultsCardiac function was significantly improved in the PI group with ESC-Rep-CM injection compared to the PBS-injected control, as indicated by increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), as well as reduced fibrotic area. However, minimal improvement by ESC-Rep-CM injection was detected in the IR mouse model. We observed similar engraftment efficiency between PI and IR groups after ESC-Rep-CM injection. However, the restricted inflammation was observed after the injection of ESC-Rep-CMs in the PI group, but not in the IR group. Transplantation of ESC-Rep-CMs can partially preserve the heart function via regulating the inflammation response in the PI model, while little improvement of cardiac function in the IR model may be due to the less dynamic inflammation response by the mild heart damage.ConclusionsOur findings identified the anti-inflammatory effect of ESC-CMs as a possible therapeutic mechanism to improve cardiac function in the ischemic heart.

Dataset Information

MircroRNA-10b Promotes Human Embryonic Stem Cell-Derived Cardiomyocyte Proliferation via Novel Target Gene LATS1.

Publications

MircroRNA-10b Promotes Human Embryonic Stem Cell-Derived Cardiomyocyte Proliferation via Novel Target Gene LATS1.

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