Biology subjects

Kimura, W.

Publications and source records attributed to Kimura, W..

3 recordsLinked to original sources

bioRxiv2021

Angiocrine IGFBP3 Spatially Coordinates IGF Signaling During Neonatal Cardiac Regeneration

To identify non-cell-autonomous effectors of cardiomyocyte mitosis, we analyzed a transcriptomic screen of regenerating and non-regenerating neonatal hearts for differentially-expressed secreted proteins - which we hypothesized could include candidate mitogens. We identified and validated IGFBP3, which has a Janus-like stabilizing and sequestering effect on IGF growth factors, as a neonatal injury-associated secreted protein. IGFBP3 is expressed by and secreted from vascular cells in the neonatal heart after cardiac injury, notably in the infarct border zone. We found that global deletion of IGFBP3 blunted neonatal regeneration, while gain-of-function experiments using recombinant IGFBP3 and a transgenic mouse model uncovered a pro-mitotic effect of IGFBP3 on cardiomyocytes in vitro and in the adult heart. We show that site-specific expression of an IGFBP3 protease (PAPP-A2) and its inhibitor (STC2) coordinate the spatial release of IGF2 in the infarct zone to regio-selectively activate the INSR-ERK-AKT cell growth pathways in cardiomyocytes. Collectively, our work highlights the spatiotemporal orchestration of endothelial-cardiomyocyte interactions that are required for neonatal cardiac regeneration.

cell biology↗

bioRxiv2021

BITC induces cardiomyocyte proliferation and heart regeneration

Cardiomyocyte proliferation is an evolutionarily conserved mechanism that supports cardiac regeneration in vertebrates. Mammalian cardiomyocytes are arrested from the cell cycle shortly after birth, and therefore mammals lose the ability to regenerate injured myocardium for the rest of their lives. Pharmacological induction of cardiomyocyte proliferation has gained a lot of interest in recent years, as researchers strive to achieve heart tissue regeneration. Here we show that a small chemical, benzyl isothiocyanate (BITC), induced cardiomyocyte proliferation through activation of the cyclin-dependent kinase (CDK) pathway. BITC treatment also allowed heart regeneration in the infarcted neonatal heart, even after the regeneration period in mice. Furthermore, administration of BITC to adult mice in parallel with mild hypoxia (10% O2) induced cell cycle reentry and tissue regeneration in the adult heart. Our findings thus suggest that pharmacological activation of the CDK pathway using BITC, concurrently with the activation of hypoxia-related signaling pathways, may be a promising approach to inducing cardiac regeneration in patients with heart disease.

pharmacology and toxicology↗

bioRxiv2020

Adducin Regulates Sarcomere Disassembly During Cardiomyocyte Mitosis

Recent interest in understanding cardiomyocyte cell-cycle has been driven by potential therapeutic applications in cardiomyopathy. However, despite recent advances, cardiomyocyte mitosis remains a poorly understood process. For example, it is unclear how sarcomeres are disassembled during mitosis to allow abscission of daughter cardiomyocytes. Here we identify adducin as a regulator of sarcomere disassembly during mammalian cardiomyocyte mitosis. /{gamma}-adducins are selectively expressed in neonatal mitotic cardiomyocytes, and their levels decline precipitously thereafter. Cardiomyocyte-specific overexpression of various splice isoforms and phosphoforms of -adducin in-vitro and in-vivo identified Thr445/Thr480 phosphorylation of a short isoform of adducin as a potent inducer of neonatal cardiomyocyte sarcomere disassembly. Concomitant overexpression of this -adducin variant along with {gamma}-adducin resulted in stabilization of the adducin complex and persistent sarcomere disassembly in adult mice, which is mediated by interaction with -actinin. These results highlight an important mechanism for coordination of cytoskeletal morphological changes during cardiomyocyte mitosis.

cell biology↗