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Shih-Lei (Ben) Lai, Ph.D. 賴時磊 博士
Assistant Research Fellow
Institute of Biomedical Sciences, Academia Sinica
中央研究院 生物醫學科學研究所 助研究員
Email: ben.s.lai@ibms.sinica.edu.tw
Immune-Cardiac Crosstalk via Nfic Regulates Cardiomyocyte Dedifferentiation and Heart Regeneration in Zebrafish
Myocardial infarction (MI) in humans causes irreversible loss of cardiomyocytes (CMs) and adverse tissue remodeling, often progressing to heart failure and death. In contrast to mammals, certain vertebrates such as zebrafish (Danio rerio) exhibit a remarkable capacity for heart regeneration. Notably, pre-depletion of cardiac-resident macrophages using clodronate liposomes (CL) significantly impairs CM proliferation and abolishes regenerative capacity, indicating that macrophages provide essential cues for CM cell-cycle reentry. However, the molecular mechanisms connecting immune activation to CM proliferation remain poorly understood.
To investigate the regulatory mechanisms underlying this immune–cardiac interaction, we performed single-nucleus ATAC sequencing (snATAC-seq) on zebrafish cardiac cells before and after injury, with and without macrophage depletion. Clustering and gene score analyses revealed a regenerative CM subset, C6, which markedly increased in proportion after cryoinjury and was enriched for dedifferentiation markers nppa and nppb. Motif enrichment analysis identified Nuclear Factor I C (Nfic) as a key transcription factor selectively activated in C6 under regenerative conditions (PBS control), but not in macrophage-depleted hearts. Consistently, nfic was reactivated in dedifferentiated CMs located at the injury border zone following injury. Functionally, nfic mutants exhibited impaired CM proliferation after cardiac injury, resulting in persistent fibrotic scarring compared to wild-type siblings. Mechanistically, we found that Nfic regulates the reactivation of cardiac progenitor genes critical for CM dedifferentiation, a prerequisite step for proliferation and replacing scar tissue during heart regeneration. Even in neonatal mouse CM (P1CM), knockdown of Nfic impaired cell proliferation, suggesting an evolutionarily conserved role of Nfic in regulating CM cycling.
Together, our findings revealed how macrophage-mediated immune activation promotes CM replenishment and identified Nfic as a key mediator of immune–cardiac crosstalk in zebrafish heart regeneration.
Position
2018-present Assistant Research Fellow, Institute of Biomedical Sciences, Academia Sinica, Taiwan
Education
2014-2017 Postdoctoral Researcher, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Hessen, Germany.
2009-2014 Postdoctoral Researcher, Institute of Zoology, National Taiwan University, Taiwan
2007-2008 Visiting Scholar, Pharmacology Department, University of Washington, Seattle, WA.
2001-2008 Ph.D. Institute of Zoology, National Taiwan University, Taiwan
1997-2001 B.S. Department of Biology, Fu-Jen Catholic University, Taiwan
Expertise
Developmental genetics, cardiovascular development and regeneration, cardioimmunology, and zebrafish disease model.
Selected Publications
1. Wei KH, Lin IT, Chowdhury K, Lim KL, Liu T, Ko TM, Chang YM, Yang KC, Lai SL*. Comparative single-cell profiling reveals distinct cardiac resident macrophages essential for zebrafish heart regeneration. eLife. 2023;12:e84679.
2. Chowdhury K, Lin S, Lai SL*. Comparative Study in Zebrafish and Medaka Unravels the Mechanisms of Tissue Regeneration. Frontiers in Ecology and Evolution. 2022. 10, 1.
3. Lai SL*, Marín-Juez R, Stainier DYR*. Immune Responses in Cardiac Repair and Regeneration-A comparative point of view. Cell Mol Life Sci. 2019;76(7):1365-1380 (Co-corresponding)
4. Lai SL*, Marín-Juez R, Moura P, Kuenne C, Lai JKH, Taddese Tsedeke A, Guenther S, Looso M, Stainier DYR*. Reciprocal analyses in zebrafish and medaka reveal that harnessing the immune response promotes cardiac regeneration. eLife. 2017;6. pii: e25605. (Co-corresponding)
Biosketch
Dr. Ben Shih-Lei Lai is a developmental biologist by training who studied gastrulation cell migration and LR asymmetry during his graduate years in Dr. Jeff Shyh-Jye Lee's laboratory and obtained a Ph.D. from the National Taiwan University. Later, Ben did his postdoctoral research in Dr. Didier Stainier's laboratory at the Max Planck Institute for Heart and Lung Research, where he established a unique platform to investigate the mechanism of heart regeneration by reciprocal analyses in regenerative zebrafish and non-regenerative medaka. His research led to the discovery that differential immune responses critically shape regenerative outcomes, and the potential of promoting heart regeneration by manipulating immunity. In 2018, Ben joined the Institute of Biomedical Sciences in Academia Sinica as a junior research fellow. Ben's research group focuses on how immune response is involved in cardiac repair and regeneration and the feasibility of translating the knowledge into therapeutics. Ben has received several young scholar awards/scholarships and serves as the Secretary General of the Taiwanese Society of Developmental Biology, Board Director and committee member of several national and international societies and organizations, and reviewer for international funding agencies and prestigious journals.
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