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Updated: Jan 13, 2026
Generation and Expansion of Human Cardiomyocytes from Patient Peripheral Blood Mononuclear Cells
Published on: February 12, 2021
Inhibiting L-type calcium channel promotes cardiomyocyte proliferation through activating the canonical Wnt signaling
Meng-Ying Feng1, Yan-Song Tang1, Su Yao1
1Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiovascular Diseases, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Abstract:
The adult human heart is incapable of regeneration after myocardial infarction (MI) injury. One potential therapeutic strategy is to enhance the proliferation of resident cardiomyocytes (CMs). In this study, we developed a high-content screening assay based on DNA synthesis in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) to identify small molecules that could promote CM proliferation. In the primary screening, we found that L-type calcium channel (LTCC) blockers induced DNA synthesis of hPSC-CMs. Among the 6 clinically approved calcium channel blockers tested in secondary screening and confirmatory experiments, nimodipine (NM) consistently enhanced CM proliferation both in vitro and in vivo. RNA-Seq analysis revealed that NM activated the canonical Wnt signaling pathway, while inhibiting Wnt signaling blunted the proliferative effect of NM. Lrp5, a co-receptor for Wnt ligands known to interact with LTCC, was found to mediate the effect of NM to promote nuclear localization of β-catenin and CM proliferation. In the MI mouse model established by ligating the left anterior descending coronary artery, administration of NM (10 mg/kg, i.p.) for 7 consecutive days significantly improved cardiac contractile function and enhanced resident CM proliferation, which was attenuated by co-treatment with Wnt inhibitor Wnt-C59 (10 mg/kg, i.p.). Our data suggest that L-type calcium channel blockers that induce CM proliferation may be potentially used in the treatment of MI and heart failure to promote cardiac regeneration.
Insights
Nimodipine, an L-type calcium channel blocker, promotes cardiomyocyte proliferation after heart injury. This finding offers a potential therapeutic strategy for heart failure and myocardial infarction by enhancing cardiac regeneration.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Pharmacology
Background:
- The adult human heart has limited regenerative capacity following myocardial infarction (MI). Enhancing cardiomyocyte (CM) proliferation is a key therapeutic goal for cardiac repair.
- Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) offer a model for studying CM biology and drug discovery.
Purpose of the Study:
- To identify small molecules that promote cardiomyocyte proliferation using a high-content screening assay.
- To investigate the potential of L-type calcium channel (LTCC) blockers, specifically nimodipine, as a therapeutic strategy for cardiac regeneration after MI.
Main Methods:
- Developed a high-content screening assay measuring DNA synthesis in hPSC-CMs.
- Screened clinically approved calcium channel blockers, including nimodipine (NM).
- Utilized RNA-sequencing (RNA-Seq) to analyze NM's effect on signaling pathways.
- Investigated the role of Wnt signaling and Lrp5 in NM-mediated CM proliferation.
- Evaluated NM's efficacy in a mouse model of myocardial infarction.
Main Results:
- L-type calcium channel (LTCC) blockers were identified as inducers of CM DNA synthesis.
- Nimodipine (NM) significantly enhanced CM proliferation both in vitro and in vivo.
- NM activated the canonical Wnt signaling pathway, which was essential for its proliferative effect.
- Lrp5 mediated NM's effect on nuclear β-catenin localization and CM proliferation.
- In a mouse MI model, NM improved cardiac function and CM proliferation, an effect blunted by Wnt inhibition.
Conclusions:
- LTCC blockers, exemplified by nimodipine, can promote cardiomyocyte proliferation.
- The Wnt signaling pathway, mediated by Lrp5, is crucial for NM-induced cardiac regeneration.
- Nimodipine represents a potential therapeutic agent for treating myocardial infarction and heart failure to promote cardiac repair.
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