Key Takeaways & Executive Findings
- •• • CDC5L overexpression significantly increased cardiomyocyte proliferation markers: Ki67+ (cell cycle re-entry), EdU+ (DNA synthesis), and pH3+ (mitosis) in OGD/R models, with concurrent reduction in TUNEL+ apoptotic cells and Bax/Bcl-2 ratio, indicating a dual pro-proliferative and anti-apoptotic effect. This dual mechanism is critical because adult cardiomyocytes are terminally differentiated; reactivating the cell cycle while suppressing apoptosis could achieve meaningful myocardial regeneration, a feat not accomplished by current reperfusion therapies. • • FGF10 knockdown completely reversed CDC5L-mediated proliferative and anti-apoptotic effects, and abolished the reduction in YAP phosphorylation. This establishes FGF10 as an obligatory downstream effector and YAP as a downstream target of FGF10. The dependence on FGF10 implies that therapeutic strategies must ensure sustained FGF10 availability; direct CDC5L activation alone would be insufficient if FGF10 is suppressed in the ischemic milieu. • • In vivo, CDC5L overexpression via AAV9 preserved cardiac function (echocardiography) and reduced infarct size in adult mice subjected to I/R injury. These functional improvements occurred alongside increased FGF10 and cyclin D1 expression and decreased phosphorylated YAP. The in vivo efficacy in adult mice, which have limited regenerative capacity, suggests translational potential, though dosing, delivery efficiency, and long-term safety of AAV9-CDC5L remain to be optimized. • • CDC5L overexpression did not affect γ-H2AX expression, a DNA damage marker, indicating that its protective effects are not mediated through DNA damage repair. This specificity narrows the mechanism to proliferation and apoptosis modulation, reducing the likelihood of off-target effects on genomic stability. Clinically, this implies that CDC5L-based therapies would not interfere with DNA repair pathways, potentially lowering oncogenic risks associated with uncontrolled proliferation.
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Abstract
Myocardial infarction (MI) causes irreversible cardiomyocyte loss, and current reperfusion therapies fail to regenerate necrotic myocardium. Cell division cycle 5-like (CDC5L), a cell cycle regulator, has an undefined role in cardiac repair. This study investigates CDC5L in mitigating ischemia-reperfusion (I/R) injury by assessing cardiomyocyte proliferation and apoptosis, and delineates the FGF10-YAP mechanism. In vitro oxygen-glucose deprivation/reoxygenation (OGD/R) in neonatal mouse cardiomyocytes and in vivo I/R in adult mice were employed. CDC5L was modulated via adenoviral or AAV9-mediated overexpression or knockdown. Proliferation markers (EdU+, Ki67+, pH3+), apoptosis (TUNEL, Bax/Bcl-2 ratio), and cardiac function (echocardiography) were quantified. Transcriptomic screening identified downstream targets, validated by FGF10 knockdown rescue. CDC5L was upregulated in post-I/R murine myocardium. Overexpression enhanced cardiomyocyte proliferation, preserved cardiac function, reduced apoptosis, and diminished infarct size. FGF10 was identified as a key downstream effector; CDC5L upregulated FGF10 expression. FGF10 knockdown reversed the proliferative and anti-apoptotic effects of CDC5L. The CDC5L-mediated reduction in YAP phosphorylation was abolished upon FGF10 knockdown. CDC5L attenuates cardiac I/R injury by promoting cardiomyocyte proliferation and inhibiting apoptosis through the FGF10-YAP pathway. This CDC5L-FGF10-YAP axis represents a promising therapeutic target to improve myocardial regeneration and recovery after myocardial infarction.
1. Introduction
Myocardial infarction (MI) remains a leading cause of mortality worldwide, with current reperfusion strategies—percutaneous coronary intervention, coronary artery bypass grafting, and thrombolysis—restoring blood flow but failing to regenerate necrotic cardiomyocytes. The adult mammalian heart is terminally differentiated, and the endogenous regenerative capacity is insufficient to compensate for the billions of cardiomyocytes lost during ischemia-reperfusion (I/R) injury. Consequently, patients progress to adverse remodeling and heart failure, and heart transplantation is limited by donor scarcity. This therapeutic impasse underscores the urgent need for interventions that can reactivate cardiomyocyte proliferation and mitigate apoptosis.
Cell division cycle 5-like (CDC5L), a regulator of cell cycle progression, has been implicated in proliferation and survival across various cell types, but its role in cardiac repair is unknown. The FGF10-YAP axis has emerged as a critical pathway in cardiomyocyte proliferation and regeneration, with FGF10 promoting cell cycle re-entry and YAP dephosphorylation driving regenerative gene programs. This study hypothesizes that CDC5L modulates the FGF10-YAP axis to confer cardioprotection. Using in vitro OGD/R and in vivo I/R models, combined with adenoviral and AAV9-mediated gene manipulation, the authors dissect the functional and mechanistic contributions of CDC5L. The findings establish CDC5L as a novel upstream regulator of FGF10 that enhances proliferation, reduces apoptosis, and preserves cardiac function, offering a potential therapeutic target for myocardial regeneration.
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WEI Tianwen, WAN Tangjiang, SUN Yuxiao, LIANG Yucheng, LIN Zhihao, SHEN Shitong, ZHANG Qi, CHEN Mengli, LI Yafei (2025). CDC5L facilitates cardiomyocyte proliferation and ameliorates myocardial ischemia-reperfusion injury via modulation of the FGF10-YAP axis. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025213
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Frequently Asked Questions
What is the mechanistic dependency of CDC5L-mediated cardioprotection on FGF10, and how was this validated?
FGF10 knockdown via siRNA in vitro and AAV9-shFGF10 in vivo completely reversed the proliferative (EdU+, Ki67+, pH3+) and anti-apoptotic (TUNEL, Bax/Bcl-2) effects of CDC5L overexpression. Additionally, the CDC5L-induced reduction in YAP phosphorylation (p-YAP) was abolished upon FGF10 knockdown, confirming that FGF10 is an obligatory downstream effector. This dependency indicates that therapeutic targeting of CDC5L would require intact FGF10 signaling, and in pathological states where FGF10 is downregulated, combination therapy may be necessary.
Does CDC5L overexpression affect DNA damage repair, and what are the implications for safety?
CDC5L overexpression did not alter γ-H2AX levels, a sensitive marker of DNA double-strand breaks, in OGD/R-induced cardiomyocytes. This suggests that the protective effects are independent of DNA damage repair pathways. From a safety perspective, this specificity reduces concerns that CDC5L would promote genomic instability or interfere with DNA repair mechanisms, which is critical for long-term therapeutic applications, especially in proliferative tissues.
What are the in vivo functional outcomes of CDC5L overexpression in adult mice after I/R injury?
AAV9-mediated CDC5L overexpression in adult mice subjected to I/R injury preserved cardiac function, as assessed by echocardiography (e.g., improved ejection fraction and fractional shortening), and significantly reduced infarct size compared to controls. These benefits were accompanied by increased FGF10 and cyclin D1 expression and decreased phosphorylated YAP. The efficacy in adult mice, which have limited regenerative capacity, supports the translational potential of CDC5L-based gene therapy, though optimization of AAV9 dose, delivery route, and long-term expression is required.
What are the scalability and delivery challenges for translating CDC5L therapy to clinical practice?
The study utilized adenoviral and AAV9 vectors for CDC5L delivery. AAV9 is preferred for cardiac gene therapy due to its cardiotropism, but manufacturing at clinical scale remains costly and complex. Immunogenicity against AAV9 capsid and pre-existing neutralizing antibodies in humans could limit efficacy. Additionally, sustained overexpression of a cell cycle regulator like CDC5L raises long-term safety concerns, including arrhythmogenesis or uncontrolled proliferation. Dose-ranging studies and tissue-specific promoters are needed to mitigate these risks.
How does the CDC5L-FGF10-YAP axis compare to existing therapeutic targets for myocardial regeneration?
Existing targets such as Hippo-YAP modulators or neuregulin-1 have shown limited clinical success due to insufficient efficacy or off-target effects. The CDC5L-FGF10-YAP axis offers a dual mechanism—promoting proliferation and inhibiting apoptosis—with demonstrated in vivo efficacy. Unlike direct YAP activation, which risks oncogenesis, CDC5L acts upstream via FGF10, potentially providing a more controlled activation. However, comparative studies against other regenerative agents (e.g., miR-199a, Hippo siRNA) are needed to establish superiority in terms of infarct size reduction and functional recovery.
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