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Phenotypic screening identifies kenpaullone as a prolymphangiogenic compound to improve heart repair following myocardial infarction

ABSTRACT: Myocardial infarction (MI) induces cardiac muscle death and its subsequent replacement by a noncontractile fibrotic scar, which underlies progression to heart failure. Current treatments restore blood flow and assist with cardiac workload but do not promote regeneration. We have previously shown endogenous growth of the cardiac lymphatic system following MI and further stimulation with the lymphatic endothelial specific mutated Vascular Endothelial Growth Factor-C (VEGF-C) isoform, VEGFC-C156S, resolves the immune response and improves cardiac function. However, the short half-life of VEGFC-C156S makes it suboptimal for clinical use, highlighting the need for alternative prolymphangiogenic strategies. We established a spheroid-based sprouting assay using human lymphatic endothelial cells to mimic lymphangiogenesis and performed a phenotypic screen of focused libraries of epigenetic regulators, kinase inhibitors, and stem cell modulators. Automated imaging and quantitative analysis identified several kinase inhibitors, previously characterized as GSK3ß inhibitors, as prolymphangiogenic regulators. Among them, the most potent was kenpaullone, which activated the same canonical prolymphangiogenic ERK pathway as VEGF-C, but induced a distinct transcriptional response in treated spheroids. Using kenpaullone-derived chemical probes and target-validation approaches, we identified MAP4K4 as a molecular target mediating the prolymphangiogenic effect observed. Finally, in a mouse MI model, kenpaullone enhanced cardiac lymphangiogenesis and improved cardiac function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE348365 | GEO | 2026/09/24

REPOSITORIES: GEO

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Project description:Inflammatory responses are crucial in the pathological cardiac remodeling and repair after myocardial infarction (MI). The lymphatic endothelial cells (LECs) significantly influence immune cell clearance and mitigate cardiac inflammation. Chemokines are known to tightly regulate immune cell mobilization within the infarcted heart, thereby significantly influencing cardiac inflammation and remodeling. However, the role of chemokines expressed by LECs in the regulation of cardiac inflammation post-MI remains unclear. Our study revealed that the expression of CC chemokine CCL2 in cardiac LECs was sharply un-regulated following MI. We thus hypothesized that lymphatic endothelial CCL2 might be involved in post-MI cardiac remodeling. To test this hypothesis, we generated LEC-conditional Ccl2 knock-out mice. In vivo experiments demonstrated that the LEC-Ccl2 deficiency deteriorated cardiac function and worsened adverse cardiac remodeling after MI. Further analysis showed that the loss of CCL2 in LECs impeded post-MI lymphangiogenesis and increased macrophage infiltration in post-MI myocardium and impaired macrophages clearance via afferent cardiac lymphatics. This led to exacerbated inflammatory responses and pathological cardiac remodeling after MI. Mechanistically, our study identified that LECs expressed and secreted CCL2, which played a dual role. LEC-CCL2 recruit macrophages from the infarcted myocardium into the lymphatic system and activated AKT/ETS1 signaling, enhancing VEGFC expression and promoting lymphangiogenesis in an autocrine manner. This study reveals that cardiac LEC-expressing CCL2 tightly control macrophage trafficking via lymphatic vessels in injured hearts and thus diminished post-MI inflammatory responses and lessened adverse cardiac remodeling. This study demonstrates that CCL2 expression in cardiac LECs tightly controls macrophage trafficking via lymphatic vessels in injured hearts, thereby diminishing post-MI inflammatory responses and lessening adverse cardiac remodeling. This study suggests that modulating CCL2 signaling in LECs could provide a promising therapeutic target for resolving excessive inflammation and ameliorating adverse cardiac remodeling after MI.

Project description:Aberrant repair after musculoskeletal injury is one of the most costly and common clinical scenarios in health care. While advances in our understanding of the key cells and pathways during the repair process have improved, there remains a gap in knowledge of the key progenitor cells and their interaction with the surrounding microenvironment. Heterotopic ossification (HO) is a pathological process caused by aberrant cell-fate determination resulting in the formation of bone in non-skeletal tissues after musculoskeletal injury. While the involvement of blood vessels in musculoskeletal repair is well-documented, the role of lymphatic vessels and the cells responsible for their ingrowth in musculoskeletal tissues during both homeostasis and after injury remains poorly understood. In this study, we employed a mouse model of traumatic HO to investigate lymphangiogenesis during musculoskeletal injury and repair and to uncover the key progenitor cells responsible to stimulate lymphangiogenesis and undergo aberrant cell fate differentiation. Our findings demonstrated that musculoskeletal injury triggered lymphangiogenesis at the injury site, including invasion of lymphatic vessels into the tendon proper. This increased lymphangiogenesis was driven by elevated levels of active Vascular Endothelial Growth Factor C (VEGF-C) one-week post-injury. Through single-cell transcriptomic analyses, we identified mesenchymal progenitor cells (MPCs) as a source of Vegfc following injury as well as the source of enzymes responsible for activating VEGF-C. These Vegfc-expressing MPCs underwent osteochondral differentiation and actively contributed to the formation of HO following injury. Notably, Vegfc haploinsufficiency resulted in a near 50% reduction in lymphangiogenesis and HO formation. Collectively, these findings suggest that MPC expression of VEGF-C and its activating enzymes in response to soft tissue trauma play a critical role in stimulating pathologic lymphatic vessel growth. Furthermore, Vegfc expressing MPCs undergo aberrant osteochondral differentiation responsible for HO. Targeting Vegfc expression and Vegfc-expressing progenitors therapeutically could potentially mitigate pathologic lymphangiogenesis, preventing aberrant tissue repair and subsequent HO formation.

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Phenotypic screening identifies kenpaullone as a prolymphangiogenic compound to improve heart repair following myocardial infarction

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