What is the clinical evidence from this study?

Study design: Other. Population: Myocardial infarction (n=17). Intervention: Human ventricular progenitors (HVPs) vs. Vehicle. Primary outcome: Infarct volume (% of LV).

May 1, 2022Nature Cell Biology49 citationsOpen Access

Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors

CPChristine M PochKlinikum rechts der Isar KFKylie S. FooKarolinska Institutet MAMaria Teresa De AngelisMagna Graecia University

Key Result

Transplantation of human ventricular progenitors significantly reduced infarct volume to 2.5% compared to 7.0% with vehicle and attenuated the decline of cardiac function in a porcine model of chronic ischemic injury.

Structured PICO

Do human cardiac progenitors promote heart regeneration and prevent heart failure progression in injured heart models?

Population

17 pigs with induced chronic ischemic injury via LAD occlusion, followed for 12 weeks after treatment.

Intervention

Human cardiac progenitors (pluripotent stem cell-based)

Outcome

Functional restoration of damaged heart muscle, de novo formation of heart muscle, scar-volume reduction, and prevention of heart failure progressionsurrogate

Human cardiac progenitors utilize inherent developmental programmes, including CXCL12/CXCR4 chemoattraction and SLIT2/ROBO1 fibroblast repulsion, to counteract injury and promote heart regeneration in preclinical models.

Main Result

Absolute Event Rate: 2.5% vs 7%

Limitations

Additional analysis is needed to demonstrate whether the neovascularization response is sufficient to restore physiological blood flow.
Need to determine whether HVP-based therapies achieve higher remuscularization compared with CM transplantation with reduced ventricular arrhythmia.

Abstract

Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host-graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differentiation contributed to graft neovascularization. Our study demonstrates that inherent developmental programmes within cardiac progenitors are sequentially activated in disease, enabling the cells to sense and counteract acute and chronic injury.

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