Angiogenic and reparative potency of a human cardiac CD90− mesenchymal subpopulation in heart ischemic model

Abstract

Background

Despite recent significant therapeutic progress, cardiovascular diseases (CVD) remain an unmet clinical, economic, and social burden worldwide. Cell-based therapies have been proposed as therapeutic strategies, however, the overall efficacy was modest.

Objective

We aimed to fully characterize a novel subpopulation of CD90⁻ mesenchymal cells derived from human heart tissue (hCmPC90^-) and evaluate its ability to induce cardiac tissue repair and functional recovery.

Methods

We performed a comprehensive phenotypic characterization of the hCmPC90⁻ by flow cytometry and RNA sequencing. A direct comparison of hCmPC90⁻ with previously clinically tested bone marrow- and cardiac-derived cell types, has been conducted both in vitro by means of various assays of angiogenic potency, and in vivo, by testing the ability to ameliorate left ventricular function in a mouse model of acute myocardial infarction (AMI).

Results

hCmPC90⁻ showed distinct surface markers and transcriptional phenotype compared with unselected mesenchymal heart cells (hCmPCs) and the positive CD90 counterpart (hCmPC90⁺). When human hCmPC90⁻, hCmPC90⁺, hCmPC, cardiosphere-derived cells (CDCs), and bone marrow-derived CD34⁺ cells were functionally tested in vitro, hCmPC90⁻ revealed a superior endothelial differentiation ability, higher anti-inflammatory, cardio-protective capacity, and angiocrine activity. Moreover, hCmPC90⁻ showed specific immune-privileged features. When intramyocardially delivered into infarcted mouse hearts, hCmPC90⁻ outperformed three weeks after injection other clinical-grade cell types, as for left ventricular (LV) function and adverse LV remodeling recovery, infarct size reduction, and vascular density augmentation.

Conclusion

hCmPC90⁻ shows a superior biological potency which deserves clinical exploitation as an advanced therapy medicinal product in the context of refractory ischemic heart disease.