Abstract
Compact cardiomyocytes that make up the ventricular wall of the adult heart represent an important therapeutic target population for modeling and treating cardiovascular diseases. Here, we established a differentiation strategy that promotes the specification, proliferation and maturation of compact ventricular cardiomyocytes from human pluripotent stem cells (hPSCs). The cardiomyocytes generated under these conditions display the ability to use fatty acids as an energy source, a high mitochondrial mass, well-defined sarcomere structures and enhanced contraction force. These ventricular cells undergo metabolic changes indicative of those associated with heart failure when challenged in vitro with pathological stimuli and were found to generate grafts consisting of more mature cells than those derived from immature cardiomyocytes following transplantation into infarcted rat hearts. hPSC-derived atrial cardiomyocytes also responded to the maturation cues identified in this study, indicating that the approach is broadly applicable to different subtypes of the heart. Collectively, these findings highlight the power of recapitulating key aspects of embryonic and postnatal development for generating therapeutically relevant cell types from hPSCs.
Highlights
Compact cardiomyocytes that make up the ventricular wall of the adult heart represent an important therapeutic target population for modeling and treating cardiovascular diseases
To be able to model diseases that affect the compact ventricular myocardium and to develop cell based therapies to treat them, we focused our initial studies on identifying the signaling pathways that regulate the generation of ventricular compact cardiomyocytes from human pluripotent stem cells (hPSCs)
Given that Wnt ligands secreted by the epicardium are known to induce proliferation of compact cardiomyocytes in vivo[4,25], we focused our efforts on investigating the role of this pathway in compact cardiomyocyte development from hPSCs
Summary
Compact cardiomyocytes that make up the ventricular wall of the adult heart represent an important therapeutic target population for modeling and treating cardiovascular diseases. The cardiomyocytes generated under these conditions display the ability to use fatty acids as an energy source, a high mitochondrial mass, well-defined sarcomere structures and enhanced contraction force These ventricular cells undergo metabolic changes indicative of those associated with heart failure when challenged in vitro with pathological stimuli and were found to generate grafts consisting of more mature cells than those derived from immature cardiomyocytes following transplantation into infarcted rat hearts. HPSC-derived atrial cardiomyocytes responded to the maturation cues identified in this study, indicating that the approach is broadly applicable to different subtypes of the heart These findings highlight the power of recapitulating key aspects of embryonic and postnatal development for generating therapeutically relevant cell types from hPSCs. Human pluripotent stem cell (hPSC)-derived cardiomyocytes represent a promising source of cells for developing in vitro models to study diseases of the human heart and for establishing therapies to treat them. It is difficult to compare the effect of the stimuli used in the different studies and it is not known if the manipulations described can impact the maturation status of different cardiomyocyte subtypes
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