Abstract
Human induced pluripotent stem cells (iPSCs) can be differentiated in vitro into bona fide cardiomyocytes for disease modelling and personalized medicine. Mitochondrial morphology and metabolism change dramatically as iPSCs differentiate into mesodermal cardiac lineages. Inhibiting mitochondrial fission has been shown to promote cardiac differentiation of iPSCs. However, the effect of hydrazone M1, a small molecule that promotes mitochondrial fusion, on cardiac mesodermal commitment of human iPSCs is unknown. Here, we demonstrate that treatment with M1 promoted mitochondrial fusion in human iPSCs. Treatment of iPSCs with M1 during embryoid body formation significantly increased the percentage of beating embryoid bodies and expression of cardiac-specific genes. The pro-fusion and pro-cardiogenic effects of M1 were not associated with changes in expression of the α and β subunits of adenosine triphosphate (ATP) synthase. Our findings demonstrate for the first time that hydrazone M1 is capable of promoting cardiac differentiation of human iPSCs, highlighting the important role of mitochondrial dynamics in cardiac mesoderm lineage specification and cardiac development. M1 and other mitochondrial fusion promoters emerge as promising molecular targets to generate lineages of the heart from human iPSCs for patient-specific regenerative medicine.
Highlights
Induced pluripotent stem cells are patient-specific somatic cells that have been reprogrammed to a pluripotent state carrying the same genetic makeup as the parental cells and show great promise for advancing autologous cell therapies
We have recently shown that cardiac differentiation of human Induced pluripotent stem cells (iPSCs) can be induced by knockdown or inhibition of the mitochondrial fission protein DRP1 (DNM1L) [7]
Loss of punctate mitochondrial morphology was not accompanied by a change in the mitochondrial DNA copy number, which remained stable with M1 treatment in the iPSC-Foreskin-2 cell line (Figure 1(c))
Summary
Induced pluripotent stem cells (iPSCs) are patient-specific somatic cells that have been reprogrammed to a pluripotent state carrying the same genetic makeup as the parental cells and show great promise for advancing autologous cell therapies. Cardiomyocytes derived from iPSCs are a renewable source of cells for cell-based therapies to treat heart disease, as well as for drug screening and disease modelling. Therapeutic success in the field of human heart disease will rely on our understanding of the molecular and cellular events that govern cardiac differentiation of iPSCs. While the transcriptional drivers of mesodermal cardiac differentiation of iPSCs have been described [1], the role of mitochondrial bioenergetics and morphology that underpin cardiomyocyte lineage specification is only just beginning to be uncovered [2,3,4,5]. It has recently emerged that as PSCs exit pluripotency and begin to differentiate into ectoderm, mesoderm, and endoderm, they undergo a brief metabolic surge [12, 13] followed by germ layer-specific metabolic
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
