Distinct Metabolic Flow Enables Large-Scale Purification of Mouse and Human Pluripotent Stem Cell-Derived Cardiomyocytes

SummaryHeart disease remains a major cause of death despite advances in medical technology. Heart-regenerative therapy that uses pluripotent stem cells (PSCs) is a potentially promising strategy for patients with heart disease, but the inability to generate highly purified cardiomyocytes in sufficient quantities has been a barrier to realizing this potential. Here, we report a nongenetic method for mass-producing cardiomyocytes from mouse and human PSC derivatives that is based on the marked biochemical differences in glucose and lactate metabolism between cardiomyocytes and noncardiomyocytes, including undifferentiated cells. We cultured PSC derivatives with glucose-depleted culture medium containing abundant lactate and found that only cardiomyocytes survived. Using this approach, we obtained cardiomyocytes of up to 99% purity that did not form tumors after transplantation. We believe that our technological method broadens the range of potential applications for purified PSC-derived cardiomyocytes and could facilitate progress toward PSC-based cardiac regenerative therapy.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (528 K)Download as PowerPoint slideHighlights► Integrated “omic” analyses reveal metabolic hallmarks in ESCs and cardiomyocytes ► Glucose depletion and lactate supplementation can purify PSC-derived cardiomyocytes ► Cardiomyocytes can use lactate efficiently for energy metabolism ► Transplanted purified human ESC-derived cardiomyocytes do not form tumors