Cardiac Cell Cycle Activation as a Strategy to Improve iPSC-Derived Cardiomyocyte Therapy
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Over the past 2 decades, scientists and clinicians have strived to leverage stem cell therapy as a treatment for heart failure. However, a myriad of clinical trials investigating the potential of adult stem cells to restore damaged myocardium showed inconsistent effectiveness.1 A subsequent paradigm shift emerged with evidence that the benefits of such treatment, if any, were derived from cardioprotective paracrine factors released by stem cells as opposed to direct myocardial regeneration. As a result, researchers have attempted to regenerate the lost myocardium by delivering cardiac cells to the sites of myocardial damage.
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With recent advances in induced pluripotent stem cell (iPSC) technology, cardiomyocytes can be efficiently and reproducibly generated from iPSCs.2 The use of iPSCs in cell therapy is particularly attractive for the following reasons. First, iPSCs have extensive self-renewal and differentiation potential, which enables generation of a large number of iPSC-derived cardiomyocytes (iPSC-CMs) required for successful cell therapy. Second, this self-renewal property of iPSCs makes them amenable to desired genetic modification before differentiation.3 Third, iPSC-CMs exhibit properties of beating cardiomyocytes and have been shown to engraft in the host myocardium and electromechanically couple to neighboring native cardiomyocytes.4 Finally, because iPSCs are derived from patients’ own somatic cells, the use of autologous iPSC-CMs may help circumvent potential immunogenicity of the transplanted cells.5 Despite these beneficial characteristics of iPSCs, poor survival and engraftment of the transplanted cells remain major obstacles for efficient myocardial regeneration.1
In this issue of Circulation Research, Zhu et al6 sought to test whether the use of genetically engineered, cell cycle–activated iPSC-CMs could improve cardiac cell therapy. Recognizing that only a small fraction of transplanted iPSC-CMs survive and engraft into the myocardium, they hypothesized that if iPSC-CMs could retain proliferative capacity, then even a small …