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Generation and Expansion of Human Cardiomyocytes from Patient Peripheral Blood Mononuclear Cells

Generating patient-specific cardiomyocytes from a single blood draw has attracted tremendous interest in precision medicine on cardiovascular disease. ...

Nationwide Children’s Hospital

The Ohio State University

The Ohio State University College of Medicine

Innate immune signaling has recently been shown to play an important role in nuclear reprogramming, by altering the epigenetic landscape and thereby facilitating transcription. However, the mechanisms that link innate immune activation and metabolic regulation in pluripotent stem cells remain poorly defined, particularly with regard to key molecular components. In this study, we show that hypoxia-inducible factor 1α (HIF1α), a central regulator of adaptation to limiting oxygen tension, is an unexpected but crucial regulator of innate immune-mediated nuclear reprogramming. HIF1α is dramatically upregulated as a consequence of Toll-like receptor 3 (TLR3) signaling and is necessary for efficient induction of pluripotency and transdifferentiation. Bioenergetics studies reveal that HIF1α regulates the reconfiguration of innate immune-mediated reprogramming through its well-established role in throwing a glycolytic switch. We believe that results from these studies can help us better understand the influence of immune signaling in tissue regeneration and lead to new therapeutic strategies.

HIF1α Regulates Early Metabolic Changes due to Activation of Innate Immunity in Nuclear Reprogramming.

Patient-derived pluripotent stem cells (PSCs) have greatly transformed the current understanding of human heart development and cardiovascular disease. Cardiomyocytes derived from personalized PSCs are powerful tools for modeling heart disease and performing patient-based cardiac toxicity testing. However, these PSC-derived cardiomyocytes (PSC-CMs) are a mixed population of atrial-, ventricular-, and pacemaker-like cells in the dish, hindering the future of precision cardiovascular medicine. Recent insights gleaned from the developing heart have paved new avenues to refine subtype-specific cardiomyocytes from patients with known pathogenic genetic variants and clinical phenotypes. Here, we discuss the recent progress on generating subtype-specific (atrial, ventricular, and nodal) cardiomyocytes from the perspectives of embryonic heart development, and how they will expand our current knowledge on molecular mechanisms of cardiovascular disease and the future of precision medicine.

Subtype-specific cardiomyocytes for precision medicine: Where are we now?

In the past few decades, cardiac regeneration has been the central target for restoring the injured heart. In mammals, cardiomyocytes are terminally differentiated and rarely divide during adulthood. Embryonic and fetal cardiomyocytes undergo robust proliferation to form mature heart chambers in order to accommodate the increased workload of a systemic circulation. In contrast, postnatal cardiomyocytes stop dividing and initiate hypertrophic growth by increasing the size of the cardiomyocyte when exposed to increased workload. Extracellular and intracellular signaling pathways control embryonic cardiomyocyte proliferation and postnatal cardiac hypertrophy. Harnessing these pathways could be the future focus for stimulating endogenous cardiac regeneration in response to various pathological stressors. Meanwhile, patient-specific cardiomyocytes derived from autologous induced pluripotent stem cells (iPSCs) could become the major exogenous sources for replenishing the damaged myocardium. Human iPSC-derived cardiomyocytes (iPSC-CMs) are relatively immature and have the potential to increase the population of cells that advance to physiological hypertrophy in the presence of extracellular stimuli. In this review, we discuss how cardiac proliferation and maturation are regulated during embryonic development and postnatal growth, and explore how patient iPSC-CMs could serve as the future seed cells for cardiac cell replacement therapy.

Ming-Tao Zhao

Center for Cardiovascular Research,
The Abigail Wexner Research Institute,
The Heart Center,
Center for Cardiovascular Research, The Abigail Wexner Research Institute

Nationwide Children’s Hospital

Generation and Expansion of Human Cardiomyocytes from Patient Peripheral Blood Mononuclear Cells

Ming-Tao Zhao

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Nationwide Children’s Hospital

Generation and Expansion of Human Cardiomyocytes from Patient Peripheral Blood Mononuclear Cells

Center for Cardiovascular Research,
The Abigail Wexner Research Institute,
The Heart Center,
Center for Cardiovascular Research, The Abigail Wexner Research Institute