Advancing physiological maturation in human induced pluripotent stem cell ‐derived cardiac muscle by gene editing an inducible adult troponin isoform switch

hiPSC ‐CMs are gene edited to contain an inducible cardiac troponin I (cTnI) expression cassette. When these cells are treated with doxycycline, they express cTnI. Expression of cTnI is sufficient to promote a phenotype with physiologic markers of mature myocytes, including faster relaxation and improve d adrenergic responsivity, compared to nonedited cells which only express slow skeletal troponin I. AbstractAdvancing maturation of stem cell ‐derived cardiac muscle represents a major barrier to progress in cardiac regenerative medicine. Cardiac muscle maturation involves a myriad of gene, protein, and cell‐based transitions, spanning across all aspects of cardiac muscle form and function. We focused here on a key developmentally con trolled transition in the cardiac sarcomere, the functional unit of the heart. Using a gene‐editing platform, human induced pluripotent stem cell (hiPSCs) were engineered with a drug‐inducible expression cassette driving the adult cardiac troponin I (cTnI) regulatory isoform, a transition shown to be a rate‐limiting step in advancing sarcomeric maturation of hiPSC cardiac muscle (hiPSC‐CM) toward the adult state. Findings show that induction of the adult cTnI isoform resulted in the physiological acquisition of adult‐like cardiac contractile function in hiPSC‐CMs in vitro. Specif ically, cTnI induction accelerated relaxation kinetics at baseline conditions, a result independent of alterations in the kinetics of the intracellul...
Source: Stem Cells - Category: Stem Cells Authors: Tags: Embryonic Stem Cells/Induced Pluripotent Stem Cells Source Type: research