Translational potential of hiPSCs in predictive modeling of heart development and disease

Abstract

Congenital heart disease (CHD) represents a major class of birth defects worldwide and is associated with cardiac malformations that often require surgical intervention immediately after birth. Despite the intense efforts from multicentric genome/exome sequencing studies that have identified several genetic variants, the etiology of CHD remains diverse and often unknown. Genetically modified animal models with candidate gene deficiencies continue to provide novel molecular insights that are responsible for fetal cardiac development. However, the past decade has seen remarkable advances in the field of human induced pluripotent stem cell (hiPSC)‐based disease modeling approaches to better understand the development of CHD and discover novel preventative therapies. The iPSCs are derived from reprogramming of differentiated somatic cells to an embryonic‐like pluripotent state via overexpression of key transcription factors. In this review, we describe how differentiation of hiPSCs to specialized cardiac cellular identities facilitates our understanding of the development and pathogenesis of CHD subtypes. We summarize the molecular and functional characterization of hiPSC‐derived differentiated cells in support of normal cardiogenesis, those that go awry in CHD and other heart diseases. We illustrate how stem cell‐based disease modeling enables scientists to dissect the molecular mechanisms of cell–cell interactions underlying CHD. We highlight the current state of hiPSC‐based studies that are in the verge of translating into clinical trials. We also address limitations including hiPSC‐model reproducibility and scalability and differentiation methods leading to cellular heterogeneity. Last, we provide future perspective on exploiting the potential of hiPSC technology as a predictive model for patient‐specific CHD, screening pharmaceuticals, and provide a source for cell‐based personalized medicine. In combination with existing clinical and animal model studies, data obtained from hiPSCs will yield further understanding of oligogenic, gene–environment interaction, pathophysiology, and management for CHD and other genetic cardiac disorders.

Generation of iPSC line NCHi015-A from a patient with truncus arteriosus carrying heterozygous variants in KMT2D and NOTCH1

“…Here, we characterize an iPSC line derived from a male infant with truncus arteriosus type I carrying genetic variants in KMT2D (c.2868G > C) and NOTCH1 (c.1099 + 1G > T) ( Table 1 ). We envision this iPSC line to be used as a patient-specific in vitro model to study abnormal cardiac development related to variants in KMT2D and NOTCH1 ( Mansfield et al, 2022 ). Since the line retains the genetic composition of the patient, it creates a biological system to study congenital heart disease in humans ( Lin et al, 2021 ).…”

Reprogramming stem cells in regenerative medicine

“…The lack of autologous stem cell sources that could be expanded over time and have true cardiovascular differentiation potential is a major obstacle to cardiac cell therapy. 44 Human iPSCs have an unlimited ability to selfrenew and to differentiate into multiple cardiac cell types. Thus, iPSC technology holds the promise of providing cell-based personalized medicine for patient-specific cardiovascular repair.…”

Gene-Edited Human-Induced Pluripotent Stem Cell Lines to Elucidate DAND5 Function throughout Cardiac Differentiation

“…The differentiation of hiPSCs towards cardiac lineages has become a routine but robust procedure in many laboratories worldwide [23][24][25]. Combined with CRISPR-Cas9 gene-editing technology, it is possible to generate a panoply of isogenically matched sets of either patient-derived or healthy and gene-edited cell lines for disease modelling [26]. Here, we made use of our available set of patient-derived hiPSCs lines, NMSUNLi001-A (DAND5-Var) [27] and NMSUNLi00 3 (DAND5-C) [28], bearing the DAND5 c.455G/A variant and the isogenic repaired control to study DAND5 activity during cardiomyocyte differentiation, respectively.…”