TY - JOUR
T1 - Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease
AU - Lewis-Israeli, Yonatan R.
AU - Wasserman, Aaron H.
AU - Gabalski, Mitchell A.
AU - Volmert, Brett D.
AU - Ming, Yixuan
AU - Ball, Kristen A.
AU - Yang, Weiyang
AU - Zou, Jinyun
AU - Ni, Guangming
AU - Pajares, Natalia
AU - Chatzistavrou, Xanthippi
AU - Li, Wen
AU - Zhou, Chao
AU - Aguirre, Aitor
N1 - Funding Information:
We wish to thank the MSU Advanced Microscopy Core and Dr. William Jackson at the MSU Department of Pharmacology and Toxicology for access to confocal microscopes, and the MSU Genomics Core for sequencing services. We also wish to thank all members of the Aguirre Lab for their valuable comments and advice. Work in Dr. Aguirre’s laboratory was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award numbers K01HL135464, R01HL151505, by the American Heart Association under award number 19IPLOI34660342 and by the Spectrum-MSU Foundation. Work in Dr. Zhou’s laboratory was supported by grants from the National Institutes of Health under award number R01EB025209. Work in Dr. Li’s laboratory was supported in part by the National Science Foundation under award number ECCS-2024270 and Michigan State University Graduate Excellence Fellowship.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Congenital heart defects constitute the most common human birth defect, however understanding of how these disorders originate is limited by our ability to model the human heart accurately in vitro. Here we report a method to generate developmentally relevant human heart organoids by self-assembly using human pluripotent stem cells. Our procedure is fully defined, efficient, reproducible, and compatible with high-content approaches. Organoids are generated through a three-step Wnt signaling modulation strategy using chemical inhibitors and growth factors. Heart organoids are comparable to age-matched human fetal cardiac tissues at the transcriptomic, structural, and cellular level. They develop sophisticated internal chambers with well-organized multi-lineage cardiac cell types, recapitulate heart field formation and atrioventricular specification, develop a complex vasculature, and exhibit robust functional activity. We also show that our organoid platform can recreate complex metabolic disorders associated with congenital heart defects, as demonstrated by an in vitro model of pregestational diabetes-induced congenital heart defects.
AB - Congenital heart defects constitute the most common human birth defect, however understanding of how these disorders originate is limited by our ability to model the human heart accurately in vitro. Here we report a method to generate developmentally relevant human heart organoids by self-assembly using human pluripotent stem cells. Our procedure is fully defined, efficient, reproducible, and compatible with high-content approaches. Organoids are generated through a three-step Wnt signaling modulation strategy using chemical inhibitors and growth factors. Heart organoids are comparable to age-matched human fetal cardiac tissues at the transcriptomic, structural, and cellular level. They develop sophisticated internal chambers with well-organized multi-lineage cardiac cell types, recapitulate heart field formation and atrioventricular specification, develop a complex vasculature, and exhibit robust functional activity. We also show that our organoid platform can recreate complex metabolic disorders associated with congenital heart defects, as demonstrated by an in vitro model of pregestational diabetes-induced congenital heart defects.
UR - http://www.scopus.com/inward/record.url?scp=85113773676&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-25329-5
DO - 10.1038/s41467-021-25329-5
M3 - Article
C2 - 34446706
AN - SCOPUS:85113773676
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5142
ER -