Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 52, Pages E11111-E11120Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1708991114
Keywords
somatic cell nuclear transfer; in vitro fertilization; embryonic stem cells; induced pluripotent stem cells; cardiomyocytes
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Funding
- NIH [S10OD020141, R01 HL113006, R01 HL126527, R01 HL123968, R01 HL130020, R24 HL117756, P01 GM099130]
- California Institute for Regenerative Medicine (CIRM) Grant [GC1R06673-A]
- CIRM Grant [RT3-07798]
- AHA Grants [17MERIT33610009, 17IRG33410532]
- Leducq Foundation
- OHSU Institutional funds
- Lucile Packard Foundation for Children's Health
- Stanford NIH-National Center for Advancing Translational Sciences-Clinical Translational Science Award [UL1 TR001085]
- Child Health Research Institute of Stanford University
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Patient-specific pluripotent stem cells (PSCs) can be generated via nuclear reprogramming by transcription factors (i.e., induced pluripotent stem cells, iPSCs) or by somatic cell nuclear transfer (SCNT). However, abnormalities and preclinical application of differentiated cells generated by different reprogramming mechanisms have yet to be evaluated. Here we investigated the molecular and functional features, and drug response of cardiomyocytes (PSC-CMs) and endothelial cells (PSC-ECs) derived from genetically relevant sets of human iPSCs, SCNT-derived embryonic stem cells (nt-ESCs), as well as in vitro fertilization embryo-derived ESCs (IVF-ESCs). We found that differentiated cells derived from isogenic iPSCs and nt-ESCs showed comparable lineage gene expression, cellular heterogeneity, physiological properties, and metabolic functions. Genome-wide transcriptome and DNA methylome analysis indicated that iPSC derivatives (iPSC-CMs and iPSC-ECs) were more similar to isogenic nt-ESC counterparts than those derived from IVF-ESCs. Although iPSCs and nt-ESCs shared the same nuclear DNA and yet carried different sources of mitochondrial DNA, CMs derived from iPSC and nt-ESCs could both recapitulate doxorubicin-induced cardiotoxicity and exhibited insignificant differences on reactive oxygen species generation in response to stress condition. We conclude that molecular and functional characteristics of differentiated cells from human PSCs are primarily attributed to the genetic compositions rather than the reprogramming mechanisms (SCNT vs. iPSCs). Therefore, human iPSCs can replace nt-ESCs as alternatives for generating patient-specific differentiated cells for disease modeling and preclinical drug testing.
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