TY - JOUR
T1 - Molecular and functional resemblance of differentiated cells derived from isogenic human iPSCs and SCNT-derived ESCs
AU - Zhao, Ming Tao
AU - Chen, Haodong
AU - Liu, Qing
AU - Shao, Ning Yi
AU - Sayed, Nazish
AU - Wo, Hung Ta
AU - Zhang, Joe Z.
AU - Ong, Sang Ging
AU - Liu, Chun
AU - Kim, Youngkyun
AU - Yang, Huaxiao
AU - Chour, Tony
AU - Ma, Hong
AU - Gutierrez, Nuria Marti
AU - Karakikes, Ioannis
AU - Mitalipov, Shoukhrat
AU - Snyder, Michael P.
AU - Wu, Joseph C.
N1 - Funding Information:
We thank Caressa Chen for helping with Ion Torrent sequencing; Yingxin Li for electrophysiological analysis; and Larry Bowen and Blake Wu for critical editing of this manuscript. Reduced-representation bisulfite sequencing was performed at the Genome Sequencing Service Center by Stanford Center for Genomics and Personalized Medicine, supported by NIH Grant S10OD020141. This study was supported by NIH Grants R01 HL113006, R01 HL126527, R01 HL123968, and R01 HL130020 (to J.C.W.), R24 HL117756 (to J.C.W. and M.P.S.), and P01 GM099130 (to M.P.S.); and California Institute for Regenerative Medicine (CIRM) Grant GC1R- 06673-A (to M.P.S.) and CIRM Grant RT3-07798 (to J.C.W.); and AHA Grants 17MERIT33610009 (to J.C.W.) and 17IRG33410532 (to I.K.). Studies in the laboratory of S.M. were supported by the Leducq Foundation and OHSU Institutional funds. M.-T.Z. and Q.L. were partially supported by research awards from the Lucile Packard Foundation for Children's Health, Stanford NIH-National Center for Advancing Translational Sciences-Clinical Translational Science Award UL1 TR001085, and the Child Health Research Institute of Stanford University.
Funding Information:
ACKNOWLEDGMENTS. We thank Caressa Chen for helping with Ion Torrent sequencing; Yingxin Li for electrophysiological analysis; and Larry Bowen and Blake Wu for critical editing of this manuscript. Reduced-representation bisulfite sequencing was performed at the Genome Sequencing Service Center by Stanford Center for Genomics and Personalized Medicine, supported by NIH Grant S10OD020141. This study was supported by NIH Grants R01 HL113006, R01 HL126527, R01 HL123968, and R01 HL130020 (to J.C.W.), R24 HL117756 (to J.C.W. and M.P.S.), and P01 GM099130 (to M.P.S.); and California Institute for Regenerative Medicine (CIRM) Grant GC1R-06673-A (to M.P.S.) and CIRM Grant RT3-07798 (to J.C.W.); and AHA Grants 17MERIT33610009 (to J.C.W.) and 17IRG33410532 (to I.K.). Studies in the laboratory of S.M. were supported by the Leducq Foundation and OHSU Institutional funds. M.-T.Z. and Q.L. were partially supported by research awards from the Lucile Packard Foundation for Children’s Health, Stanford NIH-National Center for Advancing Translational Sciences-Clinical Translational Science Award UL1 TR001085, and the Child Health Research Institute of Stanford University.
PY - 2017/12/26
Y1 - 2017/12/26
N2 - 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. Genomewide 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.
AB - 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. Genomewide 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.
KW - Cardiomyocytes
KW - Embryonic stem cells
KW - In vitro fertilization
KW - Induced pluripotent stem cells
KW - Somatic cell nuclear transfer
UR - http://www.scopus.com/inward/record.url?scp=85039707623&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85039707623&partnerID=8YFLogxK
U2 - 10.1073/pnas.1708991114
DO - 10.1073/pnas.1708991114
M3 - Article
C2 - 29203658
AN - SCOPUS:85039707623
SN - 0027-8424
VL - 114
SP - E11111-E11120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 52
ER -