Molecular and functional resemblance of differentiated cells derived from isogenic human iPSCs and SCNT-derived ESCs

Ming Tao Zhao, Haodong Chen, Qing Liu, Ning Yi Shao, Nazish Sayed, Hung Ta Wo, Joe Z. Zhang, Sang Ging Ong, Chun Liu, Youngkyun Kim, Huaxiao Yang, Tony Chour, Hong Ma, Nuria Marti Gutierrez, Ioannis Karakikes, Shoukhrat Mitalipov, Michael P. Snyder, Joseph C. Wu

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E11111-E11120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number52
DOIs
StatePublished - Dec 26 2017

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Induced Pluripotent Stem Cells
Pluripotent Stem Cells
Fertilization in Vitro
Embryonic Structures
Drug Design
DNA
Embryonic Stem Cells
Mitochondrial DNA
Transcriptome
Cardiac Myocytes
Doxorubicin
Reactive Oxygen Species
Transcription Factors
Endothelial Cells
Gene Expression

Keywords

  • Cardiomyocytes
  • Embryonic stem cells
  • In vitro fertilization
  • Induced pluripotent stem cells
  • Somatic cell nuclear transfer

ASJC Scopus subject areas

  • General

Cite this

Molecular and functional resemblance of differentiated cells derived from isogenic human iPSCs and SCNT-derived ESCs. / Zhao, Ming Tao; Chen, Haodong; Liu, Qing; Shao, Ning Yi; Sayed, Nazish; Wo, Hung Ta; Zhang, Joe Z.; Ong, Sang Ging; Liu, Chun; Kim, Youngkyun; Yang, Huaxiao; Chour, Tony; Ma, Hong; Gutierrez, Nuria Marti; Karakikes, Ioannis; Mitalipov, Shoukhrat; Snyder, Michael P.; Wu, Joseph C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 52, 26.12.2017, p. E11111-E11120.

Research output: Contribution to journalArticle

Zhao, MT, Chen, H, Liu, Q, Shao, NY, Sayed, N, Wo, HT, Zhang, JZ, Ong, SG, Liu, C, Kim, Y, Yang, H, Chour, T, Ma, H, Gutierrez, NM, Karakikes, I, Mitalipov, S, Snyder, MP & Wu, JC 2017, 'Molecular and functional resemblance of differentiated cells derived from isogenic human iPSCs and SCNT-derived ESCs', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 52, pp. E11111-E11120. https://doi.org/10.1073/pnas.1708991114
Zhao, Ming Tao ; Chen, Haodong ; Liu, Qing ; Shao, Ning Yi ; Sayed, Nazish ; Wo, Hung Ta ; Zhang, Joe Z. ; Ong, Sang Ging ; Liu, Chun ; Kim, Youngkyun ; Yang, Huaxiao ; Chour, Tony ; Ma, Hong ; Gutierrez, Nuria Marti ; Karakikes, Ioannis ; Mitalipov, Shoukhrat ; Snyder, Michael P. ; Wu, Joseph C. / Molecular and functional resemblance of differentiated cells derived from isogenic human iPSCs and SCNT-derived ESCs. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 52. pp. E11111-E11120.
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abstract = "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.",
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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.

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

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