Clonal genetic and hematopoietic heterogeneity among human-induced pluripotent stem cell lines

Jason A. Mills; Kai Wang; Prasuna Paluru; Lei Ying; Lin Lu; Aline M. Galvão; Dongbin Xu; Y. Yao; Spencer K. Sullivan; Lisa M. Sullivan; Helen Mac; Amel Omari; Jyh Chang Jean; Steve Shen; Adam Gower; Avi Spira; Gustavo Mostoslavsky; Darrell N. Kotton; Deborah L. French; Mitchell J. Weiss; Paul Gadue

doi:10.1182/blood-2013-02-484444

Clonal genetic and hematopoietic heterogeneity among human-induced pluripotent stem cell lines

Jason A. Mills, Kai Wang, Prasuna Paluru, Lei Ying, Lin Lu, Aline M. Galvão, Dongbin Xu, Y. Yao, Spencer K. Sullivan, Lisa M. Sullivan, Helen Mac, Amel Omari, Jyh Chang Jean, Steve Shen, Adam Gower, Avi Spira, Gustavo Mostoslavsky, Darrell N. Kotton, Deborah L. French, Mitchell J. WeissPaul Gadue

Institute for Health Informatics

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72 Scopus citations

Abstract

Induced pluripotent stem cells (iPSCs) hold great promise for modeling human hematopoietic diseases. However, intrinsic variability in the capacities of different iPSC lines for hematopoietic development complicates comparative studies and is currently unexplained. We created and analyzed 3 separate iPSC clones from fibroblasts of 3 different normal individuals using a standardized approach that included excision of integrated reprogramming genes by Cre-Lox mediated recombination. Gene expression profiling and hematopoietic differentiation assays showed that independent lines from the same individual were generally more similar to one another than those from different individuals. However, one iPSC line (WT2.1) exhibited a distinctly different gene expression, proliferation rate, and hematopoietic developmental potential relative to all other iPSC lines. This “outlier” clone also acquired extensive copy number variations (CNVs) during reprogramming, which may be responsible for its divergent properties. Our data indicate how inherent and acquired genetic differences can influence iPSC properties, including hematopoietic potential.

Original language	English (US)
Pages (from-to)	2047-2051
Number of pages	5
Journal	Blood
Volume	122
Issue number	12
DOIs	https://doi.org/10.1182/blood-2013-02-484444
State	Published - 2013

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grants RC2 HL101606 (M.J.W.), P30DK090969 (M.J.W.), U01 HL099656 (M.J.W., D.L.F., P.G.), and RC2HL101535 (D.N.K, G.M., P.G.).

Funding Information:
M.J.W. is a former Scholar of the Leukemia Lymphoma Society and The Jane Fishman Grinberg Professor of Pediatrics. This work was supported by National Institutes of Health grants RC2 HL101606 (M.J.W.), P30DK090969 (M.J.W.), U01 HL099656 (M.J.W., D.L.F., P.G.), and RC2HL101535 (D.N.K, G.M., P.G.).

Publisher Copyright:
© 2013 by The American Society of Hematology.

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Mills, J. A., Wang, K., Paluru, P., Ying, L., Lu, L., Galvão, A. M., Xu, D., Yao, Y., Sullivan, S. K., Sullivan, L. M., Mac, H., Omari, A., Jean, J. C., Shen, S., Gower, A., Spira, A., Mostoslavsky, G., Kotton, D. N., French, D. L., ... Gadue, P. (2013). Clonal genetic and hematopoietic heterogeneity among human-induced pluripotent stem cell lines. Blood, 122(12), 2047-2051. https://doi.org/10.1182/blood-2013-02-484444

Mills, JA, Wang, K, Paluru, P, Ying, L, Lu, L, Galvão, AM, Xu, D, Yao, Y, Sullivan, SK, Sullivan, LM, Mac, H, Omari, A, Jean, JC, Shen, S, Gower, A, Spira, A, Mostoslavsky, G, Kotton, DN, French, DL, Weiss, MJ & Gadue, P 2013, 'Clonal genetic and hematopoietic heterogeneity among human-induced pluripotent stem cell lines', Blood, vol. 122, no. 12, pp. 2047-2051. https://doi.org/10.1182/blood-2013-02-484444

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abstract = "Induced pluripotent stem cells (iPSCs) hold great promise for modeling human hematopoietic diseases. However, intrinsic variability in the capacities of different iPSC lines for hematopoietic development complicates comparative studies and is currently unexplained. We created and analyzed 3 separate iPSC clones from fibroblasts of 3 different normal individuals using a standardized approach that included excision of integrated reprogramming genes by Cre-Lox mediated recombination. Gene expression profiling and hematopoietic differentiation assays showed that independent lines from the same individual were generally more similar to one another than those from different individuals. However, one iPSC line (WT2.1) exhibited a distinctly different gene expression, proliferation rate, and hematopoietic developmental potential relative to all other iPSC lines. This “outlier” clone also acquired extensive copy number variations (CNVs) during reprogramming, which may be responsible for its divergent properties. Our data indicate how inherent and acquired genetic differences can influence iPSC properties, including hematopoietic potential.",

author = "Mills, {Jason A.} and Kai Wang and Prasuna Paluru and Lei Ying and Lin Lu and Galv{\~a}o, {Aline M.} and Dongbin Xu and Y. Yao and Sullivan, {Spencer K.} and Sullivan, {Lisa M.} and Helen Mac and Amel Omari and Jean, {Jyh Chang} and Steve Shen and Adam Gower and Avi Spira and Gustavo Mostoslavsky and Kotton, {Darrell N.} and French, {Deborah L.} and Weiss, {Mitchell J.} and Paul Gadue",

note = "Funding Information: This work was supported by National Institutes of Health grants RC2 HL101606 (M.J.W.), P30DK090969 (M.J.W.), U01 HL099656 (M.J.W., D.L.F., P.G.), and RC2HL101535 (D.N.K, G.M., P.G.). Funding Information: M.J.W. is a former Scholar of the Leukemia Lymphoma Society and The Jane Fishman Grinberg Professor of Pediatrics. This work was supported by National Institutes of Health grants RC2 HL101606 (M.J.W.), P30DK090969 (M.J.W.), U01 HL099656 (M.J.W., D.L.F., P.G.), and RC2HL101535 (D.N.K, G.M., P.G.). Publisher Copyright: {\textcopyright} 2013 by The American Society of Hematology.",

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T1 - Clonal genetic and hematopoietic heterogeneity among human-induced pluripotent stem cell lines

AU - Mills, Jason A.

AU - Wang, Kai

AU - Paluru, Prasuna

AU - Ying, Lei

AU - Lu, Lin

AU - Galvão, Aline M.

AU - Xu, Dongbin

AU - Yao, Y.

AU - Sullivan, Spencer K.

AU - Sullivan, Lisa M.

AU - Mac, Helen

AU - Omari, Amel

AU - Jean, Jyh Chang

AU - Shen, Steve

AU - Gower, Adam

AU - Spira, Avi

AU - Mostoslavsky, Gustavo

AU - Kotton, Darrell N.

AU - French, Deborah L.

AU - Weiss, Mitchell J.

AU - Gadue, Paul

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PY - 2013

Y1 - 2013

N2 - Induced pluripotent stem cells (iPSCs) hold great promise for modeling human hematopoietic diseases. However, intrinsic variability in the capacities of different iPSC lines for hematopoietic development complicates comparative studies and is currently unexplained. We created and analyzed 3 separate iPSC clones from fibroblasts of 3 different normal individuals using a standardized approach that included excision of integrated reprogramming genes by Cre-Lox mediated recombination. Gene expression profiling and hematopoietic differentiation assays showed that independent lines from the same individual were generally more similar to one another than those from different individuals. However, one iPSC line (WT2.1) exhibited a distinctly different gene expression, proliferation rate, and hematopoietic developmental potential relative to all other iPSC lines. This “outlier” clone also acquired extensive copy number variations (CNVs) during reprogramming, which may be responsible for its divergent properties. Our data indicate how inherent and acquired genetic differences can influence iPSC properties, including hematopoietic potential.

AB - Induced pluripotent stem cells (iPSCs) hold great promise for modeling human hematopoietic diseases. However, intrinsic variability in the capacities of different iPSC lines for hematopoietic development complicates comparative studies and is currently unexplained. We created and analyzed 3 separate iPSC clones from fibroblasts of 3 different normal individuals using a standardized approach that included excision of integrated reprogramming genes by Cre-Lox mediated recombination. Gene expression profiling and hematopoietic differentiation assays showed that independent lines from the same individual were generally more similar to one another than those from different individuals. However, one iPSC line (WT2.1) exhibited a distinctly different gene expression, proliferation rate, and hematopoietic developmental potential relative to all other iPSC lines. This “outlier” clone also acquired extensive copy number variations (CNVs) during reprogramming, which may be responsible for its divergent properties. Our data indicate how inherent and acquired genetic differences can influence iPSC properties, including hematopoietic potential.

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JO - Blood

JF - Blood

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ER -

Clonal genetic and hematopoietic heterogeneity among human-induced pluripotent stem cell lines

Abstract

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