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Distinct Responses of Stem Cells to Telomere Uncapping-A Potential Strategy to Improve the Safety of Cell Therapy.

Publication ,  Journal Article
Liu, CC; Ma, DL; Yan, T-D; Fan, X; Poon, Z; Poon, L-F; Goh, S-A; Rozen, SG; Hwang, WYK; Tergaonkar, V; Tan, P; Ghosh, S; Virshup, DM; Goh, ELK; Li, S
Published in: Stem Cells
October 2016

In most human somatic cells, the lack of telomerase activity results in progressive telomere shortening during each cell division. Eventually, DNA damage responses triggered by critically short telomeres induce an irreversible cell cycle arrest termed replicative senescence. However, the cellular responses of human pluripotent stem cells to telomere uncapping remain unknown. We generated telomerase knockout human embryonic stem (ES) cells through gene targeting. Telomerase inactivation in ES cells results in progressive telomere shortening. Telomere DNA damage in ES cells and neural progenitor cells induces rapid apoptosis when telomeres are uncapped, in contrast to fibroblast cells that enter a state of replicative senescence. Significantly, telomerase inactivation limits the proliferation capacity of human ES cells without affecting their pluripotency. By targeting telomerase activity, we can functionally separate the two unique properties of human pluripotent stem cells, namely unlimited self-renewal and pluripotency. We show that the potential of ES cells to form teratomas in vivo is dictated by their telomere length. By controlling telomere length of ES cells through telomerase inactivation, we can inhibit teratoma formation and potentially improve the safety of cell therapies involving terminally differentiated cells as well as specific progenitor cells that do not require sustained cellular proliferation in vivo, and thus sustained telomerase activity. Stem Cells 2016;34:2471-2484.

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Published In

Stem Cells

DOI

EISSN

1549-4918

Publication Date

October 2016

Volume

34

Issue

10

Start / End Page

2471 / 2484

Location

England

Related Subject Headings

  • Teratoma
  • Telomere Shortening
  • Telomere
  • Telomerase
  • Stem Cell Transplantation
  • Neurons
  • Mice, SCID
  • Immunology
  • Humans
  • Human Embryonic Stem Cells
 

Citation

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Liu, C. C., Ma, D. L., Yan, T.-D., Fan, X., Poon, Z., Poon, L.-F., … Li, S. (2016). Distinct Responses of Stem Cells to Telomere Uncapping-A Potential Strategy to Improve the Safety of Cell Therapy. Stem Cells, 34(10), 2471–2484. https://doi.org/10.1002/stem.2431
Liu, Chang Ching, Dong Liang Ma, Ting-Dong Yan, XiuBo Fan, Zhiyong Poon, Lai-Fong Poon, Su-Ann Goh, et al. “Distinct Responses of Stem Cells to Telomere Uncapping-A Potential Strategy to Improve the Safety of Cell Therapy.Stem Cells 34, no. 10 (October 2016): 2471–84. https://doi.org/10.1002/stem.2431.
Liu CC, Ma DL, Yan T-D, Fan X, Poon Z, Poon L-F, et al. Distinct Responses of Stem Cells to Telomere Uncapping-A Potential Strategy to Improve the Safety of Cell Therapy. Stem Cells. 2016 Oct;34(10):2471–84.
Liu, Chang Ching, et al. “Distinct Responses of Stem Cells to Telomere Uncapping-A Potential Strategy to Improve the Safety of Cell Therapy.Stem Cells, vol. 34, no. 10, Oct. 2016, pp. 2471–84. Pubmed, doi:10.1002/stem.2431.
Liu CC, Ma DL, Yan T-D, Fan X, Poon Z, Poon L-F, Goh S-A, Rozen SG, Hwang WYK, Tergaonkar V, Tan P, Ghosh S, Virshup DM, Goh ELK, Li S. Distinct Responses of Stem Cells to Telomere Uncapping-A Potential Strategy to Improve the Safety of Cell Therapy. Stem Cells. 2016 Oct;34(10):2471–2484.
Journal cover image

Published In

Stem Cells

DOI

EISSN

1549-4918

Publication Date

October 2016

Volume

34

Issue

10

Start / End Page

2471 / 2484

Location

England

Related Subject Headings

  • Teratoma
  • Telomere Shortening
  • Telomere
  • Telomerase
  • Stem Cell Transplantation
  • Neurons
  • Mice, SCID
  • Immunology
  • Humans
  • Human Embryonic Stem Cells