Distinct Responses of Stem Cells to Telomere Uncapping—A Potential Strategy to Improve the Safety of Cell Therapy. (30th June 2016)

• Record Type: Journal Article
• Authors: Liu, Chang Ching; Ma, Dong Liang; Yan, Ting-Dong; Fan, XiuBo; Poon, Zhiyong; Poon, Lai-Fong; Goh, Su-Ann; Rozen, Steve G.; Hwang, William Ying Khee; Tergaonkar, Vinay; Tan, Patrick; Ghosh, Sujoy; Virshup, David M.; Goh, Eyleen L. K.; Li, Shang
• Is Part Of: Stem cells. Volume 34:Number 10(2016:Oct.)
• Page Start: 2471
• Page End: 2484
• Publication Date: 2016-06-30
• Subjects: Stem cell transplantation -- Telomerase -- Telomere -- Pluripotent stem cells -- Malignancy -- Cellular therapy; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2431
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: 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. Abstract : Inactivation of telomerase results in the functional uncoupling of the two unique properties of human pluripotent stem cells, namely self-renewal and pluripotency. This strategy allows us to create pluripotent stem cells with limited lifespan, which dramatically reduce the tumorigenicity of human pluripotent stem cells for clinical applications.