Distinct Responses of Stem Cells to Telomere Uncapping-A Potential Strategy to Improve the Safety of Cell Therapy.
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.
Cancer and Stem Cell Biology Programme.
Chang Ching
CC
Liu
Neuroscience Academic Clinical Programme.|Department of Research, National Neuroscience Institute, Singapore.
Dong Liang
DL
Ma
Cancer and Stem Cell Biology Programme.
Ting-Dong
TD
Yan
Cancer and Stem Cell Biology Programme.|Department of Hematology, Singapore General Hospital, Singapore.
XiuBo
X
Fan
BioSystems and Micromechanics, , Singapore-MIT Alliance for Research & Technology, Singapore.
Zhiyong
Z
Poon
Cancer and Stem Cell Biology Programme.
Lai-Fong
LF
Poon
Cancer and Stem Cell Biology Programme.
Su-Ann
SA
Goh
Cancer and Stem Cell Biology Programme.
Steve G
SG
Rozen
Cancer and Stem Cell Biology Programme.|Department of Hematology, Singapore General Hospital, Singapore.
William Ying Khee
WY
Hwang
Division of Cancer Genetics and Therapeutics, Institute of Molecular and Cell Biology (IMCB), Singapore.|Department of Biochemistry.|Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.
Vinay
V
Tergaonkar
Cancer and Stem Cell Biology Programme.
Patrick
P
Tan
Cardiovascular and Metabolic Disorders Programme, Duke-NUS Medical School, Singapore.
Sujoy
S
Ghosh
Cancer and Stem Cell Biology Programme.
David M
DM
Virshup
Neuroscience Academic Clinical Programme.|Department of Research, National Neuroscience Institute, Singapore.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|KK Women's and Children's Hospital, KK Research Center, Singapore.
Eyleen L K
0000-0002-8244-6959
EL
Goh
Cancer and Stem Cell Biology Programme. shang.li@duke-nus.edu.sg.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. shang.li@duke-nus.edu.sg.
Shang
S
Li
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy / Q000009:adverse effects*; D005047:Etoposide / Q000494:pharmacology; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D005818:Genetic Engineering; D015894:Genome, Human; D000066449:Human Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D006801:Humans; D016513:Mice, SCID; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D033581:Stem Cell Transplantation; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D059506:Telomere Shortening / Q000187:drug effects; D013724:Teratoma / Q000235:genetics / Q000473:pathology
D015415:Biomarkers; D005047:Etoposide; D019098:Telomerase
Cellular therapy; Malignancy; Pluripotent stem cells; Stem cell transplantation; Telomerase; Telomere