Distinct Responses of Stem Cells to Telomere Uncapping—A Potential Strategy to Improve the Safety of Cell Therapy
| Autor: | Sujoy Ghosh, Chang Ching Liu, Steve Rozen, Dongliang Ma, Eyleen L. K. Goh, Lai-Fong Poon, Tingdong Yan, Vinay Tergaonkar, Shang Li, Zhiyong Poon, William Hwang, Xiubo Fan, Su-Ann Goh, David M. Virshup, Patrick Tan |
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| Přispěvatelé: | 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 LK, Li, Shang |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Telomerase Cellular differentiation Human Embryonic Stem Cells Cell- and Tissue-Based Therapy Mice SCID Biology telomerase stem cell transplantation Gene Knockout Techniques 03 medical and health sciences Cancer stem cell Animals Humans Telomerase reverse transcriptase Induced pluripotent stem cell Telomere Shortening Cell Proliferation Etoposide Neurons telomere Cell Death Genome Human Gene Expression Profiling Teratoma Cell Differentiation cellular therapy Cell Biology Telomere Embryonic stem cell Cell biology 030104 developmental biology Molecular Medicine pluripotent stem cells Stem cell Genetic Engineering Biomarkers Stem Cell Transplantation malignancy Developmental Biology |
| Zdroj: | Stem Cells. 34:2471-2484 |
| ISSN: | 1549-4918 1066-5099 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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