TY - JOUR
T1 - The telomere binding protein Pot1 maintains haematopoietic stem cell activity with age
AU - Hosokawa, Kentaro
AU - MacArthur, Ben D.
AU - Ikushima, Yoshiko Matsumoto
AU - Toyama, Hirofumi
AU - Masuhiro, Yoshikazu
AU - Hanazawa, Shigemasa
AU - Suda, Toshio
AU - Arai, Fumio
N1 - Funding Information:
This work was supported by the funding program for Next Generation World-Leading Researchers (NEXT Program), a Scientific Research (B) (General), a grant-in-aid for Young Scientists (A) and a Challenging Exploratory Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, Tokyo Biochemical Research funding, a research grant from the Astellas Foundation for research on metabolic disorders, The Sumitomo Foundation, SENSHIN Medical Research Foundation, Daiichi Sankyo Foundation of Life Science and the European Union's Seventh Framework Programme (FP7/2007–2013) under grant agreement no: 306240 (SyStemAge).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Repeated cell divisions and aging impair stem cell function. However, the mechanisms by which this occurs are not fully understood. Here we show that protection of telomeres 1A (Pot1a), a component of the Shelterin complex that protects telomeres, improves haematopoietic stem cell (HSC) activity during aging. Pot1a is highly expressed in young HSCs, but declines with age. In mouse HSCs, Pot1a knockdown increases DNA damage response (DDR) and inhibits self-renewal. Conversely, Pot1a overexpression or treatment with POT1a protein prevents DDR, maintained self-renewal activity and rejuvenated aged HSCs upon ex vivo culture. Moreover, treatment of HSCs with exogenous Pot1a inhibits the production of reactive oxygen species, suggesting a non-Telomeric role for Pot1a in HSC maintenance. Consistent with these results, treatment with exogenous human POT1 protein maintains human HSC activity in culture. Collectively, these results show that Pot1a/POT1 sustains HSC activity and can be used to expand HSC numbers ex vivo.
AB - Repeated cell divisions and aging impair stem cell function. However, the mechanisms by which this occurs are not fully understood. Here we show that protection of telomeres 1A (Pot1a), a component of the Shelterin complex that protects telomeres, improves haematopoietic stem cell (HSC) activity during aging. Pot1a is highly expressed in young HSCs, but declines with age. In mouse HSCs, Pot1a knockdown increases DNA damage response (DDR) and inhibits self-renewal. Conversely, Pot1a overexpression or treatment with POT1a protein prevents DDR, maintained self-renewal activity and rejuvenated aged HSCs upon ex vivo culture. Moreover, treatment of HSCs with exogenous Pot1a inhibits the production of reactive oxygen species, suggesting a non-Telomeric role for Pot1a in HSC maintenance. Consistent with these results, treatment with exogenous human POT1 protein maintains human HSC activity in culture. Collectively, these results show that Pot1a/POT1 sustains HSC activity and can be used to expand HSC numbers ex vivo.
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U2 - 10.1038/s41467-017-00935-4
DO - 10.1038/s41467-017-00935-4
M3 - Article
C2 - 28986560
AN - SCOPUS:85030786524
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 804
ER -