Repeated cell divisions induce DNA damage accumulation, which impair stem ce ll function during ageing. However
the general molecular mechanisms by whic h this occurs remain unclear. Here, we show that expression of
protection of telomeres 1a (Pot1a), a component of shelterin, is crucial for the preventi on of telomeric
DNA damage response (DDR) and maintenance of hematopoietic s tem cell (HSC) activity during ageing. We observed
that HSCs express high le vels of Pot1a during development, yet this expression declines with age. Kno ckdown
of Pot1a induced an age-related phenotype, marked by increased telome ric DDR, and reduced long-term
reconstitution activity. In contrast, overexp ression of Pot1a or treatment with exogenous Pot1a protein
prevented telomer ic DDR, enhanced telomerase activity and rejuvenated HSC activity. Similar r ejuvenation
was observed upon treatment of human HSCs with recombinant human
POT1 protein. These results highlight a general, reversible mechanism by wh ich ageing compromises mammalian
stem cell activity, with widespread implica tions for regenerative medicine.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41467-017-00935-4

Language：English  

Language：English  

Language：English  

Language：English   Publisher：Communications Biology  

Protection of telomeres 1a (POT1a) is a telomere binding protein. A decrease of POT1a is related to myeloid-skewed haematopoiesis with ageing, suggesting that protection of telomeres is essential to sustain multi-potency. Since mesenchymal stem cells (MSCs) are a constituent of the hematopoietic niche in bone marrow, their dysfunction is associated with haematopoietic failure. However, the importance of telomere protection in MSCs has yet to be elucidated. Here, we show that genetic deletion of POT1a in MSCs leads to intracellular accumulation of fatty acids and excessive ROS and DNA damage, resulting in impaired osteogenic-differentiation. Furthermore, MSC-specific POT1a deficient mice exhibited skeletal retardation due to reduction of IL-7 producing bone lining osteoblasts. Single-cell gene expression profiling of bone marrow from POT1a deficient mice revealed that B-lymphopoiesis was selectively impaired. These results demonstrate that bone marrow microenvironments composed of POT1a deficient MSCs fail to support B-lymphopoiesis, which may underpin age-related myeloid-bias in haematopoiesis.

DOI： 10.1038/s42003-023-05374-0

Web of Science

Scopus

PubMed

Responsible for pages：1266 (1): 72-77   Language：English   Book type：Scholarly book

Cell-cell and cell-extracellular matrix interactions between hematopoietic stem cells (HSCs) and their niches are critical for the maintenance of stem cell properties. Here, it is demonstrated that a cell adhesion molecule, N-cadherin, is expressed in hematopoietic stem/progenitor cells (HSPCs) and plays a critical role in the regulation of HSPC engraftment. Furthermore, overexpression of N-cadherin in HSCs promoted quiescence and preserved HSC activity during serial bone marrow (BM) transplantation (BMT). Inhibition of N-cadherin by the transduction of N-cadherin short hairpin (sh) RNA (shN-cad) reduced the lodgment of donor HSCs to the endosteal surface, resulting in a significant reduction in long-term engraftment. shN-cad-transduced cells were maintained in the spleen for six months after BMT, indicating that N-cadherin expression in HSCs is specifically required in the BM. These findings suggest that N-cadherin-mediated cell adhesion is functionally essential for the regulation of HSPC activities in the BM niche.

DOI： 10.1111/j.1749-6632.2012.06576.x.

Responsible for pages：pp. 1-13 ISBN 978-94-007-4330-4   Language：English   Book type：Scholarly book

Responsible for pages：1176:36-46   Language：English   Book type：Scholarly book

During postnatal life, the bone marrow (BM) supports both the self-renewal and differentiation of hematopoietic stem cells (HSCs) in specialized niches. The interaction of HSCs with their niches also regulates the quiescence of HSCs. HSC quiescence is critical to ensure lifelong hematopoiesis and to protect the HSC pool from myelotoxic insult and premature exhaustion under conditions of hematopoietic stress. Here we identified long-term (LT)-HSCs expressing the thrombopoietin (THPO) receptor, Mpl, as a quiescent population in adult BM. THPO was produced by bone-lining cells in the endosteum. Inhibition and stimulation of the THPO/Mpl pathway produced opposite effects on the quiescence of LT-HSC. Exogenous THPO transiently increased the quiescent LT-HSC population, such as side-population and pyronin Y-negative cells. In contrast, administration of an anti-Mpl neutralizing antibody, AMM2, suppressed the quiescence of LT-HSCs and enabled HSC engraftment without irradiation, indicating that inhibition of THPO/Mpl signaling reduces HSC-niche interactions. Moreover, it suggests that inhibiting the HSC-niche interaction could represent a novel technique for bone marrow transplantation without irradiation. Altogether, these data suggest that the THPO/Mpl signaling pathway is a novel niche component in the endosteum, and in the steady-state condition, this signaling pathway plays a critical role in the regulation of LT-HSCs in the osteoblastic niche.

Event date： 2022.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2017.8

Language：English  

Venue：Goethe University   Country：Germany  

Event date： 2015.8

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：九州大学　病院キャンパス   Country：Japan  

Event date： 2014.8

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：Hyatt Regency Montreal, Montreal   Country：Canada  

Other Link： https://iseh.site-ym.com/

Event date： 2014.5

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：福岡県　福岡市　九州大学　医学部　百年講堂   Country：Japan  

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

DOI： doi: 10.1007/s12185-018-2432-4

Other Link： https://link.springer.com/article/10.1007%2Fs12185-018-2432-4

Repository Public URL： https://hdl.handle.net/2324/7172610

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Repeated cell divisions induce DNA damage accumulation, which impairs stem cell function during aging. However, the general molecular mechanisms by which this occurs remain unclear. Herein, we show that the expression of protection of telomeres 1a (Pot1a), a component of shelterin, is crucial for prevention of telomeric DNA damage response (DDR) and maintenance of hematopoietic stem cell (HSC) activity during aging. We observed that HSCs express high levels of Pot1a during development, and this expression declines with aging. Knockdown of Pot1a induced an age-related phenotype, characterized by increased telomeric DDR and reduced long-term reconstitution activity. In contrast, treatment with exogenous Pot1a protein prevented telomeric DDR, which decreased stem cell activity and partially rejuvenated HSC activity. These results highlight a general, reversible mechanism by which aging compromises mammalian stem cell activity, with widespread implications for regenerative medicine.

DOI： 10.11406/rinketsu.58.942

Type：Competition, symposium, etc.