Challenge to the ex vivo expansion technology of human hematopoietic stem cells by exogenous telomere-binding protein POT1

2014 Fiscal Year Final Research Report

• Project/Area Number: 25670453
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Kyushu University (2014); Keio University (2013)
• Principal Investigator: HOSOKAWA Kentaro 九州大学, 医学(系)研究科(研究院), 助教 (90569584)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 造血幹細胞 / 体外増幅 / テロメア / DNA損傷応答 / 老化 / 自己複製

Outline of Final Research Achievements

Repeated cell divisions induce DNA damage accumulation, which impair stem cell function during ageing. However, the general molecular mechanisms by which this occurs remain unclear. Here, we show that expression of Pot1a, a component of shelterin, is crucial for the prevention of telomeric DNA damage response (DDR) and maintenance of hematopoietic stem cell (HSC) activity during ageing. We observed that HSCs express high levels of Pot1a during development, yet this expression declines with age. Knockdown of Pot1a induced an age-related phenotype, marked by increased telomeric DDR, and reduced long-term reconstitution activity. In contrast, overexpression of Pot1a or treatment with exogenous Pot1a protein prevented telomeric DDR, enhanced telomerase activity. Similar result was observed upon treatment of human HSCs with recombinant human POT1 protein. These results highlight a general, reversible mechanism by which ageing compromises mammalian stem cell activity.

Free Research Field

幹細胞生物学