Ageing in multicellular organisms typically involves a progressive decline in cell replacement and repair processes, resulting in several physiological deficiencies, including inefficient muscle repair, reduced bone mass, and dysregulation of blood formation (haematopoiesis). Although defects in tissue-resident stem cells clearly contribute to these phenotypes, it is unclear to what extent they reflect stem cell intrinsic alterations or age-related changes in the stem cell supportive microenvironment, or niche. Here, using complementary in vivo and in vitro heterochronic models, we show that age-associated changes in stem cell supportive niche cells deregulate normal haematopoiesis by causing haematopoietic stem cell dysfunction. Furthermore, we find that age-dependent defects in niche cells are systemically regulated and can be reversed by exposure to a young circulation or by neutralization of the conserved longevity regulator, insulin-like growth factor-1, in the marrow microenvironment. Together, these results show a new and critical role for local and systemic factors in signalling age-related haematopoietic decline, and highlight a new model in which blood-borne factors in aged animals act through local niche cells to induce age-dependent disruption of stem cell function.
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This work was supported in part by funding from the Burroughs-Welcome Fund, WM Keck Foundation, Glenn Foundation, and National Institutes of Health (NIH) 1 DP2 OD004345-01 (to A.J.W.), by fellowships from the NIH (T32DK07260-29) and the Iacocca Foundation (to S.R.M.), and by the Joslin Diabetes Center DERC (P30DK036836). We thank J. LaVecchio and G. Buruzula for expert cell sorting, C. J. Luckey for anti-IGF-1 antibody, and L. Zon, R. Lee, D. Rossi, L. P. Kane, S. Lowe and C. Dall’Osso for helpful advice and critical reading of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Author Contributions S.R.M. and A.J.W. designed and interpreted experiments. S.R.M. performed and analysed the experiments. J.L.S. assisted in parabiosis procedures, and F.S.K. assisted in LT-HSC analysis from parabiotic mice.
The authors declare no competing financial interests.
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Mayack, S., Shadrach, J., Kim, F. et al. Systemic signals regulate ageing and rejuvenation of blood stem cell niches. Nature 463, 495–500 (2010). https://doi.org/10.1038/nature08749
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