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Systemic signals regulate ageing and rejuvenation of blood stem cell niches
Shane R. Mayack1, Jennifer L. Shadrach1, Francis S. Kim1 & Amy J. Wagers1
1 Department of Stem Cell and Regenerative Biology, Harvard University, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02115, USA
2 Correspondence to: Amy J. Wagers1 Correspondence and requests for materials should be addressed to A.J.W.
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.
