Systemic signals regulate ageing and rejuvenation of blood stem cell niches.
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.
Mayack
Shane R
SR
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.
Shadrach
Jennifer L
JL
Kim
Francis S
FS
Wagers
Amy J
AJ
D000375:Aging / Q000097:blood / Q000502:physiology*; D000818:Animals; D001773:Blood Cells / Q000166:cytology / Q000502:physiology*; D001853:Bone Marrow / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D006410:Hematopoiesis / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology; D012060:Rejuvenation / Q000502:physiology*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
D007334:Insulin-Like Growth Factor I