Haematopoietic stem cells in perisinusoidal niches are protected from ageing

Nat Cell Biol. 2019 Nov;21(11):1309-1320. doi: 10.1038/s41556-019-0418-y. Epub 2019 Nov 4.

Abstract

With ageing, intrinsic haematopoietic stem cell (HSC) activity decreases, resulting in impaired tissue homeostasis, reduced engraftment following transplantation and increased susceptibility to diseases. However, whether ageing also affects the HSC niche, and thereby impairs its capacity to support HSC function, is still widely debated. Here, by using in-vivo long-term label-retention assays we demonstrate that aged label-retaining HSCs, which are, in old mice, the most quiescent HSC subpopulation with the highest regenerative capacity and cellular polarity, reside predominantly in perisinusoidal niches. Furthermore, we demonstrate that sinusoidal niches are uniquely preserved in shape, morphology and number on ageing. Finally, we show that myeloablative chemotherapy can selectively disrupt aged sinusoidal niches in the long term, which is linked to the lack of recovery of endothelial Jag2 at sinusoids. Overall, our data characterize the functional alterations of the aged HSC niche and unveil that perisinusoidal niches are uniquely preserved and thereby protect HSCs from ageing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics*
  • Aging / metabolism
  • Animals
  • Bone Marrow / drug effects
  • Bone Marrow / metabolism
  • Capillaries / cytology
  • Capillaries / drug effects
  • Capillaries / metabolism*
  • Cell Differentiation / drug effects
  • Cell Division / drug effects
  • Cell Polarity / drug effects
  • Cell Tracking / methods
  • Doxycycline / pharmacology
  • Fluorouracil / pharmacology
  • Gene Expression Regulation
  • Genes, Reporter
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism*
  • Histones / genetics
  • Histones / metabolism
  • Homeostasis / drug effects
  • Homeostasis / genetics*
  • Jagged-2 Protein / genetics
  • Jagged-2 Protein / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloablative Agonists / pharmacology
  • Stem Cell Niche / drug effects
  • Stem Cell Niche / genetics*

Substances

  • Histones
  • Jag2 protein, mouse
  • Jagged-2 Protein
  • Myeloablative Agonists
  • Green Fluorescent Proteins
  • Doxycycline
  • Fluorouracil