Bone marrow niches for hematopoietic stem cells in homeostasis and aging

Abstract

Among various types of candidate cells, including osteoblasts and Nestin⁺ periarteriolar cells, several lines of histological and genetic evidence have demonstrated that the single population of mesenchymal stem cells, termed CXC chemokine ligand 12 (CXCL12)–abundant reticular (CAR) cells, which overlap strongly with leptin receptor–expressing (LepR⁺) cells, is the major cellular component of niches for hematopoietic stem cells (HSCs) and hematopoiesis in the bone marrow (BM). Expression of p16, a marker for senescent cells, and interleukin (IL)-1β and γH2AX foci, a marker for DNA damage, were increased in CAR/LepR⁺ cells and osteoblasts with age. However, the most striking phenotype of aging in the human BM is yellow marrow, which consists predominantly of adipocytes, causing the decreased volume of the principal site of hematopoiesis probably with the decreased numbers of HSCs in the total body. BM adipocytes are derived from CAR/LepR⁺ cells and act as negative or positive regulators of HSCs during homeostasis and myelosuppressive condition. Therefore, a fundamental question is how a portion of BM CAR/LepR⁺ cells differentiate into adipocytes during aging. Many rounds of inflammatory stress induced yellow marrow in mice. On the other hand, type H vessels found in the metaphysis and peripheral nerves running along the arteries were markedly reduced in the marrow of aged mice, which might affect HSCs and/or their niche cells. Understanding the cellular and molecular function of aged HSC niches could enable pharmacological regulation of niche functions to facilitate control of disease caused by BM aging.