FBS Colloquia No.167Laboratory of Stem Cell Biology and Developmental Immunology

Numerous niches for hematopoietic stem cells remain empty during homeostasis

Hematopoietic stem cells (HSCs) reside in and are maintained by specialized bone marrow microenvironments, termed niches, and generate all lineages of blood and immune cells throughout life. It has long been assumed that the HSC niche space remains occupied by endogenous cells and that myelosuppressive conditioning is required to achieve high levels of HSC engraftment. On the other hand, previous work, including our own, identified bone marrow sinusoidal endothelial cells (ECs) and a population of mesenchymal cells with long processes, expressing high amounts of CXCL12, termed CXCL12-abundant reticular (CAR) cells, are key components of HSC niches. The numbers of sinusoidal ECs and CAR cells were markedly larger than HSC numbers, raising the possibility that there are numerous empty niches for HSC. To address this issue, we demonstrate that upon the transplantation of very large numbers of purified HSCs into normal mice not exposed to myeloablation, donor HSCs engrafted in niches distant from filled HSC niches without replacing host HSCs and subsequently proliferated and generated hematopoietic progenitors, leading to marked increases in the overall HSC numbers in bone marrow. Additionally, stem cell factor that is produced by CAR cells is involved in HSC engraftment. In contrast, host granulocyte/macrophage progenitors (GMPs) were replaced by the progeny of transplanted donor HSCs, and overall GMP numbers remained unchanged. Thus, inconsistent with the classical concept, numerous empty HSC niches are available for engraftment and proliferation in bone marrow. Our results prompt the reevaluation of a long debate on HSC niche saturation, indicate that the rarity of HSCs is not a consequence of space limitations, and suggest that we do not have to consider the availability of HSC niches to achieve efficient HSC engraftment in clinical bone marrow transplantation.