Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches

Abstract

While haematopoietic stem cells (HSCs) are commonly assumed to reside within a specialized microenvironment, or niche1, most published experimental manipulations of the HSC niche have also impacted the function of diverse restricted progenitors. This raises the fundamental question of whether HSCs1 and restricted progenitors2,3 reside within distinct, specialized niches or whether they share a common niche. Here we assess the physiological sources of the chemokine, CXCL12, for HSC and restricted progenitor maintenance. Cxcl12DsRed knock-in mice showed that Cxcl12 was primarily expressed by perivascular stromal cells and at lower levels by endothelial cells, osteoblasts, and some haematopoietic cells. Conditional deletion of Cxcl12 from haematopoietic cells or Nestin-cre-expressing cells had little or no effect on HSCs or restricted progenitors. Deletion of Cxcl12 from endothelial cells depleted HSCs but not myeloerythroid or lymphoid progenitors. Deletion of Cxcl12 from perivascular stromal cells depleted HSCs and certain restricted progenitors and mobilized these cells into circulation. Deletion of Cxcl12 from osteoblasts depleted certain early lymphoid progenitors, but not HSCs or myeloerythroid progenitors and did not mobilize these cells into circulation. Different stem/progenitor cells thus occupy distinct cellular niches in bone marrow: HSCs in a perivascular niche and early lymphoid progenitors in an endosteal niche.

Quantification and three-dimensional microanatomical organization of the bone marrow

“…13 Moreover, early lymphoid progenitor IL-7 receptor-expressing cells have been observed to preferentially distribute toward the proximity of endosteal surfaces and functionally depend on osteoblast-derived signals. 48,68 Collectively, these data point to the possibility that progression downstream of the hematopoietic hierarchy could correlate with a centripetal movement away from bone surfaces toward deeper regions of the BM. However, this conceptually attractive hypothesis is challenged by 2 recent studies.…”

“…108 Plasma B cells are long-lived antibody-secreting cells that have been found in physical association to CAR cells, megakaryoctes, and eosinophils (eos). [109][110][111] (iv) Although a significant fraction (30%) of early lymphoid progenitors (Lin 2 IL7-ra 1 ) has been shown to lie proximal to mature, bone-lining osteoblasts, 48 the vast majority of phenotypically defined CLPs are in contact with IL-7-expressing CAR cells. 50 Quiescent CD4 1 memory T cells are found scattered throughout the BM in contact with perisinusoidal IL-7-secreting stromal cells.…”

“…These fibroblast-like reticular cells have been generically defined in mice by expression of common markers (leptin receptor and CD140a), and the secretion of large amounts, at least by a substantial fraction of this population, of regulatory factors such as interleukin-7 (IL-7), stem cell factor, and CXCL12. 31,[47][48][49][50] For this feature, they were first visualized in the CXCL12-GFP knock-in mouse model and termed CXCL12-abundant reticular (CAR) cells. 51 Multiple studies have now shown that CAR cells are fundamental players in the regulation of specific and very distinct stages of hematopoiesis.…”

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

“…NG2 + LepR + Nes bright reticular‐like MSCs are mostly perisinusoidal in localization, and are located more in the central BM cavity, away from the endosteum 33 (Figure 1). Perivascular MSCs are directly involved in maintaining HSCs in the BM niche, as shown by a series of studies investigating the consequence of either Nes ‐mediated or Cxcl12 ‐mediated MSC ablation 26, 27 or Lepr ‐mediated or Prx1 ‐mediated deletion of Scf and Cxcl12 expression in MSCs 22, 23, 29. Nes‐MSCs also express genes that are important for HSC maintenance, such as Cxcl12 , Scf , and ANGPT1 , although their ablation results in a minor loss of HSCs within the BM 11.…”

Human mesenchymal and murine stromal cells support human lympho-myeloid progenitor expansion but not maintenance of multipotent haematopoietic stem and progenitor cells

“…This finding is in line with the observation that in murine HSC niches, both MSCs and endothelial cells are required for the HSC maintenance. [28][29][30] It will be interesting to learn whether MSCs together with endothelial cells or other cell types may allow for the in vitro expansion of HSCs/MPPs. Altogether, these data support our previous conclusion that testing for the erythroid potential of CD133 C CD34 C HSPCs provides a simple but meaningful assay to test for the presence of HSCs/MPPs.…”