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

While haematopoietic stem cells (HSCs) are commonly assumed to reside within a specialized microenvironment, or niche(1), most published experimental manipulations of the HSC niche have also impacted the function of diverse restricted progenitors. This raises the fundamental question of whether HSCs(1) and restricted progenitors(2,3) 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. Cxcl12(DsRed) 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.