Regulation of hematopoietic stem cells by bone marrow stromal cells

Abstract

Hematopoietic stem cells (HSCs) reside in specialized microenvironments (niches) in the bone marrow. The stem cell niche is thought to provide signals that support key HSC properties, including self-renewal capacity and long-term multilineage repopulation ability. The stromal cells that comprise the stem cell niche and the signals that they generate that support HSC function are the subjects of intense investigation. Here, we review the complex and diverse stromal cell populations that reside in the bone marrow and examine their contribution to HSC maintenance. We highlight recent data suggesting that perivascular chemokine CXC ligand (CXCL)12-expressing mesenchymal progenitors and endothelial cells are key cellular components of the stem cell niche in the bone marrow.

Keywords: CXCL12; hematopoietic stem cells; mesenchymal stem cells; osteoblasts; stem cell niche.

Figure 1. Distinct stromal cell populations in the bone marrow contribute to HSC maintenance

A complex and diverse group of stromal cells in the bone marrow have been implicated in HSC maintenance. Endothelial cells, mesenchymal stem cells (MSCs), and CXCL12-expressing mesenchymal progenitors (CEMP cells) are perivascular stromal cells that produce a number of factors that support HSCs, including CXCL12, angiopoietin, and stem cell factor (SCF). CEMP cells have been identified as CXCL12-abundant reticular (CAR) cells, leptin receptor⁺ stromal (Lepr⁺) cells, and Nestin-GFP+ cells; these stromal cell populations likely overlap considerably. Osteoblasts and spindle-shaped N-cadherin⁺ osteoblast (SNO cells) produce a number of factors that support HSCs, including thrombopoietin (TPO) and CXCL12. Sympathetic neurons indirectly regulate HSCs by targeting CXCL12 expression. Finally, glial cells, through production of active transforming growth factor-α TGF-α and adipocytes regulate HSCs.

Figure 2. The bone marrow is highly vascularized

Confocal microscopic images of the femoral diaphysis stained with the pan-vasculature marker laminin (green) and the arterial specific marker, Sca-1 (red). A Sca-1⁺ central artery runs through the central marrow. The central artery branches off to smaller arterioles towards the endosteum. Reprinted by permission from Macmillan Publishers Ltd: Nature Cell Biology; 15 (5):533-43, copyright (2013).

Figure 3. Model of murine HSC niche

Conditional deletion of two key HSC maintenance genes, Kitl (stem cell factor, SCF) and Cxcl12, in candidate niche cells has emphasized the importance of stromal cells in the perivascular region. SCF production from endothelial cells and leptin receptor⁺ stromal (Lepr⁺) cells but not osteoblasts (Ob) is required for HSC maintenance. CXCL12 production from mesenchymal stem cells (and to a lesser extent endothelial cells) is required for HSC maintenance, while CXCL12 production form CXCL12 abundant reticular (CAR) cells or Lepr⁺ cells is required for efficient retention of hematopoietic progenitors in the bone marrow. Nestin-GFP⁺ stromal cells likely overlap with CAR cells and Lepr⁺ cells.