The hematopoietic stem cell niche--home for friend and foe?

Abstract

The hematopoietic stem cell (HSC) niche is involved in the maintainance and regulation of quiescence, self-renewal and differentiation of hematopoietic stem cells and the fate of their progeny in mammals dealing with the daily stresses to the hematopoietic system. From the discovery that perturbations of the HSC niche can lead to hematopoietic disorders, we have now arrived at the prospect that the HSC niche may play a role in hematological malignancies and that this HSC niche may be a target for therapy. This review attempts to capture the discoveries of the last few years regarding the normal and malignant hematopoietic stem cell niche and possible ways to target this niche.

Fig. 1

Schematic depicting the microanatomy of the normal hematopoietic stem cell niche. The normal bone marrow microenvironment consists of a variety of cell types including osteoblasts, osteoclasts, mesenchymal stem cells, adipocytes, endothelial cells, perivascular reticular cells, sympathetic neurons, macrophages, and other hematopoietic cells. The location, proliferation, differentiation, and quiescence of hematopoietic stem cells are regulated by cytokines secreted by constituents of the bone marrow microenvironment, the extracellular matrix, the oxygen tension, and the nervous system. Not all interactions could be included. ECM = extracellular matrix; CXCL12 (SDF1alpha) = stromal derived factor alpha; Scf = stem cell factor; Ang-1 = angiopoietin-1; IL-7 = interleukin-7; OPN = osteopontin; HSC = hematopoietic stem cell; TPO = thrombopoietin; MSC = mesenchymal stem cell; OB = osteoblast; OC = osteoclast; Retic = reticular cell; Adip = adipocyte; EC = endothelial cell; Adventitital retic. Cell = adventitial reticular cell.

Fig. 2

Schematic depicting the microanatomy of the leukemic stem cell niche and strategies to target the LSC in its niche. Strategies include the blocking of cytokines or adhesion molecules like CD44 or integrins, the mobilization of LSCs out of their niche by GCSF or AMD3100, the blocking of proteins secreted by the bone marrow stroma like galectin, which promotes drug resistance, or the increase of bone remodeling by PTH in CML. For simplicity’s sake the authors have integrated interactions of lymphoid and myeloid leukemic cells with their respective niches into one figure. Details can be found in the text. CXCL12 (SDF1alpha) = stromal derived factor alpha; IL-7 = interleukin-7; HSC = hematopoietic stem cell; OB = osteoblast; VLA-4 = very late antigen 4; GCSF = granulocyte colony stimulating factor; PTH = parathyroid hormone; CXCR4 = C-X-C chemokine receptor type 4.