Stem Cell Niche: Microenvironment and Beyond

Abstract

The multipotentiality and self-renewal ability of stem cells are controlled by intrinsic genetic pathways that are subject to regulation by extrinsic signals emanating from the stem cell niche. The stem cell niche provides a microenvironment composed of cellular structures or extracellular matrix in which stem cells are maintained as undifferentiated (1-6). The concept of “the stem cell niche” was first proposed in the studies of hematopoietic stem cell (HSC) (7), however in vivo evidence of its existence was first shown in the Drosophila germline stem cell (GSC) (8-10). Over the past several years there has been much progress made in identifing stem cell niches in different mammal tissues, including nerve, hair follicle, intestine, teeth and bone marrow (11-16). In this review our focus is on comparing Drosophila GSC-niches and mouse HSC-niches (two of the best characterized niches). By such comparison, we hope to provide some common principles of stem cell niches that will be useful in other tissue stem cell niche studies. In recent years remarkable progress has been made in identification and charaterization of the stem cell niches in invertebrate systems (10,17-22). In studies of GSCs in Drosophila, the ovary and testis provide relatively simple but elegant anatomic structures with few cell types and unique stem cell markers. These advantages facilitated identification of the cellular components of the stem cell niche and definition of the molecular basis of physical interaction between stem cells and their niches (23,24), and revealed key niche signals involved in stem cell regulation (18,25-31). In the murine hematopoietic system, HSCs have been well defined (32,33) but identification of the HSC niches is just beginning. This search has been hampered by the complexity of the bone marrow (BM) structure and cellular components, and by the lack of unique HSC markers or distinctive characteristics of BM stromal cells. Two HSC-niches have been proposed in murine BM, an osteoblastic niche and a vascular niche, in which osteoblasts and vascular endothelial cells have been respectively demonstrated as major components (34-41). A recent study suggested a population of reticular cells, named CXCL12-abundant-reticular (CAR) cells, expressing a high level of CXCL12 (also known as stromal cell-derived factor [SDF]-1 or pre-B-cell-growth-stimulating factor [PBSF]), are in contact with HSCs in both osteoblastic and vascular niches (42). Intriguingly, megakaryocytic progenitors attach to vascular endothelial cells for proliferation and maturation, suggesting they are different from HSCs that directly contact CAR cells instead of endothelial cells in the vascular niche (43). Early B cell progenitors also attach to CAR cells for their growth and maintenance (44). Shared use of the vascular niche by other hematopoietic progenitors, including myeloid progenitors, suggests it may play additional roles in regulation of lineage commitment and differentiation (43,45). Thus the niche model established in studies of Drosophila GSCs may provide insight for further investigate of the different BM niches and their roles in regulation HSCs.