Regulation of hematopoietic stem cell and its interaction with stem cell niche

Hematopoietic stem cells (HSCs) are responsible for Blood cell production throughout the lifetime of individuals. Interaction of HSCs with their particular microenvironments, known as stem cell niches, is critical for maintaining the stem cell properties, including self-renewal capacity and the ability of differentiation into single or multiple lineages. In the niche, the niche cells produce signaling molecules, extracellular matrix, and cell adhesion molecules, and regulate stem cell fates. Recently, long-term bone marrow (BM) repopulating (LTR) HSCs exist frequently in BM trabecular bone surface, and it was clarified that an osteoblast (OB) is a critical component for sustainment of HSCs. HSCs balance quiescence and cell division in the osteoblastic niche and also maintain the potential for long-term hematopoiesis. Especially, the quiescent state in the cell cycle is thought to be indispensable for the maintenance of hematopoietic stem cells (HSCs). We demonstrate that c-Kit+Sca-1+Lineage- (KSL) HSCs expressing the receptor tyrosine kinase Tie2 are quiescent and anti-apoptotic, transplantable and comprise a side-population (SP) of HSCs, which contact closely to Angiopoietin-1 (Ang-1), a ligand for Tie2, expressing osteoblasts in the BM niche. Tie2 and Ang-1 are part of a key signaling interaction between HSC and osteoblasts. Tie2 and Ang-1 are expressed in a complementary pattern, and interaction of Tie2 and Ang-1 induced integrin dependent cell adhesion of HSCs to osteoblasts and extracellular matrix. This signaling pathway regulates functional criteria of HSC in the BM niche, including quiescence, anti-cell death and tight adhesion. These observations led us to a novel model in which Ang-1 produced by osteoblasts activates Tie2 on the HSCs and promote tight adhesion of HSCs to the niche, resulting in quiescence and enhanced survival of HSCs