Abstract

We have identified networks of proto-oncogenes and tumor suppressors that act intrinsically within stem cells to regulate their maintenance throughout life in the hematopoietic and nervous systems. We recently discovered that evolutionarily conserved heterochronic genes coordinate changes in these networks with age, that control changes in stem cell properties between fetal, young adult, and old adult stages. These mechanisms begin to explain how stem cell properties can change over time in a way that is appropriate to the changing growth and regeneration demands of tissues, as well as the increasing risk of neoplastic transformation with age. Our work on the extrinsic regulation of stem cell function has focused on the characterization of the hematopoietic stem cell (HSC) niche. We demonstrated that most HSCs reside adjacent to sinusoidal blood vessels in the bone marrow. However, a number of cell types have been proposed to create niches for HSCs and the expression patterns of HSC maintenance factors have not been systematically studied. No HSC maintenance factor has been conditionally deleted from any candidate niche cell. Thus, the identities of the cells that are physiologically important sources of the factors that promote HSC maintenance in vivo remain untested. Stem Cell Factor (SCF) is non-autonomously required for HSC maintenance and is a key component of the niche. Using Scfgfp knock-in mice we found Scf was primarily expressed by endothelial and perivascular stromal cells throughout the bone marrow. Using Scffl mice, we found that HSC frequency and function were not affected when Scf was conditionally deleted from hematopoietic cells, osteoblasts, or Nestin-Cre-expressing stromal cells. However, HSCs were depleted from the bone marrow when Scf was deleted from endothelial cells or Leptin receptor-expressing perivascular stromal cells. Therefore, HSCs reside in a perivascular niche in which multiple cell types secrete factors that promote HSC maintenance.