In studying the intrinsic and extrinsic mechanisms that regulate hematopoietic stem cell (HSC) maintenance and the roles these mechanisms play in cancer, Dr. Morrison and others identified a series of self-renewal regulators, revealing important principles. First, stem cell self-renewal is mechanistically distinct from restricted progenitor proliferation. Second, self-renewal mechanisms are conserved among stem cells in different tissues. Third, these mechanisms comprise networks of proto-oncogenes and tumor suppressors that are dysregulated in cancer. These networks change over time, conferring temporal changes in stem cell properties that match the changing growth and regeneration demands of tissues. Tumor suppressor expression increases with age in stem cells, suppressing cancer development but also reducing tissue regenerative capacity during aging.

In terms of cell-extrinsic mechanisms, HSC niches in adult bone marrow and spleen have been identified. They are closely associated with sinusoidal blood vessels in both tissues. Leptin Receptor-expressing (LepR⁺) perivascular stromal cells and endothelial cells are the sources of factors required for HSC maintenance in the bone marrow. The identification of these cells has revealed new mechanisms that regulate hematopoiesis in the bone marrow. There are distinct subsets of LepR⁺ cells that create perivascular niches for HSCs and restricted hematopoietic progenitors throughout the bone marrow. LepR⁺ cells also synthesize growth factors that regulate osteogenesis, vascular regeneration, and peripheral nerve maintenance in the bone marrow. A subset of LepR⁺ cells are the skeletal (mesenchymal) stem cells that give rise to the osteoblasts and adipocytes that are produced in adult bone marrow.

This lecture will focus on new insights that have been gained into the mechanisms that regulate HSC maintenance, hematopoiesis, and osteogenesis in the bone marrow as a result of identifying LepR⁺ stromal cells, as well as the implications of these findings for clinical bone marrow transplantation.