Cell cycle regulation of hematopoietic stem cells.

This review focuses on the cell cycle of hematopoietic stem cell and its regulatory mechanisms. Owing to recent advances in cell culture techniques and analyzing tools, hematopoietic stem cells can be purified from bone marrow, peripheral blood, and umbilical cord blood by using specific surface markers such as Sca-1 (murine) and CD34 (human). Stem cell compartment includes primitive stem cells with self-renewal capacity, multipotential progenitor cells, and lineage-committed progenitors. The cell cycle profile of each population corresponds to their functional status: the most primitive stem cells are dormant (in G0 phase), the majority of self-renewing stem cells are in G1 phase and slowly cycling, and committed progenitors are rapidly cycling for effective expansion. Recent investigations have defined critical components implicated in cell cycle regulation of mammalian cells, and those at work for hematopoietic stem cells are also becoming clear. It has been reported that cell cycle arrest of stem cells is mediated through inhibition of pRB phosphorylation and E2F activity, as well as induction of cyclin-dependent kinase (cdk) inhibitors. Negative growth factors such as transforming growth factor-beta, macrophage inflammatory protein-1, and the interferons may play a role in these events. De-repression of these elements by cdk/cyclin complexes, which are activated by colony stimulating factors, is associated with the expansion of immature progenitor cells. Further advancement in this field should help resolve many of the clinical problems caused by the disruption of cell cycle regulation of hematopoietic stem cells.