Cell cycle entry of hematopoietic stem and progenitor cells controlled by distinct cyclin-dependent kinase inhibitors.

The therapeutic promise of hematopoietic stem cells in medicine has been expanded as broader differentiation potential of the cells has gained experimental support. However, hurdles for stem cell manipulation in vitro and tissue regeneration in vivo remain because of lack of the molecular biology of the stem cells. In particular, elucidating the molecular control of cell cycle entry is necessary for rational stem cell expansion strategies. Understanding how the stem and progenitor cell populations are controlled by negative regulators of cell cycle entry may provide one basis for manipulating these cells. In this mini-review, we focus on the rationale of targeting the cyclin-dependent kinase inhibitors (CKIs) in stem cell biology. Two CKI members, p21(Cip1/Waf1) (p21) and p27kip1 (p27), have been shown to govern the pool sizes of hematopoietic stem and progenitor cells, respectively. Of note, their inhibitory roles in primitive hematopoietic cells are distinct from the action of the inhibitory cytokine, transforming growth factor-beta1 (TGF-beta1). Therefore, the distinct roles of p21, p27, and TGF-beta1 in hematopoietic cells offer attractive targets for specific manipulation of the stem or progenitor cell populations in therapeutic strategies.