Hematopoietic cells must be able to strike a balance between self-renewal and commitment to differentiation. Hematopoietic stem cells can give rise to at least eight distinct blood cell lineages and also maintain lifelong blood production. Therefore hematopoietic stem cells are defined by relative quiescence, while their progeny possess remarkable proliferative capacity.

Quiescence of stem cells is necessary to protect the stem cell compartment. High levels of production are needed to replace rapid turnover of mature blood cells. But proliferative activity of stem cells must be restricted to prevent consumption of the regenerative cell pool, an occurrence known as stem cell exhaustion. The control over quiescence is especially crucial in conditions of stress, such as myelotoxic injury, to prevent hematopoietic death.

p21cip1/waf1 is a cyclin-dependent kinase inhibitor that regulates the G1 checkpoint. Evidence suggests it is the molecular switch that governs the entry of stem cells into the cell cycle. Without being able to enter the cell cycle in the G1 phase, the differentiative effects of other cytokines cannot proceed. In the absence of p21, cell cycling increases, leading to stem cell exhaustion. Test mice that are p21-/- exhibit increased stem cell proliferation under homeostatic conditions, and produced hematopoietic death under conditions of stress. These experiments suggest p21 augments progenitor cell proliferation while inhibiting stem cell proliferation.

P21 may play a key role in efforts to manipulate stem cell proliferation ex vivo. (68)