HSC Cell Cycle Status

One of the most important factors in sustaining hematopoietic homeostasis and preventing exhaustion of the stem cell pool is appropriate cell cycle control. Strict regulatory mechanisms ensure that most HSCs remain quiescent and only a limited number enter cycle at any given time. Cyclin-dependent kinase inhibitors (CKIs) halt cell cycle progression and play an important role in stem cell regulation (Cheng et al. 2000b, Yuan et al. 2004, Walkley et al. 2005). The G1 checkpoint regulator, p21cip1/waf1 (p21) restricts HSC cycling, and thus contributes to the maintenance of stem cell quiescence and survival (Cheng et al. 2000b). p21-deficiency increases HSC proliferation and amplifies the size of the HSC pool under homeostatic conditions in the mouse (Cheng et al. 2000b). The proportion of quiescent cells in the G0 phase of the cell cycle is reduced in p21-/- mice and, in agreement with these findings, p21-/- mice exhibit increased sensitivity to 5-fluorouracil, a cytotoxin. Hematopoietic potential is reduced so significantly by p21 deficiency that HSCs lacking p21 are almost completely exhausted after two rounds of serial bone marrow transplantation (Cheng et al. 2000b). Together these results indicate p21 as a key regulator of stem cell cycling that functions to prevent stem cell exhaustion during prolonged stress (Ezoe et al. 2004).

Unlike p21, the CKI p27KIP1 (p27) is expressed in more mature progenitor cells rather than the primitive stem cell compartment. The number, cycling status, and self-renewal of HSCs are normal in p27-deficient mice, but the mice display an increase in the number and proliferative capacity of progenitor cells (Cheng et al. 2000a). Progenitor cells from p27-null mice expand and regenerate after serial transplantation, indicating that p27 is an important modulator of the repopulating efficiency but not overall number of HSCs (Cheng et al. 2000b). Another CKI, p18INK4C (p18), a member of the INK4 family of CKIs, appears to function similarly to p27. HSCs deficient in p18 display diminished stem cell exhaustion compared to wild-type cells after serial transplantation over three years (Yu et al. 2006). Interestingly, deletion of p18 overcomes the accelerated exhaustion of HSC repop-ulating ability induced by p21 deficiency. The advantage imparted to p18-deficient cells is thought to be due to increased self-renewal of the transplanted HSCs in vivo rather than increased donor cell proliferation (Yuan et al. 2004). These studies demonstrate the importance of CKIs in regulating HSC cell cycle kinetics and the highly divergent effects that cell cycle inhibitors can have on stem cell function.

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