Hematopoietic Stem Cell Quiescence Maintained by p21 ^cip1/waf1

TLDR

Hematopoietic stem cells maintain quiescence to preserve the stem cell pool, whereas their progeny proliferate rapidly and differentiate, and stress‑induced cell cycle restriction is essential to prevent premature depletion and hematopoietic failure. The study aimed to determine whether p21, a G1 checkpoint regulator, is essential for maintaining stem cell quiescence. This was investigated by generating p21‑deficient mice and examining hematopoietic stem cell behavior under normal and stressed conditions. Loss of p21 caused increased HSC proliferation and numbers at baseline, premature death after myelotoxic injury due to depletion, impaired self‑renewal in serial transplants, and ultimately stem cell exhaustion, confirming p21 as the molecular switch governing cell cycle entry.

Abstract

Relative quiescence is a defining characteristic of hematopoietic stem cells, while their progeny have dramatic proliferative ability and inexorably move toward terminal differentiation. The quiescence of stem cells has been conjectured to be of critical biologic importance in protecting the stem cell compartment, which we directly assessed using mice engineered to be deficient in the G 1 checkpoint regulator, cyclin-dependent kinase inhibitor, p21 cip1/waf1 (p21). In the absence of p21, hematopoietic stem cell proliferation and absolute number were increased under normal homeostatic conditions. Exposing the animals to cell cycle–specific myelotoxic injury resulted in premature death due to hematopoietic cell depletion. Further, self-renewal of primitive cells was impaired in serially transplanted bone marrow from p21 −/− mice, leading to hematopoietic failure. Therefore, p21 is the molecular switch governing the entry of stem cells into the cell cycle, and in its absence, increased cell cycling leads to stem cell exhaustion. Under conditions of stress, restricted cell cycling is crucial to prevent premature stem cell depletion and hematopoietic death.