Hematopoietic Stem Cell Quiescence Maintained by p21 ^cip1/waf1

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 G1 checkpoint regulator, cyclin-dependent kinase inhibitor, p21cip1/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.

Progenitor stem cell marker expression by pulmonary carcinomas

“…14 p21 is associated with maintenance of quiescent state in stem cells. [13][14] Upregulation of p21 and downregulation of Notch are associated with cell differentiation. Our finding that there was an inverse correlation between the expression of p21 and Musashi-1 in pulmonary carcinomas is consistent with these observations.…”

“…This protein has been implicated in the maintenance of the quiescence state of hematopoietic stem cells. 13 Downregulation of p21 is associated with quiescence and lack of differentiation. p21 is regulated by Musashi-1 through a p53-independent pathway.…”

Mesenchymal stem cell transplantation in a rabbit corneal alkali burn model: engraftment and involvement in wound healing

“…It is plausible that during steady-state conditions, HSCs reside in a quiescent state. 18 Stress, such as alkali burn, results in the release of chemocytokines that increase stem cell motility, thereby facilitating their entry into the wound site microenvironment, where they proliferate, differentiate and contribute to neovascularization. [19][20][21] Undifferentiated MSCs can respond to local cues in vivo to differentiate into endothelial cells, contributing to neovascularization in the setting of wound healing, 22 but CD34-positive endothelial and hematopoietic progenitors and stem cells from bone marrow are most important during stress angiogenesis.…”

Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation

“…These observations raise the possibility that deficiency in either gadd45b or gadd45a alters the function of the hematopoietic stem cell compartment in response to physiological stress. In this regard, it will be of interest to assess the possible role of Gadd45 protein interaction with p21 (Vairapandi et al, 1996;Azam et al, 2001), which has been implicated in the regulation of hematopoietic stem cell quiescence and cell survival (Asada et al, 1999;Cheng et al, 2000;Marone et al, 2002). Inflammatory signals arising from IP administration of sodium caseinate, which is known to rapidly stimulate myelopoiesis in murine BM (Liebermann and HoffmanLiebermann, 1989), failed to stimulate myelopoiesis in gadd45aÀ/À and gadd45bÀ/À mice, impairing accumulation of myeloid cells in the peritoneum.…”