Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 12, Pages 5091-5096Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0610819104
Keywords
bone marrow microenvironment; cell cycle; adhesion
Categories
Funding
- NCI NIH HHS [R01 CA105117] Funding Source: Medline
- NHLBI NIH HHS [HL085362, R01 HL085362] Funding Source: Medline
- NIGMS NIH HHS [GM60523, R01 GM060523] Funding Source: Medline
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Adult hernatopoietic stem cells (HSCs) exist in a relatively quiescent state in the bone marrow (BM) microenvironment to fulfill long-term self-renewal and multilineage differentiation functions, an event that is tightly regulated by extrinsic and intrinsic cues. However, the mechanism coordinating the quiescent state of HSCs and their retention in the BM microenvironment remains poorly understood. In a conditional-knockout mouse model, we show that Cdc42(-/-) HSCs enter the active cell cycle, resulting in significantly increased number and frequency of the stem/progenitor cells in the EIM. Cdc42 deficiency also causes impaired adhesion, homing, lodging, and retention of HSCs, leading to massive egress of HSCs from IBMI to distal organs and peripheral blood and to an engraftment failure. These effects are intrinsic to the HSCs and are associated with deregulated c-Myc, p21(Cip1), beta 1-integrin, and Ncadherin expressions and defective actin organization. Thus, Cdc42 is a critical coordinator of HSC quiescence maintenance and interaction with the EIM niche.
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