Key result
TIMP-1 deficiency in mice reduces bone marrow cellularity and HSC repopulation via cell cycle dysregulation.
Why the study?
TIMP-1 has been suggested to regulate cell proliferation and survival, but its role in homeostatic regulation of hematopoietic stem cells (HSCs) was unclear.
Does TIMP-1 deficiency affect cell-cycle dynamics and function in murine long-term HSCs?
Does TIMP-1 deficiency affect cell-cycle dynamics and function in murine long-term HSCs?
TIMP-1 plays an intrinsic role in regulating hematopoietic stem cell function and cell cycle dynamics, suggesting a novel mechanism for stem cell quiescence in the bone marrow.
Animal findings implicate TIMP-1 in murine HSC maintenance; leaves open any role in human hematopoiesis or disease.
In addition to the well-recognized role in extracellular matrix remodeling, the tissue inhibitor of metalloproteinases-1 (TIMP-1) has been suggested to be involved in the regulation of numerous biologic functions, including cell proliferation and survival. We therefore hypothesized that TIMP-1 might be involved in the homeostatic regulation of HSCs, whose biologic behavior is the synthesis of both microenvironmental and intrinsic cues. We found that TIMP-1(-/-) mice have decreased BM cellularity and, consistent with this finding, TIMP-1(-/-) HSCs display reduced capability of long-term repopulation. Interestingly, the cell cycle distribution of TIMP-1(-/-) stem cells appears distorted, with a dysregulation at the level of the G(1) phase. TIMP-1(-/-) HSCs also display increased levels of p57, p21, and p53, suggesting that TIMP-1 could be intrinsically involved in the regulation of HSC cycling dynamics. Of note, TIMP-1(-/-) HSCs present decreased levels of CD44 glycoprotein, whose expression has been proven to be controlled by p53, the master regulator of the G(1)/S transition. Our findings establish a role for TIMP-1 in regulating HSC function, suggesting a novel mechanism presiding over stem cell quiescence in the framework of the BM milieu.
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Rossi et al. (2011) studied TIMP-1 deficiency. TIMP-1 deficiency vs. Wild-type (implied) was evaluated on Bone marrow cellularity and long-term repopulation capability. TIMP-1 deficiency in mice leads to decreased bone marrow cellularity, reduced long-term repopulation capability of HSCs, and dysregulation of the G1 phase of the cell cycle.
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