TIMP-1 Deficiency Subverts Cell Cycle Dynamics in Long-Term HSCs.

Abstract 2514

Poster Board II-491

In addition to the consolidated role in extracellular matrix remodeling, the Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) has been suggested to be involved in the regulation of numerous biological functions, including cell proliferation and survival. We therefore hypothesized that TIMP-1 might be involved in the homeostatic regulation of hematopoietic stem cells (HSCs), whose biological behavior is the synthesis of both microenvironmental and intrinsic cues. We found that TIMP-1^−/− mice have decreased HSC numbers and, consistent with this finding, TIMP-1^−/− HSCs display reduced capability of long-term repopulation. Interestingly, the cell cycle distribution of TIMP-1^−/− LT-HSCs is profoundly distorted, with a consistent proportion of the stem cell pool arrested in the G₁ phase, suggesting that TIMP-1 is intrinsically involved in the regulation of the HSC proliferation dynamics. Indeed, HSCs exhibit a higher proliferation rate, leading to an increased formation of CFU-C in vitro and spleen colonies (CFU-S) after transplant. 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 G₁/S transition. Our findings establish TIMP-1 role in HSC function, suggesting a novel mechanism presiding over stem cell quiescence and potentially involved in the development of hematological diseases.