Blood Journal
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TIMP-1 deficiency subverts cell-cycle dynamics in murine long-term HSCs

  1. Lara Rossi1,2,
  2. Aysegul V. Ergen1,3, and
  3. Margaret A. Goodell1,4
  1. 1Center for Cell and Gene Therapy and Center for Stem Cells and Regenerative Medicine, Baylor College of Medicine, Houston, TX;
  2. 2Department of Hematology and Oncological Sciences “L. & A. Seràgnoli,” University of Bologna, Bologna, Italy;
  3. 3Interdepartemental Program of Developmental Biology, and
  4. 4Department of Pediatrics, Baylor College of Medicine, Houston TX

Abstract

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 G1 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 G1/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.

  • Submitted October 13, 2009.
  • Accepted April 8, 2011.
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