title: TIMP-1 deficiency subverts cell-cycle dynamics in murine long-term HSCs.
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 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.
authors.affiliation: Center for Cell and Gene Therapy and Center for Stem Cells and Regenerative Medicine, Baylor College of Medicine, One Baylor Plaza,Houston, TX 77030, USA. lararossi79@yahoo.it
authors.forename: Lara
authors.initials: L
authors.lastname: Rossi
authors.forename: Aysegul V
authors.initials: AV
authors.lastname: Ergen
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Goodell
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology; D016026:Bone Marrow Transplantation / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics* / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000172:deficiency / Q000235:genetics*
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1