title: The tissue inhibitor of metalloproteinases 1 increases the clonogenic efficiency of human hematopoietic progenitor cells through CD63/PI3K/Akt signaling.
abstract: Initially described as an endogenous inhibitor of proteases, the tissue inhibitor of metalloproteinases 1 (TIMP-1) also displays cytokine-like functions. TIMP-1 is a soluble protein whose levels are increased under inflammatory conditions. We recently found that TIMP-1(-/-) mice have decreased bone marrow (BM) cellularity and that the engraftment capability of TIMP-1(-/-) hematopoietic stem cells (HSCs) is impaired, owing to proliferation defects. Here, we investigated the role of recombinant human TIMP-1 (rhTIMP-1) in human hematopoietic stem/progenitor cells (HSPCs) and elucidated the downstream pathway ignited by rhTIMP-1. We found that rhTIMP-1 affects in vitro cell survival, proliferation, and particularly clonogenic expansion of CD34(+) HSPCs without compromising their short-term engraftment potential after transplantation into immunodeficient mice. These effects are independent on matrix metalloproteinase (MMP) inhibition and rely on TIMP-1's binding to the tetraspanin membrane receptor CD63. Further investigation indicated that rhTIMP-1 stimulation induces phosphatidylinositol 3-kinase (PI3K) recruitment and Akt phosphorylation, both presiding over survival/proliferation pathways in HSPCs. Downstream targets of phosphorylated Akt (pAkt) are also modulated, including the proliferation marker cyclin D1 (CycD1), whose levels are increased upon exposure to rhTIMP-1. These findings indicate that rhTIMP-1 promotes clonogenic expansion and survival in human progenitors via the activation of the CD63/PI3K/pAkt signaling pathway, suggesting that TIMP-1 might be a key player in the network of proinflammatory factors modulating HSPC functions.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology L. and A. Seràgnoli, University of Bologna, Bologna, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Rossi
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology L. and A. Seràgnoli, University of Bologna, Bologna, Italy.
authors.forename: Dorian
authors.initials: D
authors.lastname: Forte
authors.affiliation: Department of Oncology, Institute for Cancer Research and Treatment, School of Medicine, University of Turin, Candiolo, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Migliardi
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology L. and A. Seràgnoli, University of Bologna, Bologna, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Salvestrini
authors.affiliation: Immunohaematology and Transfusion Medicine Service, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Buzzi
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Ricciardi
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Licchetta
authors.affiliation: Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Tafuri
authors.affiliation: Center for Genome Research Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Bicciato
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology L. and A. Seràgnoli, University of Bologna, Bologna, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cavo
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology L. and A. Seràgnoli, University of Bologna, Bologna, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Catani
authors.affiliation: Chair of Hematology, Department of Internal Medicine, University of Genoa, Genoa, Italy.
authors.forename: Roberto M
authors.initials: RM
authors.lastname: Lemoli
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology L. and A. Seràgnoli, University of Bologna, Bologna, Italy. Electronic address: antonio.curti2@unibo.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Curti
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D060149:Tetraspanin 30 / Q000235:genetics / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C530104:CCND1 protein, human; C554586:CD63 protein, human; C530105:Ccnd1 protein, mouse; C554587:Cd63 protein, mouse; C560822:TIMP1 protein, human; D060149:Tetraspanin 30; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt