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.

The tissue inhibitor of metalloproteinases 1 increases the clonogenic efficiency of human hematopoietic progenitor cells through CD63/PI3K/Akt signaling / Rossi, L; Forte, D; Migliardi, G; Salvestrini, V; Buzzi, M; Ricciardi, Maria Rosaria; Licchetta, Roberto; Tafuri, Agostino; Bicciato, S; Cavo, M; Catani, L; Lemoli, Rm; Curti, A.. - In: EXPERIMENTAL HEMATOLOGY. - ISSN 0301-472X. - STAMPA. - 43:11(2015), pp. 974-985. [doi:10.1016/j.exphem.2015.07.003]

The tissue inhibitor of metalloproteinases 1 increases the clonogenic efficiency of human hematopoietic progenitor cells through CD63/PI3K/Akt signaling

RICCIARDI, Maria Rosaria;LICCHETTA, ROBERTO;TAFURI, Agostino;
2015

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.
2015
tissue inhibitor of metalloproteinases 1; hematopoietic stem cells; CD63/PI3K/pAkt signaling pathway
01 Pubblicazione su rivista::01a Articolo in rivista
The tissue inhibitor of metalloproteinases 1 increases the clonogenic efficiency of human hematopoietic progenitor cells through CD63/PI3K/Akt signaling / Rossi, L; Forte, D; Migliardi, G; Salvestrini, V; Buzzi, M; Ricciardi, Maria Rosaria; Licchetta, Roberto; Tafuri, Agostino; Bicciato, S; Cavo, M; Catani, L; Lemoli, Rm; Curti, A.. - In: EXPERIMENTAL HEMATOLOGY. - ISSN 0301-472X. - STAMPA. - 43:11(2015), pp. 974-985. [doi:10.1016/j.exphem.2015.07.003]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/797787
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