The matrix metalloproteinase inhibitor marimastat promotes neural progenitor cell differentiation into neurons by gelatinase-independent TIMP-2-dependent mechanisms
| Autor: | Pasquale Caramanica, Luisa Minghetti, Emanuele Cacci, Virginia Medda, Maria Antonietta Ajmone-Cat, Ferdinando Mannello, Maddalena Sinno, Gaetana A. Tonti, Stefano Biagioni, Irene Pafumi |
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| Přispěvatelé: | Department of Biology and Biotechnology 'Charles Darwin', Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Department of Cell Biology and Neuroscience, Istituto Superiore di Sanita [Rome], Section of Clinical Biochemistry, Unit of Cell Biology, University 'Carlo Bo', This work was supported by Fondazione Cenci Bolognetti and by Sapienza University of Rome to E.C. and by MIUR (PRIN 20088JEHW3_002) to S.B. |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Nervous system
MESH: Neural Stem Cells MESH: Hydroxamic Acids Matrix metalloproteinase inhibitor MESH: Neurons Gene Expression Matrix metalloproteinase Hydroxamic Acids Mice 0302 clinical medicine Neural Stem Cells MESH: RNA Small Interfering Gelatinase MESH: Animals HES1 RNA Small Interfering Cells Cultured Neurons 0303 health sciences Cell Differentiation Hematology Cell biology medicine.anatomical_structure Matrix Metalloproteinase 9 MESH: Cell Survival Gene Knockdown Techniques Matrix Metalloproteinase 2 Marimastat medicine.drug MESH: Cells Cultured MESH: Cell Differentiation MESH: Gene Expression Cell Survival Subventricular zone [SDV.BC]Life Sciences [q-bio]/Cellular Biology Biology Matrix Metalloproteinase Inhibitors 03 medical and health sciences medicine Animals Progenitor cell MESH: Mice 030304 developmental biology Tissue Inhibitor of Metalloproteinase-2 MESH: Matrix Metalloproteinase 9 MESH: Matrix Metalloproteinase Inhibitors Cell Biology MESH: Gene Knockdown Techniques MESH: Matrix Metalloproteinase 2 MESH: Tissue Inhibitor of Metalloproteinase-2 Immunology 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Stem Cells and Development Stem Cells and Development, Mary Ann Liebert, 2013, 22 (3), pp.345-58. ⟨10.1089/scd.2012.0299⟩ |
| ISSN: | 1547-3287 |
| DOI: | 10.1089/scd.2012.0299⟩ |
| Popis: | International audience; Metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs), produced in the brain by cells of non-neural and neural origin, including neural progenitors (NPs), are emerging as regulators of nervous system development and adult brain functions. In the present study, we explored whether MMP-2, MMP-9, and TIMP-2, abundantly produced in the brain, modulate NP developmental properties. We found that treatment of NPs, isolated from the murine fetal cerebral cortex or adult subventricular zone, with the clinically tested broad-spectrum MMP inhibitor Marimastat profoundly affected the NP differentiation fate. Marimastat treatment allowed for an enrichment of our cultures in neuronal cells, inducing NPs to generate higher percentage of neurons and a lower percentage of astrocytes, possibly affecting NP commitment. Consistently with its proneurogenic effect, Marimastat early downregulated the expression of Notch target genes, such as Hes1 and Hes5. MMP-2 and MMP-9 profiling on proliferating and differentiating NPs revealed that MMP-9 was not expressed under these conditions, whereas MMP-2 increased in the medium as pro-MMP-2 (72 kDa) during differentiation; its active form (62 kDa) was not detectable by gel zymography. MMP-2 silencing or administration of recombinant active MMP-2 demonstrated that MMP-2 does not affect NP neuronal differentiation, nor it is involved in the Marimastat proneurogenic effect. We also found that TIMP-2 is expressed in NPs and increases during late differentiation, mainly as a consequence of astrocyte generation. Endogenous TIMP-2 did not modulate NP neurogenic potential; however, the proneurogenic action of Marimastat was mediated by TIMP-2, as demonstrated by silencing experiments. In conclusion, our data exclude a major involvement of MMP-2 and MMP-9 in the regulation of basal NP differentiation, but highlight the ability of TIMP-2 to act as key effector of the proneurogenic response to an inducing stimulus such as Marimastat. |
| Databáze: | OpenAIRE |
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