Article
Preservation of positional identity in fetus-derived neural stem (NS) cells from different mouse central nervous system compartments.
Department of Pharmacological Sciences and Center for Stem Cell Research, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.
Cellular and Molecular Life Sciences CMLS (impact factor:
6.57).
10/2010;
68(10):1769-83.
DOI:10.1007/s00018-010-0548-7
pp.1769-83
Source: PubMed
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Citations (0)
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Article: The matrix metalloproteinase inhibitor Marimastat promotes neural progenitor cell differentiation into neurons by gelatinase independent TIMP-2- dependent mechanisms.
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ABSTRACT: 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 murine fetal cerebral cortex or adult subventricular zone, with the clinically tested broad-spectrum MMP inhibitor Marimastat profoundly affected 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 pro-neurogenic effect, Marimastat early down-regulated 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 proMMP-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 Marimastat pro-neurogenic 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 pro-neurogenic 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 pro-neurogenic response to an inducing stimulus such as Marimastat.Stem cells and development 10/2012; · 4.15 Impact Factor
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Keywords
anterior transcription factors
complete neurochemical identity
consistent transcription factor profile
developing mouse nervous system
different regions
electrophysiologically active neurons
exhibit distinct positional identities
fetal NS cells
homogeneous expansion
Hoxb9
monolayer
multipotent radial glia-like
neuronal differentiation
NS
NS cells
self-renewal
spinal cord-derived NS cells
Marco Onorati |