title: Bystander effect on brain tissue of mesoangioblasts producing neurotrophins.
abstract: Neurotrophic factors (NTFs) are involved in the regulation of neuronal survival and function and, thus, may be used to treat neurological diseases associated with neuronal death. A major hurdle for their clinical application is the delivery mode. We describe here a new strategy based  on the use of progenitor cells called mesoangioblasts (MABs). MABs can be isolated from postnatal mesoderm tissues and, because of a high adhesin-dependent migratory capacity, can reach perivascular targets especially in damaged areas. We generated genetically modified MABs producing nerve  growth factor (MABs-NGF) or brain-derived neurotrophic factor (MABs-BDNF) and assessed their bystander effects in vitro using PC12 cells, primary cultures, and organotypic cultures of adult hippocampal slices. MABs-NGF-conditioned medium induced differentiation of PC12 cells, while MABs-BDNF-conditioned  medium increased viability of cultured neurons and slices. Slices cultured with MABs-BDNF medium also better retained their morphology and functional connections, and all these effects were abolished by the TrkB kinase blocker K252a or the BDNF scavenger TrkB-IgG. Interestingly, the amount  of BDNF released by MABs-BDNF produced greater effects than an identical amount of recombinant BDNF, suggesting that other NTFs produced by MABs synergize with BDNF. Thus, MABs can be an effective vehicle for NTF delivery, promoting differentiation, survival, and functionality of neurons.  In summary, MABs hold distinct advantages over other currently evaluated approaches for NTF delivery in the CNS, including synergy of MAB-produced NTF with the neurotrophins. Since MABs may be capable of homing into damaged brain areas, they represent a conceptually novel, promising therapeutic  approach to treat neurodegenerative diseases.
authors.affiliation: Department of Clinical and Experimental Medicine, Section of Pharmacology, Neuroscience Center, University of Ferrara, Ferrara, Italy.
authors.forename: Tao
authors.initials: T
authors.lastname: Su
authors.forename: Raffaella
authors.initials: R
authors.lastname: Scardigli
authors.forename: Luisa
authors.initials: L
authors.lastname: Fasulo
authors.forename: Beatrice
authors.initials: B
authors.lastname: Paradiso
authors.forename: Mario
authors.initials: M
authors.lastname: Barbieri
authors.forename: Anna
authors.initials: A
authors.lastname: Binaschi
authors.forename: Roberta
authors.initials: R
authors.lastname: Bovolenta
authors.forename: Silvia
authors.initials: S
authors.lastname: Zucchini
authors.forename: Giulio
authors.initials: G
authors.lastname: Cossu
authors.forename: Antonino
authors.initials: A
authors.lastname: Cattaneo
authors.forename: Michele
authors.initials: M
authors.lastname: Simonato
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D024201:Bystander Effect; D002227:Carbazoles / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006624:Hippocampus / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology; D026121:Indole Alkaloids / Q000494:pharmacology; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D007074:Immunoglobulin G; D026121:Indole Alkaloids; D011994:Recombinant Proteins; D020932:Nerve Growth Factor; C049985:staurosporine aglycone; D020813:Receptor, trkB