title: The therapeutic potential of neural stem/progenitor cells in murine globoid cell leukodystrophy is conditioned by macrophage/microglia activation.
abstract: Twitcher (GALC(twi/twi)) is the murine model of globoid cell leukodystrophy (GLD or Krabbe disease), a disease caused by mutations of the lysosomal enzyme galactocerebrosidase (GALC). To verify the therapeutic potential on twitcher of neural stem/progenitor cells (NSPC), we transduced them with a GALC lentiviral vector. Brain injection of NSPC-GALC increased survival of GALC(twi/twi) from 36.1 +/- 4.1 to 52.2 +/- 5.6 days (P < 0.0001). Detection of GALC activity and flow cytometry showed that NSPC-GALC and NSPC expressing the green fluorescent protein were attracted to the posterior area of twitcher brain, where demyelination occurs first. GALC(twi/twi) microglia, also more abundant in posterior regions of the brain, released significant amounts of the cytotoxic cytokine TNF-alpha when matched with NSPC-GALC. Thus, in murine GLD, and possibly in other demyelinating diseases, NSPC are attracted to regions of active demyelination but have limited survival and therapeutic potential if attacked by activated macrophages/microglia.
authors.affiliation: Istituto Nazionale Neurologico C. Besta, Department of Experimental Neuro-Oncology and Diagnostics, via Celoria 11, 20133 Milano, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Pellegatta
authors.forename: Patrizia
authors.initials: P
authors.lastname: Tunici
authors.forename: Pietro Luigi
authors.initials: PL
authors.lastname: Poliani
authors.forename: Diego
authors.initials: D
authors.lastname: Dolcetta
authors.forename: Laura
authors.initials: L
authors.lastname: Cajola
authors.forename: Cristina
authors.initials: C
authors.lastname: Colombelli
authors.forename: Emilio
authors.initials: E
authors.lastname: Ciusani
authors.forename: Stefano
authors.initials: S
authors.lastname: Di Donato
authors.forename: Gaetano
authors.initials: G
authors.lastname: Finocchiaro
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005698:Galactosylceramidase / Q000235:genetics / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D007965:Leukodystrophy, Globoid Cell / Q000628:therapy*; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000637:transplantation*; D033581:Stem Cell Transplantation; D014161:Transduction, Genetic
chemical_list: D005698:Galactosylceramidase