title: Mesenchymal lineage stem cells have pronounced anti-inflammatory effects in the twitcher mouse model of Krabbe's disease.
abstract: The twitcher mouse is an animal model of Krabbe's disease (KD), which is a neurodegenerative lysosomal storage disorder resulting from the absence of functional lysosomal enzyme galactocerebrosidase (GALC). This disease affects the central and peripheral nervous systems and in its most severe form results in death before the age of 2 in humans and approximately 30-40 days in mice. This study evaluates the effect of intracerebroventricular administration of mesenchymal stem cells derived from adipose tissue (ASCs) and bone marrow (BMSCs) on the pathology of KD. Subsequent to the intracerebroventricular injection of ASCs or BMSCs on postnatal day (PND) 3-4, body weight, lifespan, and neuromotor function were evaluated longitudinally beginning on PND15. At sacrifice, tissues were harvested for analysis of GALC activity, presence of myelin, infiltration of macrophages, microglial activation, inflammatory markers, and cellular persistence. Survival analysis curves indicate a statistically significant increase in lifespan in stem cell-treated twitcher mice as compared with control twitcher mice. Body weight and motor function were also improved compared with controls. The stem cells may mediate some of these benefits through an anti-inflammatory mechanism because the expression of numerous proinflammatory markers was downregulated at both transcriptional and translational levels. A marked decrease in the levels of macrophage infiltration and microglial activation was also noted. These data indicate that mesenchymal lineage stem cells are potent inhibitors of inflammation associated with KD progression and offer potential benefits as a component of a combination approach for in vivo treatment by reducing the levels of inflammation.
authors.affiliation: Division of Regenerative Medicine, Tulane National Primate Research Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Ripoll
authors.forename: Mette
authors.initials: M
authors.lastname: Flaat
authors.forename: Jessica
authors.initials: J
authors.lastname: Klopf-Eiermann
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Fisher-Perkins
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Trygg
authors.forename: Brittni A
authors.initials: BA
authors.lastname: Scruggs
authors.forename: Marjorie L
authors.initials: ML
authors.lastname: McCants
authors.forename: Helen Paige
authors.initials: HP
authors.lastname: Leonard
authors.forename: Amy F
authors.initials: AF
authors.lastname: Lin
authors.forename: Shijia
authors.initials: S
authors.lastname: Zhang
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Eagle
authors.forename: Xavier
authors.initials: X
authors.lastname: Alvarez
authors.forename: Yu Teh
authors.initials: YT
authors.lastname: Li
authors.forename: Su Chen
authors.initials: SC
authors.lastname: Li
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Gimble
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Bunnell
mesh_terms: D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D001853:Bone Marrow / Q000502:physiology*; D019070:Cell Lineage; D004195:Disease Models, Animal; D005698:Galactosylceramidase / Q000032:analysis / Q000378:metabolism; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000601:surgery; D007965:Leukodystrophy, Globoid Cell / Q000601:surgery*; D008247:Lysosomes / Q000201:enzymology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors
chemical_list: C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D005698:Galactosylceramidase