Mesenchymal Lineage Stem Cells Have Pronounced Anti-Inflammatory Effects in the Twitcher Mouse Model of Krabbe's Disease

被引:58
作者
Ripoll, Cynthia B. [3 ]
Flaat, Mette [4 ,5 ]
Klopf-Eiermann, Jessica
Fisher-Perkins, Jeanne M.
Trygg, Cynthia B.
Scruggs, Brittni A. [3 ,4 ]
McCants, Marjorie L. [4 ]
Leonard, Helen Paige [4 ]
Lin, Amy F. [4 ]
Zhang, Shijia [3 ,4 ]
Eagle, Michelle E.
Alvarez, Xavier [2 ]
Li, Yu Teh [5 ]
Li, Su Chen [5 ]
Gimble, Jeffrey M. [6 ]
Bunnell, Bruce A. [1 ,3 ,4 ,5 ]
机构
[1] Tulane Univ, Sch Med, Ctr Gene Therapy, Div Regenerat Med, New Orleans, LA 70112 USA
[2] Tulane Univ, Sch Med, Div Comparat Pathol, Tulane Natl Primate Res Ctr, New Orleans, LA 70112 USA
[3] Tulane Univ, Sch Med, Dept Pharmacol, New Orleans, LA 70112 USA
[4] Tulane Univ, Sch Med, Ctr Stem Cell Res & Regenerat Med, New Orleans, LA 70112 USA
[5] Tulane Univ, Sch Med, Dept Biochem, New Orleans, LA 70112 USA
[6] Pennington Biomed Res Ctr, Stem Cell Biol Lab, Baton Rouge, LA USA
关键词
Stem cells; Bone marrow; Adipose tissue; Krabbe's Disease; Globoid cell leukodystrophy; Twitcher mouse; Therapy; BONE-MARROW-TRANSPLANTATION; SUPPRESS T-LYMPHOCYTE; NITRIC-OXIDE; MURINE MODEL; STEM/PROGENITOR CELLS; LEUKODYSTROPHY; THERAPY; MICE; DEMYELINATION; EXPRESSION;
D O I
10.1002/stem.555
中图分类号
Q813 [细胞工程];
学科分类号
摘要
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. STEM CELLS 2011;29:67-77
引用
收藏
页码:67 / 77
页数:11
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