Minimum requirement of donor cells to reduce the glycolipid storage following bone marrow transplantation in a murine model of Fabry disease

Yokoi, Takayuki; Kobayashi, Hiroshi; Shimada, Yohta; Eto, Yoshikatsu; Ishige, Nobuyuki; Kitagawa, Teruo; Otsu, Makoto; Nakauchi, Hiromitsu; Ida, Hiroyuki; Ohashi, Toya

doi:10.1002/jgm.1566

Cited by 10 publications

(2 citation statements)

References 34 publications

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“…During the preparation of this manuscript (Cougnoux et al , , ) described a similar microglia phenotype in the Npc1 −/− mouse, which mimics the most aggressive forms of NPC. Also supportive are the reports showing that microglial activation precedes neuronal death in Sandhoff disease (Wada et al , ); defective clearance capacity of glia cells promotes neurodegeneration in a Drosophila model of mucolipidosis type IV (Venkatachalam et al , ); and bone marrow transplants with non‐mutated cells that transmigrate into the brain and produce microglia‐like cells are protective in mouse models of mucolipidosis type IV (Walker & Montell, ), mucopolysaccharidosis type I (Pievani et al , ), Fabry disease (Yokoi et al , ), Sandhoff disease (Wada et al , ) and NPC (Lee et al , ).…”

Section: Discussionmentioning

confidence: 68%

“…Scale bars, 10 lm. G Mean AE SEM percentage of microglia showing internalised myelin debris in wt and Npc1 nmf164 mice (n = 5 mice per group Data information: *P < 0.05; **P < 0.005; ***P < 0.001. mucolipidosis type IV (Walker & Montell, 2016), mucopolysaccharidosis type I (Pievani et al, 2015), Fabry disease (Yokoi et al, 2011), Sandhoff disease (Wada et al, 2000) and NPC (Lee et al, 2010). Microglia cells arise from a unique type of embryonic precursors (Ginhoux et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Lipid‐induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders

et al. 2018

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Neuropathic lysosomal storage disorders ( LSD s) present with activated pro‐inflammatory microglia. However, anti‐inflammatory treatment failed to improve disease pathology. We characterise the mechanisms underlying microglia activation in Niemann–Pick disease type A ( NPA ). We establish that an NPA patient and the acid sphingomyelinase knockout ( ASM ko) mouse model show amoeboid microglia in neurodegeneration‐prone areas. In vivo microglia ablation worsens disease progression in ASM ko mice. We demonstrate the coexistence of different microglia phenotypes in ASM ko brains that produce cytokines or counteract neuronal death by clearing myelin debris. Overloading microglial lysosomes through myelin debris accumulation and sphingomyelin build‐up induces lysosomal damage and cathepsin B extracellular release by lysosomal exocytosis. Inhibition of cathepsin B prevents neuronal death and behavioural anomalies in ASM ko mice. Similar microglia phenotypes occur in a Niemann–Pick disease type C mouse model and patient. Our results show a protective function for microglia in LSD s and how this is corrupted by lipid lysosomal overload. Data indicate cathepsin B as a key molecule mediating neurodegeneration, opening research pathways for therapeutic targeting of LSD s and other demyelinating diseases.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Lipid‐induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders

et al. 2018

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Stem Cell-Based Therapy for Lysosomal Storage Diseases

Scruggs

Zhang

Gimble

et al. 2011

Stem Cells and Human Diseases

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Effect of donor chimerism to reduce the level of glycosaminoglycans following bone marrow transplantation in a murine model of mucopolysaccharidosis type II

Yokoi

Akiyama

Kaneshiro

et al. 2014

J of Inher Metab Disea

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Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficient activity of the iduronate-2-sulfatase. This leads to accumulation of glycosaminoglycans (GAGs) in the lysosomes of various cells. Although it has been proposed that bone marrow transplantation (BMT) may have a beneficial effect for patients with MPS II, the requirement for donor-cell chimerism to reduce GAG levels is unknown. To address this issue, we transplanted various ratios of normal and MPS II bone marrow cells in a mouse model of MPS II and analyzed GAG accumulation in various tissues. Chimerism of whole leukocytes and each lineage of BMT recipients' peripheral blood was similar to infusion ratios. GAGs were significantly reduced in the liver, spleen, and heart of recipients. The level of GAG reduction in these tissues depends on the percentage of normal-cell chimerism. In contrast to these tissues, a reduction in GAGs was not observed in the kidney and brain, even if 100 % donor chimerism was achieved. These observations suggest that a high degree of chimerism is necessary to achieve the maximum effect of BMT, and donor lymphocyte infusion or enzyme replacement therapy might be considered options in cases of low-level chimerism in MPS II patients.

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Minimum requirement of donor cells to reduce the glycolipid storage following bone marrow transplantation in a murine model of Fabry disease

Abstract: In FD mice, reconstitution with 100% donor cells is not required to obtain a therapeutic effect following bone marrow transplantation. These results suggest that a 30% gene correction might be sufficient to reverse disease manifestations in FD.

Cited by 10 publications

References 34 publications

Lipid‐induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders

Lipid‐induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders

Stem Cell-Based Therapy for Lysosomal Storage Diseases

Effect of donor chimerism to reduce the level of glycosaminoglycans following bone marrow transplantation in a murine model of mucopolysaccharidosis type II

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