Murine neural stem cells model Hunter disease in vitro: Glial cell-mediated neurodegeneration as a possible mechanism involved

E. Fusar Poli, C. Zalfa, F. D'Avanzo, R. Tomanin, L. Carlessi, M. Bossi, L. Rota Nodari, E. Binda, P. Marmiroli, M. Scarpa, D. Delia, A. L. Vescovi, L. De Filippis

Research output: Contribution to journalArticle

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Abstract

Mucopolysaccharidosis type II (MPSII or Hunter Syndrome) is a lysosomal storage disorder caused by the deficit of iduronate 2-sulfatase (IDS) activity and characterized by progressive systemic and neurological impairment. As the early mechanisms leading to neuronal degeneration remain elusive, we chose to examine the properties of neural stem cells (NSCs) isolated from an animal model of the disease in order to evaluate whether their neurogenic potential could be used to recapitulate the early phases of neurogenesis in the brain of Hunter disease patients. Experiments here reported show that NSCs derived from the subventricular zone (SVZ) of early symptomatic IDS-knockout (IDS-ko) mouse retained self-renewal capacity in vitro, but differentiated earlier than wild-type (wt) cells, displaying an evident lysosomal aggregation in oligodendroglial and astroglial cells. Consistently, the SVZ of IDS-ko mice appeared similar to the wt SVZ, whereas the cortex and striatum presented a disorganized neuronal pattern together with a significant increase of glial apoptotic cells, suggesting that glial degeneration likely precedes neuronal demise. Interestingly, a very similar pattern was observed in the brain cortex of a Hunter patient. These observations both in vitro, in our model, and in vivo suggest that IDS deficit seems to affect the late phases of neurogenesis and/or the survival of mature cells rather than NSC self-renewal. In particular, platelet-derived growth factor receptor-a-positive (PDGFR-α+) glial progenitors appeared reduced in both the IDS-ko NSCs and in the IDS-ko mouse and human Hunter brains, compared with the respective healthy controls. Treatment of mutant NSCs with IDS or PDGF throughout differentiation was able to increase the number of PDGFR-α+ cells and to reduce that of apoptotic cells to levels comparable to wt. This evidence supports IDS-ko NSCs as a reliable in vitro model of the disease, and suggests the rescue of PDGFR-α+ glial cells as a therapeutic strategy to prevent neuronal degeneration.

Original languageEnglish
Article numbere906
JournalCell Death and Disease
Volume4
Issue number11
DOIs
Publication statusPublished - Nov 2013

Fingerprint

Iduronate Sulfatase
Neural Stem Cells
Neuroglia
Lateral Ventricles
Mucopolysaccharidosis II
Neurogenesis
Animal Disease Models
Platelet-Derived Growth Factor Receptors
In Vitro Techniques
Brain
Brain Diseases
Knockout Mice
Cell Survival
Cell Count

Keywords

  • Glial cells
  • Hunter Syndrome
  • Lysosomal storage disorders
  • MPSII
  • Neural stem cells

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

Fusar Poli, E., Zalfa, C., D'Avanzo, F., Tomanin, R., Carlessi, L., Bossi, M., ... De Filippis, L. (2013). Murine neural stem cells model Hunter disease in vitro: Glial cell-mediated neurodegeneration as a possible mechanism involved. Cell Death and Disease, 4(11), [e906]. https://doi.org/10.1038/cddis.2013.430

Murine neural stem cells model Hunter disease in vitro : Glial cell-mediated neurodegeneration as a possible mechanism involved. / Fusar Poli, E.; Zalfa, C.; D'Avanzo, F.; Tomanin, R.; Carlessi, L.; Bossi, M.; Rota Nodari, L.; Binda, E.; Marmiroli, P.; Scarpa, M.; Delia, D.; Vescovi, A. L.; De Filippis, L.

In: Cell Death and Disease, Vol. 4, No. 11, e906, 11.2013.

Research output: Contribution to journalArticle

Fusar Poli, E, Zalfa, C, D'Avanzo, F, Tomanin, R, Carlessi, L, Bossi, M, Rota Nodari, L, Binda, E, Marmiroli, P, Scarpa, M, Delia, D, Vescovi, AL & De Filippis, L 2013, 'Murine neural stem cells model Hunter disease in vitro: Glial cell-mediated neurodegeneration as a possible mechanism involved', Cell Death and Disease, vol. 4, no. 11, e906. https://doi.org/10.1038/cddis.2013.430
Fusar Poli, E. ; Zalfa, C. ; D'Avanzo, F. ; Tomanin, R. ; Carlessi, L. ; Bossi, M. ; Rota Nodari, L. ; Binda, E. ; Marmiroli, P. ; Scarpa, M. ; Delia, D. ; Vescovi, A. L. ; De Filippis, L. / Murine neural stem cells model Hunter disease in vitro : Glial cell-mediated neurodegeneration as a possible mechanism involved. In: Cell Death and Disease. 2013 ; Vol. 4, No. 11.
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abstract = "Mucopolysaccharidosis type II (MPSII or Hunter Syndrome) is a lysosomal storage disorder caused by the deficit of iduronate 2-sulfatase (IDS) activity and characterized by progressive systemic and neurological impairment. As the early mechanisms leading to neuronal degeneration remain elusive, we chose to examine the properties of neural stem cells (NSCs) isolated from an animal model of the disease in order to evaluate whether their neurogenic potential could be used to recapitulate the early phases of neurogenesis in the brain of Hunter disease patients. Experiments here reported show that NSCs derived from the subventricular zone (SVZ) of early symptomatic IDS-knockout (IDS-ko) mouse retained self-renewal capacity in vitro, but differentiated earlier than wild-type (wt) cells, displaying an evident lysosomal aggregation in oligodendroglial and astroglial cells. Consistently, the SVZ of IDS-ko mice appeared similar to the wt SVZ, whereas the cortex and striatum presented a disorganized neuronal pattern together with a significant increase of glial apoptotic cells, suggesting that glial degeneration likely precedes neuronal demise. Interestingly, a very similar pattern was observed in the brain cortex of a Hunter patient. These observations both in vitro, in our model, and in vivo suggest that IDS deficit seems to affect the late phases of neurogenesis and/or the survival of mature cells rather than NSC self-renewal. In particular, platelet-derived growth factor receptor-a-positive (PDGFR-α+) glial progenitors appeared reduced in both the IDS-ko NSCs and in the IDS-ko mouse and human Hunter brains, compared with the respective healthy controls. Treatment of mutant NSCs with IDS or PDGF throughout differentiation was able to increase the number of PDGFR-α+ cells and to reduce that of apoptotic cells to levels comparable to wt. This evidence supports IDS-ko NSCs as a reliable in vitro model of the disease, and suggests the rescue of PDGFR-α+ glial cells as a therapeutic strategy to prevent neuronal degeneration.",
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