Search: onr:"swepub:oai:gup.ub.gu.se/269103" >
Human iPSC-based mo...
Human iPSC-based models highlight defective glial and neuronal differentiation from neural progenitor cells in metachromatic leukodystrophy
-
Frati, G. (author)
-
Luciani, M. (author)
-
Meneghini, V. (author)
-
show more...
-
De Cicco, S. (author)
-
- Ståhlman, Marcus, 1975 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
-
- Blomqvist, Maria K., 1975 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för klinisk kemi och transfusionsmedicin,Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
-
Grossi, S. (author)
-
Filocamo, M. (author)
-
Morena, F. (author)
-
Menegon, A. (author)
-
Martino, S. (author)
-
Gritti, A. (author)
-
show less...
-
(creator_code:org_t)
- 2018-06-13
- 2018
- English.
-
In: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 9
- Related links:
-
https://www.nature.c...
-
show more...
-
https://gup.ub.gu.se...
-
https://doi.org/10.1...
-
show less...
Abstract
Subject headings
Close
- The pathological cascade leading from primary storage to neural cell dysfunction and death in metachromatic leukodystrophy (MLD) has been poorly elucidated in human-derived neural cell systems. In the present study, we have modeled the progression of pathological events during the differentiation of patient-specific iPSCs to neuroepithelial progenitor cells (iPSC-NPCs) and mature neurons, astrocytes, and oligodendrocytes at the morphological, molecular, and biochemical level. We showed significant sulfatide accumulation and altered sulfatide composition during the differentiation of MLD iPSC-NPCs into neuronal and glial cells. Changes in sulfatide levels and composition were accompanied by the expansion of the lysosomal compartment, oxidative stress, and apoptosis. The neuronal and glial differentiation capacity of MLD iPSC-NPCs was significantly impaired. We showed delayed appearance and/or reduced levels of oligodendroglial and astroglial markers as well as reduced number of neurons and disorganized neuronal network. Restoration of a functional Arylsulfatase A (ARSA) enzyme in MLD cells using lentiviral-mediated gene transfer normalized sulfatide levels and composition, globally rescuing the pathological phenotype. Our study points to MLD iPSC-derived neural progeny as a useful in vitro model to assess the impact of ARSA deficiency along NPC differentiation into neurons and glial cells. In addition, iPSC-derived neural cultures allowed testing the impact of ARSA reconstitution/overexpression on disease correction and, importantly, on the biology and functional features of human NPCs, with important therapeutic implications.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- pluripotent stem-cells
- a-deficient mice
- pelizaeus-merzbacher disease
- gene-therapy
- mouse model
- sulfatide storage
- nonhuman-primates
- gaucher-disease
- null mice
- oligodendrocytes
- Cell Biology
- haerenwiemers n
- 1995
- journal of neurochemistry
- v65
- p2267
Publication and Content Type
- ref (subject category)
- art (subject category)
Find in a library
To the university's database
- By the author/editor
-
Frati, G.
-
Luciani, M.
-
Meneghini, V.
-
De Cicco, S.
-
Ståhlman, Marcus ...
-
Blomqvist, Maria ...
-
show more...
-
Grossi, S.
-
Filocamo, M.
-
Morena, F.
-
Menegon, A.
-
Martino, S.
-
Gritti, A.
-
show less...
- About the subject
-
- MEDICAL AND HEALTH SCIENCES
-
MEDICAL AND HEAL ...
-
and Basic Medicine
-
and Neurosciences
-
- MEDICAL AND HEALTH SCIENCES
-
MEDICAL AND HEAL ...
-
and Basic Medicine
-
and Cell and Molecul ...
- Articles in the publication
-
Cell Death & Dis ...
- By the university
-
University of Gothenburg