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Modeling Alexander disease with patient iPSCs reveals cellular and molecular pathology of astrocytes.

Kondo T, Funayama M, Miyake M, Tsukita K, Era T, Osaka H, Ayaki T, Takahashi R, Inoue H - Acta Neuropathol Commun (2016)

Bottom Line: Alexander disease is a fatal neurological illness characterized by white-matter degeneration and formation of Rosenthal fibers, which contain glial fibrillary acidic protein as astrocytic inclusion.We established induced pluripotent stem cells from Alexander disease patients, and differentiated induced pluripotent stem cells into astrocytes.Alexander disease patient astrocytes exhibited Rosenthal fiber-like structures, a key Alexander disease pathology, and increased inflammatory cytokine release compared to healthy control.

View Article: PubMed Central - PubMed

Affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

ABSTRACT
Alexander disease is a fatal neurological illness characterized by white-matter degeneration and formation of Rosenthal fibers, which contain glial fibrillary acidic protein as astrocytic inclusion. Alexander disease is mainly caused by a gene mutation encoding glial fibrillary acidic protein, although the underlying pathomechanism remains unclear. We established induced pluripotent stem cells from Alexander disease patients, and differentiated induced pluripotent stem cells into astrocytes. Alexander disease patient astrocytes exhibited Rosenthal fiber-like structures, a key Alexander disease pathology, and increased inflammatory cytokine release compared to healthy control. These results suggested that Alexander disease astrocytes contribute to leukodystrophy and a variety of symptoms as an inflammatory source in the Alexander disease patient brain. Astrocytes, differentiated from induced pluripotent stem cells of Alexander disease, could be a cellular model for future translational medicine.

No MeSH data available.


Related in: MedlinePlus

Generation of iPSCs from Alexander disease patients and healthy controls. a Morphology and expression of human embryonic stem cell markers. iPSCs from both controls and patients with Alexander disease showed ESC-like morphology (phase image) and expressed pluripotent stem cell markers, NANOG and TRA1-60. Scale bars = 200 μm. bIn vitro differentiation of established iPSCs to representative three-germ layer: TUJ1 (ectoderm), αSMA (mesoderm), and SOX17 (endoderm). Scale bars = 50 μm
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Fig1: Generation of iPSCs from Alexander disease patients and healthy controls. a Morphology and expression of human embryonic stem cell markers. iPSCs from both controls and patients with Alexander disease showed ESC-like morphology (phase image) and expressed pluripotent stem cell markers, NANOG and TRA1-60. Scale bars = 200 μm. bIn vitro differentiation of established iPSCs to representative three-germ layer: TUJ1 (ectoderm), αSMA (mesoderm), and SOX17 (endoderm). Scale bars = 50 μm

Mentions: In the present study, we generated iPSCs from three AxD patients with heterozygous GFAP mutation (Alex1, Alex2 and Alex3) and three healthy controls (HC1, HC2, and HC3) (Table 1). The disease onset of Alex1 and Alex2 was infantile and that of Alex3 was adult (Table 1). Primary cultures of somatic cells from all six individuals were independently reprogrammed to iPSCs, as judged by colony morphology, similar to human embryonic stem cells (ESCs), growth dynamics, and sustained long-term passaging (>20 passages) (Fig. 1a). The established iPSCs expressed NANOG and TRA1-60, markers of pluripotency (Fig. 1a). The pluripotency of the iPSCs was also evaluated in vitro through the formation of EBs. All iPSC lines spontaneously differentiated into cell types of the three embryonic germ layers as indicated by expression of the specific markers, including TUJ1 (ectoderm marker), αSMA (mesoderm marker), and SOX17 (endoderm marker) (Fig. 1b).Table 1


Modeling Alexander disease with patient iPSCs reveals cellular and molecular pathology of astrocytes.

Kondo T, Funayama M, Miyake M, Tsukita K, Era T, Osaka H, Ayaki T, Takahashi R, Inoue H - Acta Neuropathol Commun (2016)

Generation of iPSCs from Alexander disease patients and healthy controls. a Morphology and expression of human embryonic stem cell markers. iPSCs from both controls and patients with Alexander disease showed ESC-like morphology (phase image) and expressed pluripotent stem cell markers, NANOG and TRA1-60. Scale bars = 200 μm. bIn vitro differentiation of established iPSCs to representative three-germ layer: TUJ1 (ectoderm), αSMA (mesoderm), and SOX17 (endoderm). Scale bars = 50 μm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4940830&req=5

Fig1: Generation of iPSCs from Alexander disease patients and healthy controls. a Morphology and expression of human embryonic stem cell markers. iPSCs from both controls and patients with Alexander disease showed ESC-like morphology (phase image) and expressed pluripotent stem cell markers, NANOG and TRA1-60. Scale bars = 200 μm. bIn vitro differentiation of established iPSCs to representative three-germ layer: TUJ1 (ectoderm), αSMA (mesoderm), and SOX17 (endoderm). Scale bars = 50 μm
Mentions: In the present study, we generated iPSCs from three AxD patients with heterozygous GFAP mutation (Alex1, Alex2 and Alex3) and three healthy controls (HC1, HC2, and HC3) (Table 1). The disease onset of Alex1 and Alex2 was infantile and that of Alex3 was adult (Table 1). Primary cultures of somatic cells from all six individuals were independently reprogrammed to iPSCs, as judged by colony morphology, similar to human embryonic stem cells (ESCs), growth dynamics, and sustained long-term passaging (>20 passages) (Fig. 1a). The established iPSCs expressed NANOG and TRA1-60, markers of pluripotency (Fig. 1a). The pluripotency of the iPSCs was also evaluated in vitro through the formation of EBs. All iPSC lines spontaneously differentiated into cell types of the three embryonic germ layers as indicated by expression of the specific markers, including TUJ1 (ectoderm marker), αSMA (mesoderm marker), and SOX17 (endoderm marker) (Fig. 1b).Table 1

Bottom Line: Alexander disease is a fatal neurological illness characterized by white-matter degeneration and formation of Rosenthal fibers, which contain glial fibrillary acidic protein as astrocytic inclusion.We established induced pluripotent stem cells from Alexander disease patients, and differentiated induced pluripotent stem cells into astrocytes.Alexander disease patient astrocytes exhibited Rosenthal fiber-like structures, a key Alexander disease pathology, and increased inflammatory cytokine release compared to healthy control.

View Article: PubMed Central - PubMed

Affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

ABSTRACT
Alexander disease is a fatal neurological illness characterized by white-matter degeneration and formation of Rosenthal fibers, which contain glial fibrillary acidic protein as astrocytic inclusion. Alexander disease is mainly caused by a gene mutation encoding glial fibrillary acidic protein, although the underlying pathomechanism remains unclear. We established induced pluripotent stem cells from Alexander disease patients, and differentiated induced pluripotent stem cells into astrocytes. Alexander disease patient astrocytes exhibited Rosenthal fiber-like structures, a key Alexander disease pathology, and increased inflammatory cytokine release compared to healthy control. These results suggested that Alexander disease astrocytes contribute to leukodystrophy and a variety of symptoms as an inflammatory source in the Alexander disease patient brain. Astrocytes, differentiated from induced pluripotent stem cells of Alexander disease, could be a cellular model for future translational medicine.

No MeSH data available.


Related in: MedlinePlus