Origin-Dependent Neural Cell Identities in Differentiated Human iPSCs In Vitro and after Transplantation into the Mouse Brain

Hargus, Gunnar; Ehrlich, Marc; Araúzo-Bravo, Marcos J.; Hemmer, Kathrin; Hallmann, Anna-Lena; Reinhardt, Peter; Kim, Kee-Pyo; Adachi, Kenjiro; Santourlidis, Simeon; Ghanjati, Foued; Fauser, Mareike; Ossig, Christiana; Storch, Alexander; Schwamborn, Jens Christian; Sterneckert, Jared; Schöler, Hans R.; Zaehres, Holm

doi:10.1016/j.celrep.2014.08.014

Cited by 45 publications

(45 citation statements)

References 21 publications

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“…S1d)8910. This approach revealed efficient neuronal differentiation in both groups and demonstrated that neuronal differentiation per se was not impaired in FTD NPCs, as similarly seen in a previous study on N279K MAPT mutant neurons10.…”

Section: Resultssupporting

confidence: 82%

“…Also, co-cultured neurons and astrocytes carried comparable regional profiles, consistent with the fact that both neural cell types had been derived from the same NPC population with similar regional programs (Fig. S4e)9. Altogether, these findings indicated that FTD astrocytes could render neighboring neurons more vulnerable to respiratory stress.…”

Section: Resultssupporting

confidence: 77%

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Astrocyte pathology in a human neural stem cell model of frontotemporal dementia caused by mutant TAU protein

Hallmann

Araúzo-Bravo

Mavrommatis

et al. 2017

Sci Rep

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Astroglial pathology is seen in various neurodegenerative diseases including frontotemporal dementia (FTD), which can be caused by mutations in the gene encoding the microtubule-associated protein TAU (MAPT). Here, we applied a stem cell model of FTD to examine if FTD astrocytes carry an intrinsic propensity to degeneration and to determine if they can induce non-cell-autonomous effects in neighboring neurons. We utilized CRISPR/Cas9 genome editing in human induced pluripotent stem (iPS) cell-derived neural progenitor cells (NPCs) to repair the FTD-associated N279K MAPT mutation. While astrocytic differentiation was not impaired in FTD NPCs derived from one patient carrying the N279K MAPT mutation, FTD astrocytes appeared larger, expressed increased levels of 4R-TAU isoforms, demonstrated increased vulnerability to oxidative stress and elevated protein ubiquitination and exhibited disease-associated changes in transcriptome profiles when compared to astrocytes derived from one control individual and to the isogenic control. Interestingly, co-culture experiments with FTD astrocytes revealed increased oxidative stress and robust changes in whole genome expression in previously healthy neurons. Our study highlights the utility of iPS cell-derived NPCs to elucidate the role of astrocytes in the pathogenesis of FTD.

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Section: Resultssupporting

confidence: 82%

Section: Resultssupporting

confidence: 77%

Astrocyte pathology in a human neural stem cell model of frontotemporal dementia caused by mutant TAU protein

Hallmann

Araúzo-Bravo

Mavrommatis

et al. 2017

Sci Rep

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“…The studies of cell-of-origin indicated that the parental cell could influence the differentiation capacity of the resultant iPS cells [33]. There were some reports that showed iPS cells derived from nonhematopoietic cells (neural progenitors and fibroblasts) retained residual methylation [34–36]. Some evidences showed iPS cells retained a residual transcriptional memory of the somatic cells and provided data in support of inefficient promoter DNA methylation as the underlying mechanism [14, 17].…”

Section: Discussionmentioning

confidence: 99%

Survivin Improves Reprogramming Efficiency of Human Neural Progenitors by Single Molecule OCT4

Zhou

Liu

Feng

et al. 2016

Stem Cells International

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Induced pluripotent stem (iPS) cells have been generated from human somatic cells by ectopic expression of four Yamanaka factors. Here, we report that Survivin, an apoptosis inhibitor, can enhance iPS cells generation from human neural progenitor cells (NPCs) together with one factor OCT4 (1F-OCT4-Survivin). Compared with 1F-OCT4, Survivin accelerates the process of reprogramming from human NPCs. The neurocyte-originated induced pluripotent stem (NiPS) cells generated from 1F-OCT4-Survivin resemble human embryonic stem (hES) cells in morphology, surface markers, global gene expression profiling, and epigenetic status. Survivin keeps high expression in both iPS and ES cells. During the process of NiPS cell to neural cell differentiation, the expression of Survivin is rapidly decreased in protein level. The mechanism of Survivin promotion of reprogramming efficiency from NPCs may be associated with stabilization of β-catenin in WNT signaling pathway. This hypothesis is supported by experiments of RT-PCR, chromatin immune-precipitation, and Western blot in human ES cells. Our results showed overexpression of Survivin could improve the efficiency of reprogramming from NPCs to iPS cells by one factor OCT4 through stabilization of the key molecule, β-catenin.

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“…Indeed, iPSCs derived from primary human fetal retinal pigmented epithelial (RPE) cells can retain memory of their previous differentiation state and exhibited a preference to redifferentiate into RPE (Hu et al, 2010). In some iPSC lines, this epigenetic memory is reduced with each passage in culture (Kim et al, 2010) but it is possible that some forms of epigenetic memory are more stable and can be exploited in selecting iPSC lines for stem cell based therapies (Hargus et al, 2014). To date, most studies of epigenetic memory in iPSCs have focused on DNA methylation but higher order chromatin organization mediated by insulator element such as CTCF may also play a role in iPSC epigenetic memory (Narendra et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Quantification of Retinogenesis in 3D Cultures Reveals Epigenetic Memory and Higher Efficiency in iPSCs Derived from Rod Photoreceptors

et al. 2015

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Summary Cell-based therapies to treat retinal degeneration are now being tested in clinical trials. However, it is not known if the source of stem cells is important for the production of differentiated cells suitable for transplantation. To test this, we generated iPSCs murine rod photoreceptors (r-iPSCs) and scored their ability to make retina using a standardized quantitative protocol called STEM-RET. We discovered that r-iPSCs were more efficient at producing differentiated retina than embryonic stem cells (ESCs) or fibroblast-derived iPSCs (f-iPSCs). Retinae derived from f-iPSCs had a reduction in amacrine cells and other inner nuclear layer cells. Integrated epigenetic analysis showed that DNA methylation contributes to the defects in f-iPSC retinogenesis and that rod specific CTCF insulator protein binding sites may promote retinogenes in r-iPSCs. Taken together, our data suggest that the source of stem cells are important for producing retinal neurons in 3D organ cultures.

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Origin-Dependent Neural Cell Identities in Differentiated Human iPSCs In Vitro and after Transplantation into the Mouse Brain

Cited by 45 publications

References 21 publications

Astrocyte pathology in a human neural stem cell model of frontotemporal dementia caused by mutant TAU protein

Astrocyte pathology in a human neural stem cell model of frontotemporal dementia caused by mutant TAU protein

Survivin Improves Reprogramming Efficiency of Human Neural Progenitors by Single Molecule OCT4

Quantification of Retinogenesis in 3D Cultures Reveals Epigenetic Memory and Higher Efficiency in iPSCs Derived from Rod Photoreceptors

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