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Direct conversion of fibroblasts into stably expandable neural stem cells

ABSTRACT: Recent advances have suggested that direct induction of neural stem cells could provide an alternative to derivation from somatic tissues or pluripotent cells. Here we show direct derivation of stably expandable NS cells from mouse fibroblasts through a curtailed version of reprogramming to pluripotency. By constitutively inducing Sox2, Klf4, and c-Myc while strictly limiting Oct4 activity to the initial phase of reprogramming, we generated neurosphere-like colonies that could be expanded for more than 50 passages and do not depend on sustained expression of the reprogramming factors. These induced NS (iNS) cells uniformly display morphological and molecular features of NS cells such as the expression of Nestin, Pax6, and Olig2 and have a similar genome-wide transcriptional profile to brain-derived NSCs. iNS cells can differentiate into neurons, astrocytes and oligodendrocytes in vitro and in vivo. Our results demonstrate that functional neural stem cells can be generated from somatic cells by factor-driven induction.

ORGANISM(S): Mus musculus

PROVIDER: GSE36484 | GEO | 2012/04/12

SECONDARY ACCESSION(S): PRJNA158995

REPOSITORIES: GEO

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Direct conversion of fibroblasts into stably expandable neural stem cells

Project description:Recent advances have suggested that direct induction of neural stem cells could provide an alternative to derivation from somatic tissues or pluripotent cells. Here we show direct derivation of stably expandable NS cells from mouse fibroblasts through a curtailed version of reprogramming to pluripotency. By constitutively inducing Sox2, Klf4, and c-Myc while strictly limiting Oct4 activity to the initial phase of reprogramming, we generated neurosphere-like colonies that could be expanded for more than 50 passages and do not depend on sustained expression of the reprogramming factors. These induced NS (iNS) cells uniformly display morphological and molecular features of NS cells such as the expression of Nestin, Pax6, and Olig2 and have a similar genome-wide transcriptional profile to brain-derived NSCs. iNS cells can differentiate into neurons, astrocytes and oligodendrocytes in vitro and in vivo. Our results demonstrate that functional neural stem cells can be generated from somatic cells by factor-driven induction. mRNA extracted from Murine Embryonic Fibroblasts (MEF), murine Embryonic Stem Cell (ES), murine Neuronal Stem Cell (NS) and three murine induces Neuronal Stem Cell clones 2, 3 and 5 (iNS2, iNS3, iNS5) has been hybridized on Illumina MouseWG6 V2 arrays for genome wide expression analysis. Samples were run at least as triple, MEF, iNS3, iNS5 as quadruple technical replicates. Differential gene expression analysis has been performed on the grouped expression data with the Murine Embryonic Fibroblasts group as the reference.

2012-04-11 | E-GEOD-36484 | biostudies-arrayexpress

Pericyte-to-neuron reprogramming via unfolding of a neural stem cell-like program

Project description:Ectopic expression of defined transcription factors can force direct cell fate conversion from one lineage to another in the absence of cell division. Several transcription factor cocktails have enabled successful reprogramming of various somatic cell types into induced neurons (iNs) of distinct neurotransmitter phenotype. However, the nature of the intermediate states that drive the reprogramming trajectory towards distinct iN types is largely unknown. Here we show that successful direct reprogramming of adult human brain pericytes into functional iNs by Ascl1 and Sox2 (AS) encompasses transient activation of a neural stem cell-like gene expression program that precedes bifurcation into distinct neuronal lineages. Intriguingly, during this transient state key signaling components relevant for neural induction and neural stem cell maintenance are regulated and functionally contribute to iN reprogramming and maturation. Thus, AS-mediated reprogramming into a broad spectrum of iN types involves the unfolding of a developmental program via neural stem cell-like intermediates.

2018-06-05 | GSE113036 | GEO

Three-dimensional cell-cell interactions promote direct reprogramming of patient fibroblasts into functional and transplantable neurons

Project description:Direct reprogramming of somatic cells into induced neurons (iNs) has become an attractive strategy for the generation of patient-specific neurons for disease modeling and regenerative neuroscience. To this end, adult human dermal fibroblasts (hDFs) present one of the most relevant cell sources. However, iNs generated from adult hDFs using traditional two-dimensional (2D) cultures are difficult to maintain long-term in vitro and face challenges in survival upon transplantation into the adult brain. These limitations impose considerable constraints on the biomedical applications and translational potential of iN technology. Here, we present a platform for direct in vitro reprogramming of adult hDFs inside three-dimensional suspension microcultures (3D-iNs) that eliminates some of the major bottlenecks in the direct neuronal reprogramming field. We show that the 3D environment favors neuronal over fibroblast cellular identity to yield more robust conversion into functional neurons with extended culturing span. The 3D reprogramming approach also provides a platform for fusion of different neuronal populations into induced assembloids. Importantly, unlike conventional iNs, 3D-iNs can be gently harvested and transplanted into the adult rodent brain to reproducibly generate functionally integrated neuron-rich grafts. Due to its simplicity, versatility, and robustness, our approach could readily be adapted as a culturing platform used for a broad range of in vitro and in vivo studies to improve disease modeling, drug screening, and other biomedical applications.

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Direct Conversion of Fibroblasts into Oligodendrocyte Progenitor Cells

Project description:Many studies have already shown the reprogramming of somatic cells into other cell types such as neural stem cells, blood progenitor cells, and hepatocytes by inducing combinations of transcription factors. One of the recent development in cellular reprogramming is the direct reprogramming, that can change cell fate towards different lineages. This strategy provides an alternative to the use of pluripotent stem cells ruling out the concerns of tumorigenicity caused by undifferentiated cell populations. Here, we generated induced oligodendrocyte progenitor cells (iOPCs) from mouse fibroblasts by direct reprogramming. The generated iOPCs are homogenous, self-renewing, and multipotent. Once differentiated, the somatic stem cells exhibit morphological and molecular characteristics of oligodendrocyte progenitor cells (OPCs). Thus, we demonstrated that terminally differentiated somatic cells can be converted into functional iOPCs by induction of transcription factors offering a new strategies to cure myelin disorders. To identify the global gene expression profiles of iOPCs, we analyzed total 6 samples.

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Project description:Induced pluripotent stem cell (iPSC) technology allows for the generation of patient-specific pluripotent stem cells, from somatic cell sources, thereby providing a novel cell therapy platform for severe degenerative diseases. One of the key issues for clinical-grade iPSC derivation is the accessibility of donor cells used for reprogramming and subsequent feasiblity of reprogramming into a pluripotent state. We used microarrays to detail the global gene expression profiles from blood cells. The use of blood cells allows for minimally invasive tissue procurement under GMP conditions and rapid cellular reprogramming, mobilized HPCs and unmobilized PBMCs would be ideal somatic cell sources for clinical-grade iPSC derivation. We examined the feasibility of reprogramming mobilized GMP-grade hematopoietic progenitor cells (HPCs) and mononuclear myeloid cells and tested the pluripotency of derived iPS clones.

2011-11-09 | E-GEOD-33536 | biostudies-arrayexpress

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Small molecules enable highly efficient neuronal conversion of human fibroblasts

Project description:Forced expression of pro-neural transcription factors was shown to mediate direct neuronal conversion of human fibroblasts. Since neurons are postmitotic, the conversion efficiency represents an important parameter. Here we present a minimalist approach combining two factor neuronal programming with small molecule-based inhibition of GSK3ß and SMAD signaling, which gives rise to functional neuron-like cells (iNs) of various neurotransmitter phenotypes with an overall yield of up to >200% and a final neuronal purity of up to >80%. Timcourse of reprogramming of fibroblasts towards an neuronal phenotype in two independent fibroblast lines

2012-04-07 | E-GEOD-36246 | biostudies-arrayexpress

Expression data from human keratinocyte and PBMC-derived iPS cells

2011-11-09 | GSE33536 | GEO

Dual modulation of neuron specific microRNAs and the REST complex promotes functional maturation of induced human adult neurons

Project description:Direct neural reprogramming can be achieved using different approaches, including by expressing neuronal transcription factors or microRNAs, and by knocking down neuronal repressive elements. However, there still exists a high variability in terms of the quality and maturity of the induced neurons (iNs) obtained, depending on the reprogramming strategy employed. Here, we evaluate different long-term culture conditions and study the effect of expressing the neuronal-specific microRNAs miR124 and miR9/9* while reprogramming with Ascl1, Brn2 and knockdown of the neuronal repressor REST. We show that addition of microRNA supports neuronal maturation both in terms of gene and protein expression, as well as promotes the development of active ion channels and the ability of iNs to generate current induced and spontaneous action potentials.

2019-10-01 | GSE132154 | GEO

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