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Direct conversion of fibroblasts to neurons by a new mechanism – p53 regulation

ABSTRACT: Direct conversion from fibroblast to neuron has recently been successfully induced bypassing the pluripotent state. However, the conversion takes a few months with low percentages of success. Here we found that depletion of p53, which can converted fibroblasts into three major neural lineages: neurons, astrocytes and oligodendrocytes. Furthermore, our method provided a high efficiency of conversion in aging fibroblasts, where published methods failed. This finding may help developing a prototype for neuron replacement therapy, including foraging people vulnerable to neurological disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE46392 | GEO | 2013/04/26

SECONDARY ACCESSION(S): PRJNA199749

REPOSITORIES: GEO

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Direct conversion of fibroblasts to neurons by a new mechanism – p53 regulation

Project description:Direct conversion from fibroblast to neuron has recently been successfully induced bypassing the pluripotent state. However, the conversion takes a few months with low percentages of success. Here we found that depletion of p53, which can converted fibroblasts into three major neural lineages: neurons, astrocytes and oligodendrocytes. Furthermore, our method provided a high efficiency of conversion in aging fibroblasts, where published methods failed. This finding may help developing a prototype for neuron replacement therapy, including foraging people vulnerable to neurological disorders. p53 has been shown to inhibit reprogramming of fibroblasts to iPS cells, by depletion of p53 in human fibroblasts, we study the function of p53 in induced neuron process. By induction of p53 knockdown fibroblasts with special neuron medium, we can get mature neurons directly. In the induction process, many neurogenic transcription factors were up-regulated, and we prove that p21 is not involved in this process.

2013-04-26 | E-GEOD-46392 | biostudies-arrayexpress

Linking immortalization to direct conversion of human fibroblasts to neurons

Project description:Direct conversion from fibroblasts to neurons is a potential cell replacement therapy for neurological disorders, and a variety of combinations of transcription factors have been tried. We notice that the efficiency of conversion from aging fibroblasts was much lower than in early stage cells, which is consistent with the notion that cellular senescence impairs conversion of fibroblasts to neurons. Here, we found that the transient knockdown of the p16Ink4a/p19Arf locus was sufficient to convert human fibroblasts to neurons. Futhermore, expression of hTERT alone, another mechanism behind immortalization, also induced neuron conversion. Our results show that the acquisition of immortality is a crucial step for the conversion of human fibroblasts into induced neurons. Transient knockdown of p16/p19 or p53 expression or exogenous overexpression of hTERT can induce primary fibroblasts to immortality. In the following, treated cells were cultured in neuron-induction medium. We can observe the morphology change and detect the neuronal markers. Also, some of the induced neurons could generate action potentials and neurotransmitter-induced currents in optimal conditions.

2012-12-28 | E-GEOD-43175 | biostudies-arrayexpress

Senescence impairs direct conversion of human somatic cells to neurons

2012-12-28 | GSE43175 | GEO

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

RNA-seq timeline of fibroblast to neuron conversion using traditional NC media and NC+ZPAK media

Project description:Bulk RNA was extracted via trizol at Fibroblasts stage, 5 days, 10 days, 15 days, and 20 days of fibroblast to neuron conversion using traditional NC media, or NC media supplemented with ZM336372, pyrintegrin, AZ960, and KC7F2

2019-05-23 | E-MTAB-7250 | biostudies-arrayexpress

Mitochondrial reprogramming using dCas9 boosts glia-to-neuron conversion

Project description:Astrocyte-to-neuron conversion has developed into a promising avenue for neuronal replacement therapy. Neurons depend critically on mitochondria function and often die by ferroptosis during the conversion process. Here we examined the extent of adequate mitochondrial reprogramming by morphology and proteome analysis. While mitochondria profoundly changed their morphology during Neurogenin2 (Neurog2) – or Achaete-scute homolog 1 (Ascl1)-mediated astrocyte-to-neuron reprogramming, we found neuron-specific mitochondrial proteins, here identified in a comprehensive proteome analysis of isolated mitochondria from primary neurons and astrocytes, to be only partially and at late stages regulated during the process. To improve this, we used dCas9 technology to induce neuron-specific mitochondrial proteins early during reprogramming. This resulted not only in increased conversion efficiency, but also in faster neuronal generation. Taken together, reprogramming mitochondria in a cell type-specific manner has powerful effects on astrocyte-to-neuron conversion, suggesting mitochondria to be a driving force in this process.

2021-03-29 | PXD014886 | Pride

Small molecules enable highly efficient neuronal conversion of human fibroblasts

2012-04-08 | GSE36246 | GEO

Fusion of reprogramming factors alters trajectory of somatic lineage conversion

Project description:Simultaneous expression of Oct4, Klf4, Sox2, and cMyc induces pluripotency in somatic cells (iPSCs). Replacing Oct4 with the neuro-specific factor Brn4 leads to the transdifferentiation of fibroblasts into induced neural stem cells (iNSCs). However, Brn4 was recently found to induce a transient acquisition of pluripotency before establishing the neural fate. We employed genetic lineage tracing and found that induction of iNSCs with individual vectors leads to direct lineage conversion. In contrast, polycistronic expression produces a Brn4-Klf4 fusion protein that enables the induction of pluripotency. Our study demonstrates that a combination of pluripotency and tissue-specific factors allows for direct somatic cell transdifferentiation, bypassing the acquisition of a pluripotent state. This result has major implications for lineage conversion technologies, which hold potential for providing a safer alternative to iPSCs for clinical application both in vitro and in vivo.

2019-01-29 | GSE125740 | GEO

Attenuation of PTBP2 facilitates fibroblast to neuron conversion by promoting alternative splicing of neuronal genes

Project description:The direct conversion of human skin fibroblasts to neurons has a low efficiency and unclear mechanism. Here, we show that the knockdown of PTBP2 (nPTB) significantly enhanced the transdifferentiation induced by ASCL1, MiR124-9/9* and p53 shRNA to generate mostly GABAergic neurons. Longitudinal RNAseq analyses identified the continuous induction of many RNA Splicing Regulators (RSRs). Among these, the knockdown of RBFOX3, which encodes the mature neuronal marker NeuN, significantly abrogated the transdifferentiation. Overexpression of RBFOX3 significantly enhanced the conversion induced by AMp; the enhancement was occluded by PTBP2 knockdown. We found that PTBP2 attenuation significantly favored neuron-specific alternative splicing (AS) of many genes involved in synaptic transmission, signal transduction, and axon formation. RBFOX3 knockdown significantly reversed the effect, while RBFOX3 overexpression enhanced it. The study reveals the critical role of neuron-specific AS in the direct conversion of human skin fibroblasts to neurons by showing that PTBP2 attenuation enhances this mechanism in concert with RBFOX3.

2023-10-12 | GSE210131 | GEO

Conversion of human fibroblasts into vascular cells

Project description:This SuperSeries is composed of the following subset Series: GSE40793: Conversion of human fibroblasts into vascular cells (gene expression) GSE40909: Conversion of human fibroblasts into vascular cells (methylation) Refer to individual Series

2012-09-18 | E-GEOD-40927 | biostudies-arrayexpress

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