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Direct Generation of Human Neuronal Cells from Adult Astrocytes by Small Molecules

ABSTRACT: Astrocytes, due to the proximity to neuronal lineage and capability to proliferate, are ideal starting cells to regenerate neurons. Human fetal astrocytes have been successfully converted into neuronal cells by small molecules, which offer a broader range of further applications than transcription factor-mediated neuronal reprogramming. Here we report human adult astrocytes could also be converted into neuronal cells by a different set with fewer small molecules. These induced neuronal cells exhibited typical neuronal morphologies, expressed neuronal markers, and displayed neuronal electrophysiological properties. Genome-wide RNA-sequencing analysis showed the gene expression profile of induced neuronal cells resembled that of human embryonic stem cell-differentiated neurons. When transplanted into postnatal mouse brains, these induced neuronal cells could survive in vivo. Altogether, our study provides a new strategy to directly generate transgene-free neurons from human adult astrocytes by small molecules.

ORGANISM(S): Homo sapiens

PROVIDER: GSE84826 | GEO | 2017/06/12

SECONDARY ACCESSION(S): PRJNA335315

REPOSITORIES: GEO

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Homo sapiens

Project description:Direct Generation of Human Neuronal Cells from Adult Astrocytes by Small Molecules

| PRJNA335315 | ENA

In vivo Chemical Reprogramming of Astrocytes into Functional Neurons

Project description:In mammals, many organs lack robust regenerative abilities. Lost cells in impaired tissue could potentially be compensated by converting nearby cells in situ through in vivo reprogramming. Small molecule-induced reprogramming offers a spatiotemporally flexible and non-integrative strategy for altering cell fate, which is, in principle, favorable for in vivo reprogramming in organs with notoriously poor regenerative abilities, such as the brain. Here, we demonstrate that in adult mouse brain, small molecules can reprogram astrocytes into functional neurons. The in situ chemically induced neurons resemble endogenous neurons in gene expression profiles, electrophysiological properties and synaptic connectivity. Our study demonstrates, for the first time, in vivo chemical reprogramming in the adult brain and provides a novel approach for developing neuronal replacement therapies.

2023-02-02 | GSE144993 | GEO

Genome-wide expression analysis of human fibroblasts and converted neurons

Project description:Human fibroblasts can be directly converted into cholinergic neurons by Neurogenin 2 (Neurog2 or NGN2) under the treatments of small molecules. Genome-wide analysis of gene expression was performed to examine the similarity of converted neurons to samples from human brain or spinal cord. Total RNA obtained from isolated human fetal lung fibroblasts or converted neurons at 21 days. Commercially available total RNAs from adult human brains and spinal cords were used as controls.

2014-01-16 | E-GEOD-45954 | biostudies-arrayexpress

An Efficient Direct Conversion Strategy to Generate Functional Astrocytes from Human Adult Fibroblasts

Project description:Direct reprogramming approaches offer an attractive alternative to stem-cell-derived models, allowing the retention of epigenetic information and age-associated cellular phenotypes, as well as a fast method to reach a target cell type. Several groups have previously generated multiple neuronal subtypes, neural progenitor cells, oligodendrocytes, and other cell types directly from fibroblasts. Other groups have had success at the efficient conversion of embryonic fibroblasts to astrocytes but have not yet achieved similar conversion efficiency for adult human fibroblasts. In order to generate astrocytes for the study of adult-stage disorders, we developed an improved direct conversion strategy employing a combination of small molecules to activate specific pathways that induce trans-differentiation of human adult fibroblasts to astrocytes. We demonstrate that this method produces mature GFAP+/S100β+ cells at high efficiency (40-45%), comparable to previous studies utilizing embryonic fibroblasts. Further, Fibroblast-derived induced Astrocytes (FdiAs) are enriched for markers of astrocyte functionality, including ion-channel buffering, gap-junction communication, and glutamate uptake; and exhibit astrocyte-like calcium signaling and neuroinflammatory phenotypes. RNA-Seq analysis indicates an adult rather than fetal astrocytic gene expression signature, with a greater correlation to temporal lobe astrocytes. Fibroblast-derived induced astrocytes provide a useful tool in studying the adult brain and complement existing in vitro models of induced neurons (iNs), providing an additional platform to study late-stage brain disorders.

2024-07-19 | GSE272279 | GEO

An Efficient Direct Conversion Strategy to Generate Functional Astrocytes from Human Adult Fibroblasts

Project description:Direct reprogramming approaches offer an attractive alternative to stem-cell-derived models, allowing the retention of epigenetic information and age-associated cellular phenotypes. To explore such age-related phenotypes, several groups have generated multiple neuronal subtypes, neural progenitor cells, oligodendrocytes, and other cell types directly from fibroblasts. Other groups have had success at the efficient conversion of embryonic fibroblasts to astrocytes but have not yet achieved similar conversion efficiency for adult human fibroblasts. In order to generate astrocytes for the study of age-related diseases, we developed an improved direct conversion strategy employing a combination of small molecules to activate specific pathways that induce trans-differentiation of human adult fibroblasts to astrocytes. We demonstrate that this method produces mature GFAP+/S100β+ cells at high efficiency (40-45%), comparable to previous studies utilizing embryonic fibroblasts. Further, Fibroblast-derived induced Astrocytes (FdiAs) are enriched for markers of astrocyte functionality, including ion-channel buffering, gap-junction communication, and glutamate uptake; and exhibit astrocyte-like calcium signaling and neuroinflammatory phenotypes. RNA-Seq analysis indicates an adult rather than fetal astrocytic gene expression signature, with a greater correlation to temporal lobe astrocytes. Fibroblast-derived induced astrocytes provide a useful tool in understanding age-associated disease processes and complement existing in vitro models of induced neurons (iNs), providing an additional platform to study late-stage brain disorders.

2024-08-31 | GSE239320 | GEO

Genome-wide expression analysis of human fibroblasts and converted neurons

2014-01-16 | GSE45954 | GEO

Direct Reprogramming of Human Astrocytes into Spinal Cord Organoids Facilitating Spinal Cord Regeneration

Project description:Human astrocytes have reported to reprogram into neurons, but they have yet to be induced to three-dimensional (3D) neural tissue for neural organogenesis. Here, we demonstrate a remarkable strategy for 3D organoid generation by direct reprogramming human astrocytes. By combining overexpression OCT4, suppression p53 and small molecules CHIR99021, SB431542, RepSox and Y27632, termed as Op53-CSBRY, we successfully reprogramed human astrocytes into neural ectodermal cells and further induced human 3D-brain organoid. Those organoids can be finally induced into spinal cord organoids by activating FGF, SHH and BMP signaling. The grafts of Human astrocyte derived spinal cord organoids (hADSC-Organs) can survived, differentiated into spinal cord neurons, migrated long distance, formed synaptic connectivity with host neurons, bridged complete injury spinal cord tissue in mice. This method indicates that human astrocytes could be directly triggered neural organogenesis, and may hold a great promising to support local astrocytes in situ organogenesis after brain damages, such as stroke and spinal cord injury.

2024-02-01 | GSE168635 | GEO

Reprogramming of primary human hepatocytes (PHHs) into hCLiPs

Project description:PHHs were cultured in the presence of small molecules and converted to proliferative progenitor cells named human chemcically induced progenitors (hCLiPs).

2019-07-04 | GSE133776 | GEO

Suppression of glioblastoma by a drug cocktail inducing tumor cells toward a neuronal fate

Project description:Glioblastoma (GBM), the most common and aggressive malignant tumor in adult brain, is a notoriously fatal tumor. For many years, surgical resection and postoperative radiotherapy had been used for the treatment of GBM, which resulted in a poor median survival of about 12 months. Currently, Temozolomide (TMZ) as a clinically meaningful chemotherapy drug has become the standard first-line treatment for GBM, but with an increase of the median survival for about only 2.5 months. In this study, encouraged by previous findings that human astrocytes could be converted into neuronal cells with small molecules and that human GBM cells could be induced into neuronal like cells by transcription factors, we intended to test whether GBM cells could be induced into neuronal like cells by a cocktail of approved drugs and whether this drug cocktail help to suppress GBM in patient derived xenograft (PDX). Here we screened and identified TMZ, Tranilast, and Fasudil, three approved clinical drugs (TTF), to induce GBM cells toward a neuronal fate. Both serum and serum-free cultured GBM cells exhibited neuronal morphology and expressed neuronal genes under TTF treatment. Malignant properties including uncontrolled proliferation and intensive invasion of GBM cells were also attenuated with TTF treatment. Most importantly, when administrated in PDX, TTF cocktail significantly suppressed GBM growth in vivo and prolonged the survival of tumor-bearing mice, as compared to TMZ alone. Our study indicated that using the approved drug cocktail to induce tumor cells toward a neuronal fate might be a clinically promising strategy for GBM treatment.

2019-03-12 | GSE110130 | GEO

Direct conversion of normal and patient human fibroblasts into neuronal cells

Project description:Neuronal conversion from human fibroblasts can be induced by lineage-specific transcription factors, holding great promise for human neurological disease modeling and regenerative medicine. However, the introduction of ectopic genes limits their therapeutic applications. Here, we report that neuronal cells could be directly induced from human fibroblasts by a chemical cocktail of seven small molecules bypassing neural progenitor stage. These chemical-induced neuronal cells (hciN cells) resembled hES-derived neurons regarding morphology, gene expression profiles, and electrophysiological properties. Our further experiments show that hciN cells were able to develop into mature neurons in vivo in embryonic mouse brain. Moreover, this approach was further applied to induce hciN cells from fibroblasts of familial Alzheimer’s disease patients and the hciN cells showed abnormal A? production. Together, we established a transgene-free chemical approach to directly induce neuronal cells from human fibroblasts, thus providing alternative strategies for modeling of related neurological diseases and regenerative medicine. We used microarray to comparethe global gene expression patterns of hES-derived neurons (control neurons), HAFs, pre-hciN cells (VCRFSGY-treated HAFs at day 3 and 7) and hciN cells (induced with VCRFSGY for 14 days) hciNs RNA samples were selected at different time points, i.e. pre-hciN cells (VCRFSGY-treated HAFs at day 3 and 7) and hciN cells (induced with VCRFSGY for 14 days), to study molecular mechanism and marker gene expression happened at the early stage of chemical induction by compared with hES-neurons (positve control) and HAFs (negtive control).

2015-07-28 | E-GEOD-69480 | biostudies-arrayexpress

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