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Chemical Conversion of Human Fetal Astrocytes into Neurons through Modulation of Multiple Signaling Pathways.

ABSTRACT: We have previously developed a cocktail of nine small molecules to convert human fetal astrocytes into neurons, but a nine-molecule recipe is difficult for clinical applications. Here, we identify a chemical formula with only three to four small molecules for astrocyte-to-neuron conversion. We demonstrate that modulation of three to four signaling pathways among Notch, glycogen synthase kinase 3, transforming growth factor ?, and bone morphogenetic protein pathways is sufficient to change an astrocyte into a neuron. The chemically converted human neurons can survive >7 months in culture, fire repetitive action potentials, and display robust synaptic burst activities. Interestingly, cortical astrocyte-converted neurons are mostly glutamatergic, while midbrain astrocyte-converted neurons can yield some GABAergic neurons in addition to glutamatergic neurons. When administered in vivo through intracranial or intraperitoneal injection, the four-drug combination can significantly increase adult hippocampal neurogenesis. Together, human fetal astrocytes can be chemically converted into functional neurons using three to four small molecules, bringing us one step forward for developing future drug therapy.

SUBMITTER: Yin JC

PROVIDER: S-EPMC6409415 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Chemical Conversion of Human Fetal Astrocytes into Neurons through Modulation of Multiple Signaling Pathways.

Yin Jiu-Chao JC Zhang Lei L Ma Ning-Xin NX Wang Yue Y Lee Grace G Hou Xiao-Yi XY Lei Zhuo-Fan ZF Zhang Feng-Yu FY Dong Feng-Ping FP Wu Gang-Yi GY Chen Gong G

Stem cell reports 20190207 3

We have previously developed a cocktail of nine small molecules to convert human fetal astrocytes into neurons, but a nine-molecule recipe is difficult for clinical applications. Here, we identify a chemical formula with only three to four small molecules for astrocyte-to-neuron conversion. We demonstrate that modulation of three to four signaling pathways among Notch, glycogen synthase kinase 3, transforming growth factor β, and bone morphogenetic protein pathways is sufficient to change an ast ...[more]

PMID: 30745031

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Project description:BackgroundThe conversion of astrocytes activated by nerve injuries to oligodendrocytes is not only beneficial to axonal remyelination, but also helpful for reversal of glial scar. Recent studies have shown that pathological niche promoted the Sox10-mediated astrocytic transdifferentiation to oligodendrocytes. The extracellular factors underlying the cell fate switching are not known.MethodsAstrocytes were obtained from mouse spinal cord dissociation culture and purified by differential adherent properties. The lineage conversion of astrocytes into oligodendrocyte lineage cells was carried out by Sox10-expressing virus infection both in vitro and in vivo, meanwhile, epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) inhibitor Gefitinib were adopted to investigate the function of EGF signaling in this fate transition process. Pharmacological inhibition analyses were performed to examine the pathway connecting the EGF with the expression of oligodendrogenic genes and cell fate transdifferentiation.ResultsEGF treatment facilitated the Sox10-induced transformation of astrocytes to O4+ induced oligodendrocyte precursor cells (iOPCs) in vitro. The transdifferentiation of astrocytes to iOPCs went through two distinct but interconnected processes: (1) dedifferentiation of astrocytes to astrocyte precursor cells (APCs); (2) transformation of APCs to iOPCs, EGF signaling was involved in both processes. And EGF triggered astrocytes to express oligodendrogenic genes Olig1 and Olig2 by activating extracellular signal-regulated kinase 1 and 2 (Erk1/2) pathway. In addition, we discovered that EGF can enhance astrocyte transdifferentiation in injured spinal cord tissues.ConclusionsThese findings provide strong evidence that EGF facilitates the transdifferentiation of astrocytes to oligodendrocytes, and suggest that targeting the EGF-EGFR-Erk1/2 signaling axis may represent a novel therapeutic strategy for myelin repair in injured central nervous system (CNS) tissues.

Dataset Information

Chemical Conversion of Human Fetal Astrocytes into Neurons through Modulation of Multiple Signaling Pathways.

Publications

Chemical Conversion of Human Fetal Astrocytes into Neurons through Modulation of Multiple Signaling Pathways.

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