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

Jiu Chao Yin, Lei Zhang, Ning Xin Ma, Yue Wang, Grace Lee, Xiao Yi Hou, Zhuo Fan Lei, Feng Yu Zhang, Feng Ping Dong, Gang Yi Wu, Gong Chen

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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 β, 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. In this article, Chen and colleagues identified a chemical formula using only three to four small molecules to reprogram human fetal astrocytes into functional neurons, paving the way for a potential drug therapy for neuroregeneration and brain repair.

Original languageEnglish (US)
Pages (from-to)488-501
Number of pages14
JournalStem Cell Reports
Volume12
Issue number3
DOIs
StatePublished - Mar 5 2019

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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