Direct conversion of mouse astrocytes into neural progenitor cells and specific lineages of neurons

Kangmu Ma, Xiaobei Deng, Xiaohuan Xia, Zhaohuan Fan, Xinrui Qi, Yongxiang Wang, Yuju Li, Yizhao Ma, Qiang Chen, Hui Peng, Jianqing Ding, Chunhong Li, Yunlong Huang, Changhai Tian, Jialin C. Zheng

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Background: Cell replacement therapy has been envisioned as a promising treatment for neurodegenerative diseases. Due to the ethical concerns of ESCs-derived neural progenitor cells (NPCs) and tumorigenic potential of iPSCs, reprogramming of somatic cells directly into multipotent NPCs has emerged as a preferred approach for cell transplantation. Methods: Mouse astrocytes were reprogrammed into NPCs by the overexpression of transcription factors (TFs) Foxg1, Sox2, and Brn2. The generation of subtypes of neurons was directed by the force expression of cell-type specific TFs Lhx8 or Foxa2/Lmx1a. Results: Astrocyte-derived induced NPCs (AiNPCs) share high similarities, including the expression of NPC-specific genes, DNA methylation patterns, the ability to proliferate and differentiate, with the wild type NPCs. The AiNPCs are committed to the forebrain identity and predominantly differentiated into glutamatergic and GABAergic neuronal subtypes. Interestingly, additional overexpression of TFs Lhx8 and Foxa2/Lmx1a in AiNPCs promoted cholinergic and dopaminergic neuronal differentiation, respectively. Conclusions: Our studies suggest that astrocytes can be converted into AiNPCs and lineage-committed AiNPCs can acquire differentiation potential of other lineages through forced expression of specific TFs. Understanding the impact of the TF sets on the reprogramming and differentiation into specific lineages of neurons will provide valuable strategies for astrocyte-based cell therapy in neurodegenerative diseases.

Original languageEnglish
Article number29
JournalTranslational Neurodegeneration
Volume7
Issue number1
DOIs
StatePublished - Nov 5 2018

Bibliographical note

Funding Information:
This work was supported in part by research grants from the National Basic Research Program of China (973 ProgramGrant No. 2014CB965001 to JZ), Innovative Research Groups of the National Natural Science Foundation of China (#81221001 to JZ), and Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China (#81329002 to JZ), the National Institutes of Health: 2R56NS041858-15A1 (JZ), 1R01NS097195–01 (JZ), and R03 NS094071–01 (YH), the State of Nebraska, DHHS-LB606 Stem Cell 2009–10 to JZ.

Publisher Copyright:
© 2018 The Author(s).

Keywords

  • Astrocytes
  • Cholinergic neurons
  • Dopaminergic neurons
  • Foxa2
  • Lhx8
  • Lmx1a
  • Neuronal lineage
  • Reprogramming
  • Transcription factor
  • iNPCs

ASJC Scopus subject areas

  • Clinical Neurology
  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

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