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 journalArticle

3 Citations (Scopus)

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 (US)
Article number29
JournalTranslational Neurodegeneration
Volume7
Issue number1
DOIs
StatePublished - Nov 5 2018

Fingerprint

Cell Lineage
Astrocytes
Stem Cells
Neurons
Transcription Factors
Cell- and Tissue-Based Therapy
Neurodegenerative Diseases
Cell Transplantation
DNA Methylation
Prosencephalon
Cholinergic Agents
Genes

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

Cite this

Direct conversion of mouse astrocytes into neural progenitor cells and specific lineages of neurons. / Ma, Kangmu; Deng, Xiaobei; Xia, Xiaohuan; Fan, Zhaohuan; Qi, Xinrui; Wang, Yongxiang; Li, Yuju; Ma, Yizhao; Chen, Qiang; Peng, Hui; Ding, Jianqing; Li, Chunhong; Huang, Yunlong; Tian, Changhai; Zheng, Jialin C.

In: Translational Neurodegeneration, Vol. 7, No. 1, 29, 05.11.2018.

Research output: Contribution to journalArticle

Ma, Kangmu ; Deng, Xiaobei ; Xia, Xiaohuan ; Fan, Zhaohuan ; Qi, Xinrui ; Wang, Yongxiang ; Li, Yuju ; Ma, Yizhao ; Chen, Qiang ; Peng, Hui ; Ding, Jianqing ; Li, Chunhong ; Huang, Yunlong ; Tian, Changhai ; Zheng, Jialin C. / Direct conversion of mouse astrocytes into neural progenitor cells and specific lineages of neurons. In: Translational Neurodegeneration. 2018 ; Vol. 7, No. 1.
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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.",
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T1 - Direct conversion of mouse astrocytes into neural progenitor cells and specific lineages of neurons

AU - Ma, Kangmu

AU - Deng, Xiaobei

AU - Xia, Xiaohuan

AU - Fan, Zhaohuan

AU - Qi, Xinrui

AU - Wang, Yongxiang

AU - Li, Yuju

AU - Ma, Yizhao

AU - Chen, Qiang

AU - Peng, Hui

AU - Ding, Jianqing

AU - Li, Chunhong

AU - Huang, Yunlong

AU - Tian, Changhai

AU - Zheng, Jialin C

PY - 2018/11/5

Y1 - 2018/11/5

N2 - 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.

AB - 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.

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KW - Cholinergic neurons

KW - Dopaminergic neurons

KW - Foxa2

KW - Lhx8

KW - Lmx1a

KW - Neuronal lineage

KW - Reprogramming

KW - Transcription factor

KW - iNPCs

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JF - Translational Neurodegeneration

SN - 2047-9158

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