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Translational Neurodegeneration
Published in: Translational Neurodegeneration 1/2018

Open Access 01-12-2018 | Research

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

Authors: 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

Published in: Translational Neurodegeneration | Issue 1/2018

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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.
Appendix
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Literature
1.
Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992;255(5052):1707–10.CrossRef
2.
Bonnamain V, Neveu I, Naveilhan P. In vitro analyses of the immunosuppressive properties of neural stem/progenitor cells using anti-CD3/CD28-activated T cells. Methods Mol Biol. 2011;677:233–43.CrossRef
3.
Mosher KI, et al. Neural progenitor cells regulate microglia functions and activity. Nat Neurosci. 2012;15(11):1485–7.CrossRef
4.
Amor S, et al. Inflammation in neurodegenerative diseases. Immunology. 2010;129(2):154–69.CrossRef
5.
Whitney NP, et al. Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders. J Neurochem. 2009;108(6):1343–59.CrossRef
6.
Rosenberg GA, et al. Tumor necrosis factor-a-induced gelatinase B causes delayed opening of the blood-brain barrier: an expanded therapuetic window. Brain Res. 1995;703:151–5.CrossRef
7.
Tapscott SJ, et al. MyoD1: a nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts. Science. 1988;242(4877):405–11.CrossRef
8.
Smith DK, et al. The therapeutic potential of cell identity reprogramming for the treatment of aging-related neurodegenerative disorders. Prog Neurobiol. 2017;157:212–29.CrossRef
9.
Lai S, et al. Direct reprogramming of induced neural progenitors: a new promising strategy for AD treatment. Transl Neurodegener. 2015;4:7.CrossRef
10.
Miura K, et al. Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol. 2009;27(8):743–5.CrossRef
11.
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.CrossRef
12.
Karumbayaram S, et al. Directed differentiation of human-induced pluripotent stem cells generates active motor neurons. Stem Cells. 2009;27(4):806–11.CrossRef
13.
Han DW, et al. Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell Stem Cell. 2012;10(4):465–72.CrossRef
14.
Koehler KR, et al. Extended passaging increases the efficiency of neural differentiation from induced pluripotent stem cells. BMC Neurosci. 2011;12:82.CrossRef
15.
Kim JB, et al. Oct4-induced pluripotency in adult neural stem cells. Cell. 2009;136(3):411–9.CrossRef
16.
Wernig M, et al. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci U S A. 2008;105(15):5856–61.CrossRef
17.
Tian C, et al. Direct conversion of dermal fibroblasts into neural progenitor cells by a novel cocktail of defined factors. Curr Mol Med. 2012;12(2):126–37.CrossRef
18.
Thier M, et al. Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell. 2012;10(4):473–9.CrossRef
19.
Lujan E, et al. Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells. Proc Natl Acad Sci U S A. 2012;109(7):2527–32.CrossRef
20.
Sheng C, et al. Direct reprogramming of Sertoli cells into multipotent neural stem cells by defined factors. Cell Res. 2012;22(1):208–18.CrossRef
21.
Corti S, et al. Direct reprogramming of human astrocytes into neural stem cells and neurons. Exp Cell Res. 2012;318(13):1528–41.CrossRef
22.
Kim J, et al. Direct reprogramming of mouse fibroblasts to neural progenitors. Proc Natl Acad Sci U S A. 2011;108(19):7838–43.CrossRef
23.
Tian C, et al. Selective generation of dopaminergic precursors from mouse fibroblasts by direct lineage conversion. Sci Rep. 2015;5:12622.CrossRef
24.
Barreto GE, et al. Astrocyte proliferation following stroke in the mouse depends on distance from the infarct. PLoS One. 2011;6(11):e27881.CrossRef
25.
Verkhratsky A, et al. Neurological diseases as primary gliopathies: a reassessment of neurocentrism. ASN Neuro. 2012;4(3):e00082.CrossRef
26.
Sirko S, et al. Reactive glia in the injured brain acquire stem cell properties in response to sonic hedgehog glia. Cell Stem Cell. 2013;12(4):426–39.CrossRef
27.
Torper O, et al. Generation of induced neurons via direct conversion in vivo. Proc Natl Acad Sci U S A. 2013;110(17):7038–43.CrossRef
28.
Walter L, et al. Astrocytes in culture produce anandamide and other acylethanolamides. J Biol Chem. 2002;277(23):20869–76.CrossRef
29.
Baizabal JM, et al. Telencephalic neural precursor cells show transient competence to interpret the dopaminergic niche of the embryonic midbrain. Dev Biol. 2011;349(2):192–203.CrossRef
30.
Laywell ED, et al. Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc Natl Acad Sci U S A. 2000;97(25):13883–8.CrossRef
31.
Capela A, Temple S. LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron. 2002;35(5):865–75.CrossRef
32.
Western PS, et al. Male fetal germ cell differentiation involves complex repression of the regulatory network controlling pluripotency. FASEB J. 2010;24(8):3026–35.CrossRef
33.
Hebert JM, Fishell G. The genetics of early telencephalon patterning: some assembly required. Nat Rev Neurosci. 2008;9(9):678–85.CrossRef
34.
Rallu M, Corbin JG, Fishell G. Parsing the prosencephalon. Nat Rev Neurosci. 2002;3(12):943–51.CrossRef
35.
Rouaux C, Bhai S, Arlotta P. Programming and reprogramming neuronal subtypes in the central nervous system. Dev Neurobiol. 2012;72(7):1085–98.CrossRef
36.
Lee HK, et al. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature. 2000;405(6789):955–9.CrossRef
37.
Tian C, et al. Reprogrammed mouse astrocytes retain a “memory” of tissue origin and possess more tendencies for neuronal differentiation than reprogrammed mouse embryonic fibroblasts. Protein Cell. 2011;2(2):128–40.CrossRef
38.
Blusztajn JK, Berse B. The cholinergic neuronal phenotype in Alzheimer's disease. Metab Brain Dis. 2000;15(1):45–64.PubMed
39.
Mufson EJ, et al. Cholinergic system during the progression of Alzheimer's disease: therapeutic implications. Expert Rev Neurother. 2008;8(11):1703–18.CrossRef
40.
Panman L, et al. Transcription factor-induced lineage selection of stem-cell-derived neural progenitor cells. Cell Stem Cell. 2011;8(6):663–75.CrossRef
41.
Lee HS, et al. Foxa2 and Nurr1 synergistically yield A9 nigral dopamine neurons exhibiting improved differentiation, function, and cell survival. Stem Cells. 2010;28(3):501–12.PubMed
42.
Peng H, et al. HIV-1-infected and/or immune-activated macrophage-secreted TNF-alpha affects human fetal cortical neural progenitor cell proliferation and differentiation. Glia. 2008;56(8):903–16.CrossRef
43.
Abeliovich A, Doege CA. Reprogramming therapeutics: iPS cell prospects for neurodegenerative disease. Neuron. 2009;61(3):337–9.CrossRef
44.
Chen Y, Pu J, Zhang B. Progress and challenges of cell replacement therapy for neurodegenerative diseases based on direct neural reprogramming. Hum Gene Ther. 2016;27(12):962–70.CrossRef
45.
Masserdotti G, et al. Transcriptional mechanisms of proneural factors and REST in regulating neuronal reprogramming of astrocytes. Cell Stem Cell. 2015;17(1):74–88.CrossRef
46.
Addis RC, et al. Efficient conversion of astrocytes to functional midbrain dopaminergic neurons using a single polycistronic vector. PLoS One. 2011;6(12):e28719.CrossRef
47.
Berninger B, et al. Functional properties of neurons derived from in vitro reprogrammed postnatal astroglia. J Neurosci. 2007;27(32):8654–64.CrossRef
48.
Chouchane M, et al. Lineage reprogramming of Astroglial cells from different origins into distinct neuronal subtypes. Stem Cell Rep. 2017;9(1):162–76.CrossRef
49.
Niu W, et al. In vivo reprogramming of astrocytes to neuroblasts in the adult brain. Nat Cell Biol. 2013;15(10):1164–75.CrossRef
50.
Heinrich C, et al. Directing astroglia from the cerebral cortex into subtype specific functional neurons. PLoS Biol. 2010;8(5):e1000373.CrossRef
51.
Wanner IB. An in vitro trauma model to study rodent and human astrocyte reactivity. Methods Mol Biol. 2012;814:189–219.CrossRef
52.
Tezel G, Hernandez MR, Wax MB. In vitro evaluation of reactive astrocyte migration, a component of tissue remodeling in glaucomatous optic nerve head. Glia. 2001;34(3):178–89.CrossRef
53.
Wang K, et al. TNF-alpha promotes extracellular vesicle release in mouse astrocytes through glutaminase. J Neuroinflammation. 2017;14(1):87.CrossRef
54.
Costa MR, Gotz M, Berninger B. What determines neurogenic competence in glia? Brain Res Rev. 2010;63(1–2):47–59.CrossRef
55.
Merkle FT, Mirzadeh Z, Alvarez-Buylla A. Mosaic organization of neural stem cells in the adult brain. Science. 2007;317(5836):381–4.CrossRef
56.
Wood HB, Episkopou V. Comparative expression of the mouse Sox1, Sox2 and Sox3 genes from pre-gastrulation to early somite stages. Mech Dev. 1999;86(1–2):197–201.CrossRef
57.
Manuel M, et al. The transcription factor Foxg1 regulates the competence of telencephalic cells to adopt subpallial fates in mice. Development. 2010;137(3):487–97.CrossRef
58.
Martynoga B, et al. Foxg1 is required for specification of ventral telencephalon and region-specific regulation of dorsal telencephalic precursor proliferation and apoptosis. Dev Biol. 2005;283(1):113–27.CrossRef
59.
Rash BG, Grove EA. Patterning the dorsal telencephalon: a role for sonic hedgehog? J Neurosci. 2007;27(43):11595–603.CrossRef
60.
Marin O, Rubenstein JL. A long, remarkable journey: tangential migration in the telencephalon. Nat Rev Neurosci. 2001;2(11):780–90.CrossRef
61.
Li XJ, et al. Coordination of sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells. Development. 2009;136(23):4055–63.CrossRef
62.
Matsumoto K, et al. L3, a novel murine LIM-homeodomain transcription factor expressed in the ventral telencephalon and the mesenchyme surrounding the oral cavity. Neurosci Lett. 1996;204(1):113–6.CrossRef
63.
Manabe T, et al. L3/Lhx8 is involved in the determination of cholinergic or GABAergic cell fate. J Neurochem. 2005;94(3):723–30.CrossRef
64.
Ferri AL, et al. Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner. Development. 2007;134(15):2761–9.CrossRef
65.
Lin W, et al. Foxa1 and Foxa2 function both upstream of and cooperatively with Lmx1a and Lmx1b in a feedforward loop promoting mesodiencephalic dopaminergic neuron development. Dev Biol. 2009;333(2):386–96.CrossRef
66.
Nakatani T, et al. Lmx1a and Lmx1b cooperate with Foxa2 to coordinate the specification of dopaminergic neurons and control of floor plate cell differentiation in the developing mesencephalon. Dev Biol. 2010;339(1):101–13.CrossRef
67.
Yarygin KN, et al. Mechanisms of positive effects of transplantation of human placental mesenchymal stem cells on recovery of rats after experimental ischemic stroke. Bull Exp Biol Med. 2009;148(6):862–8.CrossRef
68.
Lee H, et al. Bone-marrow-derived mesenchymal stem cells promote proliferation and neuronal differentiation of Niemann-pick type C mouse neural stem cells by upregulation and secretion of CCL2. Hum Gene Ther. 2013;24(7):655–69.CrossRef
Metadata
Title
Direct conversion of mouse astrocytes into neural progenitor cells and specific lineages of neurons
Authors
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
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Translational Neurodegeneration / Issue 1/2018
Electronic ISSN: 2047-9158
DOI
https://doi.org/10.1186/s40035-018-0132-x

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