Direct Neuronal Conversion of Microglia/macrophages Reinstates Neurological Function After Stroke

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2023 Oct 9

PMID 37812721

Authors

Takashi Irie

Taito Matsuda

Yoshinori Hayashi

Kanae Matsuda-Ito

Akihide Kamiya

Takahiro Masuda

Marco Prinz

Noriko Isobe

Jun-Ichi Kira

Kinichi Nakashima

Affiliations

Soon will be listed here.

Abstract

Although generating new neurons in the ischemic injured brain would be an ideal approach to replenish the lost neurons for repairing the damage, the adult mammalian brain retains only limited neurogenic capability. Here, we show that direct conversion of microglia/macrophages into neurons in the brain has great potential as a therapeutic strategy for ischemic brain injury. After transient middle cerebral artery occlusion in adult mice, microglia/macrophages converge at the lesion core of the striatum, where neuronal loss is prominent. Targeted expression of a neurogenic transcription factor, NeuroD1, in microglia/macrophages in the injured striatum enables their conversion into induced neuronal cells that functionally integrate into the existing neuronal circuits. Furthermore, NeuroD1-mediated induced neuronal cell generation significantly improves neurological function in the mouse stroke model, and ablation of these cells abolishes the gained functional recovery. Our findings thus demonstrate that neuronal conversion contributes directly to functional recovery after stroke.

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References

Balkaya M, Krober J, Gertz K, Peruzzaro S, Endres M . Characterization of long-term functional outcome in a murine model of mild brain ischemia. J Neurosci Methods. 2013; 213(2):179-87. DOI: 10.1016/j.jneumeth.2012.12.021. View

Gulyas B, Toth M, Schain M, Airaksinen A, Vas A, Kostulas K . Evolution of microglial activation in ischaemic core and peri-infarct regions after stroke: a PET study with the TSPO molecular imaging biomarker [((11))C]vinpocetine. J Neurol Sci. 2012; 320(1-2):110-7. DOI: 10.1016/j.jns.2012.06.026. View

Greenhalgh A, David S, Bennett F . Immune cell regulation of glia during CNS injury and disease. Nat Rev Neurosci. 2020; 21(3):139-152. DOI: 10.1038/s41583-020-0263-9. View

Torper O, Ottosson D, Pereira M, Lau S, Cardoso T, Grealish S . In Vivo Reprogramming of Striatal NG2 Glia into Functional Neurons that Integrate into Local Host Circuitry. Cell Rep. 2015; 12(3):474-81. PMC: 4521079. DOI: 10.1016/j.celrep.2015.06.040. View

Matsuda T, Irie T, Katsurabayashi S, Hayashi Y, Nagai T, Hamazaki N . Pioneer Factor NeuroD1 Rearranges Transcriptional and Epigenetic Profiles to Execute Microglia-Neuron Conversion. Neuron. 2019; 101(3):472-485.e7. DOI: 10.1016/j.neuron.2018.12.010. View

Irie T, Matsuda-Ito K, Matsuda T, Masuda T, Prinz M, Isobe N . Lineage tracing identifies in vitro microglia-to-neuron conversion by NeuroD1 expression. Genes Cells. 2023; 28(7):526-534. PMC: 11447828. DOI: 10.1111/gtc.13033. View

Ade K, Janssen M, Ortinski P, Vicini S . Differential tonic GABA conductances in striatal medium spiny neurons. J Neurosci. 2008; 28(5):1185-97. PMC: 6671393. DOI: 10.1523/JNEUROSCI.3908-07.2008. View

Kita T, Kita H, Kitai S . Passive electrical membrane properties of rat neostriatal neurons in an in vitro slice preparation. Brain Res. 1984; 300(1):129-39. DOI: 10.1016/0006-8993(84)91347-7. View

Niu W, Zang T, Wang L, Zou Y, Zhang C . Phenotypic Reprogramming of Striatal Neurons into Dopaminergic Neuron-like Cells in the Adult Mouse Brain. Stem Cell Reports. 2018; 11(5):1156-1170. PMC: 6234859. DOI: 10.1016/j.stemcr.2018.09.004. View

10.

Matsuda T, Nakashima K . Clarifying the ability of NeuroD1 to convert mouse microglia into neurons. Neuron. 2021; 109(24):3912-3913. DOI: 10.1016/j.neuron.2021.11.012. View

11.

Kawaguchi Y, Wilson C, Emson P . Intracellular recording of identified neostriatal patch and matrix spiny cells in a slice preparation preserving cortical inputs. J Neurophysiol. 1989; 62(5):1052-68. DOI: 10.1152/jn.1989.62.5.1052. View

12.

Chen Y, Ma N, Pei Z, Wu Z, Do-Monte F, Keefe S . A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair after Ischemic Injury through In Vivo Astrocyte-to-Neuron Conversion. Mol Ther. 2019; 28(1):217-234. PMC: 6952185. DOI: 10.1016/j.ymthe.2019.09.003. View

13.

Hayashi Y, Morinaga S, Zhang J, Satoh Y, Meredith A, Nakata T . BK channels in microglia are required for morphine-induced hyperalgesia. Nat Commun. 2016; 7:11697. PMC: 4895018. DOI: 10.1038/ncomms11697. View

14.

Wu Z, Parry M, Hou X, Liu M, Wang H, Cain R . Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington's disease. Nat Commun. 2020; 11(1):1105. PMC: 7046613. DOI: 10.1038/s41467-020-14855-3. View

15.

Willett J, Cao J, Dorris D, Johnson A, Ginnari L, Meitzen J . Electrophysiological Properties of Medium Spiny Neuron Subtypes in the Caudate-Putamen of Prepubertal Male and Female -tdTomato Line 6 BAC Transgenic Mice. eNeuro. 2019; 6(2). PMC: 6426437. DOI: 10.1523/ENEURO.0016-19.2019. View

16.

Jin W, Shi S, Li Z, Li M, Wood K, Gonzales R . Depletion of microglia exacerbates postischemic inflammation and brain injury. J Cereb Blood Flow Metab. 2017; 37(6):2224-2236. PMC: 5444553. DOI: 10.1177/0271678X17694185. View

17.

Arlotta P, Molyneaux B, Jabaudon D, Yoshida Y, Macklis J . Ctip2 controls the differentiation of medium spiny neurons and the establishment of the cellular architecture of the striatum. J Neurosci. 2008; 28(3):622-32. PMC: 6670353. DOI: 10.1523/JNEUROSCI.2986-07.2008. View

18.

Brulet R, Matsuda T, Zhang L, Miranda C, Giacca M, Kaspar B . NEUROD1 Instructs Neuronal Conversion in Non-Reactive Astrocytes. Stem Cell Reports. 2017; 8(6):1506-1515. PMC: 5470076. DOI: 10.1016/j.stemcr.2017.04.013. View

19.

Price C, Wang D, Menon D, Guadagno J, Cleij M, Fryer T . Intrinsic activated microglia map to the peri-infarct zone in the subacute phase of ischemic stroke. Stroke. 2006; 37(7):1749-53. DOI: 10.1161/01.STR.0000226980.95389.0b. View

20.

Wang L, Serrano C, Zhong X, Ma S, Zou Y, Zhang C . Revisiting astrocyte to neuron conversion with lineage tracing in vivo. Cell. 2021; 184(21):5465-5481.e16. PMC: 8526404. DOI: 10.1016/j.cell.2021.09.005. View