Outer radial glia promotes white matter regeneration after neonatal brain injury

Hideo Jinnou; Lauren M. Rosko; Satoshi Yamashita; Soichiro Henmi; Jaya Prasad; Van K. Lam; Artur Agaronyan; Tsang Wei Tu; Yuka Imamura; Kazuya Kuboyama; Kazunobu Sawamoto; Kazue Hashimoto-Torii; Nobuyuki Ishibashi; Vittorio Gallo

doi:10.1016/j.xcrm.2025.101986

Outer radial glia promotes white matter regeneration after neonatal brain injury

Hideo Jinnou
, Lauren M. Rosko
, Satoshi Yamashita
, Soichiro Henmi
, Jaya Prasad
, Van K. Lam
, Artur Agaronyan
, Tsang Wei Tu
, Yuka Imamura
, Kazuya Kuboyama
, Kazunobu Sawamoto
, Kazue Hashimoto-Torii
, Nobuyuki Ishibashi
, Vittorio Gallo

Department of Neuroscience and Experimental Therapeutics

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

The developing gyrencephalic brain contains a large population of neural stem cells in the ventricular zone and outer subventricular zone (OSVZ), the latter populated by outer radial glia (oRG). The role of oRG during postnatal development is not well understood. We show that oRG cells increase proliferative capacity and contribute to oligodendrocyte precursor cell (OPC) production following brain injury in human infants and neonatal piglets, whose brains resemble the human brain in structure and development. RNA sequencing revealed oRG-specific transcriptional responses to injury in piglets and showed that the activating transcription factor 5 (ATF5) pathway positively regulates oRG proliferation. Intranasal activation of ATF5 using salubrinal enhanced OSVZ-derived oligodendrogenesis in the injured periventricular white matter and improved functional recovery. These results reveal a key role for postnatal oRG in brain injury recovery and identify ATF5 as a potential therapeutic target for treating white matter injury in infants.

Original language	English (US)
Article number	101986
Journal	Cell Reports Medicine
Volume	6
Issue number	3
DOIs	https://doi.org/10.1016/j.xcrm.2025.101986
State	Published - Mar 18 2025

All Science Journal Classification (ASJC) codes

General Medicine
General Biochemistry, Genetics and Molecular Biology

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10.1016/j.xcrm.2025.101986

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title = "Outer radial glia promotes white matter regeneration after neonatal brain injury",

abstract = "The developing gyrencephalic brain contains a large population of neural stem cells in the ventricular zone and outer subventricular zone (OSVZ), the latter populated by outer radial glia (oRG). The role of oRG during postnatal development is not well understood. We show that oRG cells increase proliferative capacity and contribute to oligodendrocyte precursor cell (OPC) production following brain injury in human infants and neonatal piglets, whose brains resemble the human brain in structure and development. RNA sequencing revealed oRG-specific transcriptional responses to injury in piglets and showed that the activating transcription factor 5 (ATF5) pathway positively regulates oRG proliferation. Intranasal activation of ATF5 using salubrinal enhanced OSVZ-derived oligodendrogenesis in the injured periventricular white matter and improved functional recovery. These results reveal a key role for postnatal oRG in brain injury recovery and identify ATF5 as a potential therapeutic target for treating white matter injury in infants.",

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doi = "10.1016/j.xcrm.2025.101986",

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AU - Jinnou, Hideo

AU - Rosko, Lauren M.

AU - Yamashita, Satoshi

AU - Henmi, Soichiro

AU - Prasad, Jaya

AU - Lam, Van K.

AU - Agaronyan, Artur

AU - Tu, Tsang Wei

AU - Imamura, Yuka

AU - Kuboyama, Kazuya

AU - Sawamoto, Kazunobu

AU - Hashimoto-Torii, Kazue

AU - Ishibashi, Nobuyuki

AU - Gallo, Vittorio

PY - 2025/3/18

Y1 - 2025/3/18

N2 - The developing gyrencephalic brain contains a large population of neural stem cells in the ventricular zone and outer subventricular zone (OSVZ), the latter populated by outer radial glia (oRG). The role of oRG during postnatal development is not well understood. We show that oRG cells increase proliferative capacity and contribute to oligodendrocyte precursor cell (OPC) production following brain injury in human infants and neonatal piglets, whose brains resemble the human brain in structure and development. RNA sequencing revealed oRG-specific transcriptional responses to injury in piglets and showed that the activating transcription factor 5 (ATF5) pathway positively regulates oRG proliferation. Intranasal activation of ATF5 using salubrinal enhanced OSVZ-derived oligodendrogenesis in the injured periventricular white matter and improved functional recovery. These results reveal a key role for postnatal oRG in brain injury recovery and identify ATF5 as a potential therapeutic target for treating white matter injury in infants.

AB - The developing gyrencephalic brain contains a large population of neural stem cells in the ventricular zone and outer subventricular zone (OSVZ), the latter populated by outer radial glia (oRG). The role of oRG during postnatal development is not well understood. We show that oRG cells increase proliferative capacity and contribute to oligodendrocyte precursor cell (OPC) production following brain injury in human infants and neonatal piglets, whose brains resemble the human brain in structure and development. RNA sequencing revealed oRG-specific transcriptional responses to injury in piglets and showed that the activating transcription factor 5 (ATF5) pathway positively regulates oRG proliferation. Intranasal activation of ATF5 using salubrinal enhanced OSVZ-derived oligodendrogenesis in the injured periventricular white matter and improved functional recovery. These results reveal a key role for postnatal oRG in brain injury recovery and identify ATF5 as a potential therapeutic target for treating white matter injury in infants.

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DO - 10.1016/j.xcrm.2025.101986

M3 - Article

C2 - 40023165

AN - SCOPUS:86000778508

SN - 2666-3791

VL - 6

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 3

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ER -

Outer radial glia promotes white matter regeneration after neonatal brain injury

Abstract

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