Outer radial glia promotes white matter regeneration after neonatal brain injury

Hideo Jinnou, Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA; Department of Pediatrics and Neonatology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
Lauren M. Rosko, Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA.
Satoshi Yamashita, Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA.
Soichiro Henmi, Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA.
Jaya Prasad, Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA.
Van K. Lam, Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA.
Artur Agaronyan, Molecular Imaging Laboratory, Department of Radiology, Howard University, Washington, DC 20059, USA.
Tsang-Wei Tu, Molecular Imaging Laboratory, Department of Radiology, Howard University, Washington, DC 20059, USA.
Yuka Imamura, Departments of Pharmacology and Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Kazuya Kuboyama, Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
Kazunobu Sawamoto, Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
Kazue Hashimoto-Torii, Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA; Department of Pediatrics, Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
Nobuyuki Ishibashi, Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA; Department of Pediatrics, Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA. Electronic address: nishibas@childrensnational.org.
Vittorio Gallo, Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA; Department of Pediatrics, Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA; Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA 98105, USA. Electronic address: vittorio.gallo@seattlechildrens.org.

Document Type

Journal Article

Publication Date

2-20-2025

Journal

Cell reports. Medicine

DOI

10.1016/j.xcrm.2025.101986

Keywords

ATF5; MCL1; diffusion tensor imaging; gait behavior; neural stem cells; oligodendrocyte precursor cells; outer radial glia; outer subventricular zone; piglet brain; white matter regeneration

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.

Department

Pharmacology and Physiology

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