020 - Outer radial glia promotes white matter regeneration after neonatal brain injury

Publication Number: 20.5599

Hideo Jinnou, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan; Nobuyuki Ishibashi, Children's National Hospital, Washington, DC, United States; Vittorio Gallo, Seattle Children's Hospital, Seattle, WA, United States

Background: The incidence of neonatal brain injury has not decreased, and the white matter is susceptible to ischemic insult as impaired myelination is the hallmark of neonatal white matter injury.. There are no available therapies to repair injured brain tissues, but neural stem cells (NSCs) are abundant in the mouse subventricular zone (SVZ) and generate oligodendrocyte precursor cells (OPCs). After brain injury, SVZ–derived OPCs migrate toward the injured area and mature into oligodendrocytes, raising the possibility that the SVZ could be a source of cells to promote endogenous myelination and neural regeneration. However, it is unknown whether this regenerative capacity is conserved in the brain of large mammals and in the neonatal human brain.

Objective: 1) To investigate the regenerative capacity of the brain SVZ in the human neonate and in piglet, 2) To define mechanisms regulating OPC generation from NSCs and white matter regeneration.

Design/Methods: We analyzed fixed human neonatal brain tissue. Furthermore, in view of the structural and physiological similarities between the human and piglet brain, we established a piglet ischemic brain injury model and used a multidisciplinary approach to analyze white matter regeneration after injury, including immunohistochemistry, RNA-seq, MR imaging, and behavioral testing.

Results: After human ischemic brain injury, the SVZ was expanded in infants but not in adults. In human infants, cell proliferation and OPC production were enhanced mainly in the outer region of the SVZ (OSVZ). We found that outer radial glia (oRG; NSCs in the OSVZ) increased their proliferative capacity after bran injury. Similar to the human infant brain, our piglet brain ischemic injury model also displayed increased oRG proliferation and SVZ expansion. Furthermore, in piglet, OPCs migrated from the OSVZ towards the injured periventricular white matter and differentiated into mature oligodendrocytes. RNA–seq analysis in oRG showed that neonatal brain injury upregulated ATF5 signaling, which induced oRG proliferation. Finally, intranasal ATF5 activation after piglet brain injury promoted OSVZ-derived oligodendrogenesis and myelination, and improved gait function.

Conclusion(s): Our findings demonstrate the endogenous potential of white matter regeneration in the human neonate, with a major functional role played by the oRG in the OSVZ. We also identify ATF5 as a regulator of white mater regeneration and a potential therapeutic target to attenuate the impact of neonatal brain injury.