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ORIGINAL RESEARCH article
Front. Cell. Neurosci.
Sec. Cellular Neuropathology
Volume 19 - 2025 | doi: 10.3389/fncel.2025.1550139
This article is part of the Research Topic Oligodendroglia Biology and Pathology: Myelination and Beyond View all 3 articles
Intrinsic retinoic acid synthesis is required for oligodendrocyte progenitor expansion during CNS remyelination
Provisionally accepted
Sonia E Nanescu 1 Natacha M Wathieu 1 Lauren Rosko 1
David Soobum Cha 1 Mahesh N Kumar 1
Rafal Olszewski 1
Joan Reger 1
Maryna Baydyuk 1
Alisa N Dua 1
Wojciech Krezel 2
Violetta Zujovic 3
Jeffrey K Huang 1*- 1 Biology, Georgetown University, Washington, DC, United States
- 2 INSERM U964 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, Alsace, France
- 3 INSERM U1127 Institut du Cerveau et de la Moelle épinière (ICM), Paris, Île-de-France, France
Myelin regeneration (remyelination) in the CNS depends on the recruitment, proliferation and differentiation of oligodendrocyte precursor cells (OPCs) at demyelinated lesions. However, despite the presence of OPCs, very few oligodendrocytes and myelin are regenerated in chronic multiple sclerosis (MS) lesions for reasons that remain poorly understood. Here, using a spontaneous remyelination model in mice, we found that retinaldehyde dehydrogenase 2 (Raldh2), a rate-limiting enzyme for retinoic acid (RA) synthesis, is upregulated in OPCs and in a subpopulation of microglia/macrophages during remyelination. Tamoxifen induced deletion of Raldh2 globally, or conditionally in OPCs, resulted in significantly fewer proliferating OPCs in lesions, leading to decreased oligodendrocyte numbers and myelin density. Moreover, induced deletion of Raldh2 globally also resulted in increased microglia/macrophage density in lesions. Further, exogenous RA delivery into lesions significantly increased oligodendrocyte lineage cells, while also decreasing proinflammatory microglia/macrophages, with no significant effect on anti-inflammatory microglia/macrophages. Postmortem MS brain sections revealed Raldh2 was absent in the majority of OPCs in chronic inactive lesions compared to the other lesion types. These results suggest that Raldh2 upregulation in lesions is critical for OPC proliferation during remyelination, and reveal that the failure to regenerate sufficient oligodendrocytes and myelin in chronic MS lesions may arise from impaired OPC expansion due to the failure to intrinsically synthesize RA.
Keywords: remyelination, Oligodendrocyte progenitor cell (OPCs), Microglia, Multiple Sclerosis, Retinoic acid, Raldh2 (Aldh1a2)
Received: 22 Dec 2024; Accepted: 06 Feb 2025.
Copyright: © 2025 Nanescu, Wathieu, Rosko, Cha, Kumar, Olszewski, Reger, Baydyuk, Dua, Krezel, Zujovic and Huang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Jeffrey K Huang, Biology, Georgetown University, Washington, 20057, DC, United States
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