Myelin endocytosis by brain endothelial cells causes endothelial iron overload and oligodendroglial iron hunger in hypoperfusion‐induced white matter injury

Author:

Liu Yuxin1,Kang Xinmei1,Lin Jiahao1,Liu Yixin1,Liu Sanxin1,Li Chunyi1,Deng Xiaohui1,Huang Huipeng1,Li Tiemei1,Wang Shisi1,Lu Danli1,Jiang Yuxuan1,Lu Zhengqi1ORCID,Cai Wei12,Lu Tingting1

Affiliation:

1. Department of Neurology, Mental and Neurological Disease Research Center The Third Affiliated Hospital of Sun Yat‐sen University Guangzhou China

2. Guangdong Provincial Key Laboratory of Brain Function and Disease Guangzhou China

Abstract

AbstractAimsHypoperfusion induces significant white matter injury in cerebral vascular disorders, including arteriosclerotic cerebral small vessel disease (aCSVD), which is prevalent among the elderly. Iron transport by blood vessel endothelial cells (BVECs) from the periphery supports oligodendrocyte maturation and white matter repair. This study aims to elucidate the association between iron homeostasis changes and white matter injury severity, and explore the crosstalk between BVECs and oligodendroglial lineage cells.MethodsIn vivo: C57BL/6 mice were subjected to unilateral common carotid artery occlusion (UCCAO). In vitro: BVECs with myelin pretreatment were co‐cultured with oligodendrocyte progenitor cells (OPCs) or organotypic cerebellar slices subjected to oxygen and glucose deprivation.ResultsCirculatory iron tends to be stored in aCSVD patients with white matter injury. Myelin debris endocytosis by BVECs impairs iron transport, trapping iron in the blood and away from the brain, worsening oligodendrocyte iron deficiency in hypoperfusion‐induced white matter injury. Iron accumulation in BVECs triggers ferroptosis, suppressing iron transport and hindering white matter regeneration. Intranasal holo‐transferrin (hTF) administration bypassing the BBB alleviates oligodendrocyte iron deficiency and promotes myelin regeneration in hypoperfusion‐induced white matter injury.ConclusionThe iron imbalance between BVECs and oligodendroglial lineage cells is a potential therapeutic target in hypoperfusion‐induced white matter injury.

Funder

National Natural Science Foundation of China

Guangzhou Municipal Science and Technology Program key projects

Guangzhou Municipal Science and Technology Project

Science and Technology Planning Project of Guangdong Province

Publisher

Wiley

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