Human iPSC ‐derived endothelial cells promote CNS remyelination via BDNF and mTORC1 pathway

Abstract

Damage of myelin is a component of many diseases in the central nervous system (CNS). The activation and maturation of the quiescent oligodendrocyte progenitor cells (OPCs) are the crucial cellular processes for CNS remyelination, which is influenced by neuroinflammation in the lesion microenvironment. Endothelial cells derived from human induced pluripotent stem cells (hiPSC‐ECs) have shown promise in restoring function in various preclinical animal models. Here we ask whether and whether transplantation of hiPSC‐ECs could benefit remyelination in a mouse model of CNS demyelination. Our results show that in vitro, hiPSC‐ECs increase OPC proliferation, migration and differentiation via secreted soluble factors including brain‐derived neurotrophic factor (BDNF). hiPSC‐ECs also promote the survival of oligodendrocyte lineage cells in vitro and in vivo. Transplantation of hiPSC‐ECs into a toxin‐induced demyelination lesion in mouse corpus callosum (CC) leads to increased density of oligodendrocyte lineage cells and level of myelin in demyelinated area, correlated with a decreased neuroinflammation and an increased proportion of pro‐regenerative M2 phenotype in microglia/macrophages. The hiPSC‐EC‐exposed oligodendrocyte lineage cells showed significant increase in the level of phosphorylated S6 ribosomal protein (pS6) both in vitro and in vivo, indicating an involvement of mTORC1 pathway. These results suggest that hiPSC‐ECs may benefit myelin protection and regeneration which providing a potential source of cell therapy for a wide range of diseases and injuries associated with myelin damage.

Publication DOI: https://doi.org/10.1002/glia.24466
Divisions: College of Health & Life Sciences > Aston Medical School
College of Health & Life Sciences > Aston Medical School > Translational Medicine Research Group (TMRG)
Additional Information: Copyright © 2023 The Authors. GLIA published by Wiley Periodicals LLC. This is an open access article under the terms of the Creative Commons Attribution License [https://creativecommons.org/licenses/by/4.0/], which permits use, distribution and reproduction in any medium,provided the original work is properly cited. Funding Information: This work was supported by Aston University to Dan Ma and Royal Society‐Newton Advanced Fellowship to Zhiguo Chen and Chao Zhao (NA150482). The authors thank Dr. Daniel Morrison from University of Cambridge and Dr. David Nagel from Aston University for scientific and technical support. The authors also thank Chris Brown from University of Cambridge, Matthew Crossley and Wayne Fleary from Aston University for research facility work.
Uncontrolled Keywords: oligodendrocyte,iPSC,endothelial cell,BDNF,mTORC1,neuroinflammation,remyelination
Publication ISSN: 0894-1491
Last Modified: 14 Jun 2024 07:31
Date Deposited: 08 Sep 2023 16:56
Full Text Link:
Related URLs: https://onlinel ... 1002/glia.24466 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2024-01
Published Online Date: 2023-09-07
Accepted Date: 2023-08-08
Submitted Date: 2022-09-01
Authors: Ma, Dan (ORCID Profile 0000-0001-8628-8954)
Zhang, Huiyuan
Yin, Le
Xu, Hao
Wu, Lida
Shaji, Rahul
Rezai, Fatema
Mulla, Ayesha
Kaur, Sukhteerath
Tan, Shengjiang
Kysela, Boris (ORCID Profile 0000-0002-1096-6816)
Wang, Yilong
Chen, Zhiguo
Zhao, Chao
Gu, Yuchun

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