Glia-Like Cells From Late-Passage Human MSCs Protect Against Ischemic Stroke Through IGFBP-4

Abstract

Summary: Early-passage human mesenchymal stem cells (hMSCs) are typically used in clinical trials because of safety and efficacy issues. However, obtaining sufficient cells for treatment is difficult and expensive. Many more late-passage hMSCs can be obtained at lower cost, although efficacy is a large hurdle in clinical trials. The use of late-passage MSCs with better efficacy would be a revolutionary solution for reducing cost and facilitating clinical trials. In the present study, glia-like cells (ghMSCs) were induced from hMSCs and used for both in vitro and in vivo models of ischemia, effectively protecting neurons from ischemia and restoring brain tissue damaged by cerebral infarction. These beneficial effects were significantly blocked by insulin-like growth factor-binding protein-4 (IGFBP-4) antibody. The current study demonstrated that late-passage hMSCs can be efficiently induced into ghMSCs with a better neuroprotective effect against ischemic stroke and that IGFBP-4 may be a key neuronal survival factor secreted by ghMSCs. Funding Statement: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI17C2160). Declaration of Interests: One of the corresponding authors, Mi-Sook Chang, has a patent related to this work, which is noted in the Declaration of Interests section of the manuscript. She obtained a Korean patent for glia-like human mesenchymal stem cells in 2012. Ethics Approval Statements: All procedures involving animals were approved by the Institutional Animal Care and Use Committee, Seoul National University (Seoul, Republic of Korea). In addition, all animal procedures were performed in accordance with the Hanyang University guidelines for the care and use of laboratory animals and were approved by the Institutional Animal Care and Use Committee (IACUC) of Hanyang University. In accordance with Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines, all experiments were carried out in a strictly blinded fashion, inclusion and exclusion criteria were predetermined, and attrition due to mortality and other causes was reported