Hepatocyte growth factor pretreatment boosts functional recovery after spinal cord injury through human iPSC-derived neural stem/progenitor cell transplantation
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Published:2023-10-16
Issue:1
Volume:43
Page:
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ISSN:1880-8190
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Container-title:Inflammation and Regeneration
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language:en
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Short-container-title:Inflamm Regener
Author:
Suematsu Yu, Nagoshi Narihito, Shinozaki Munehisa, Kase Yoshitaka, Saijo Yusuke, Hashimoto Shogo, Shibata Takahiro, Kajikawa Keita, Kamata Yasuhiro, Ozaki Masahiro, Yasutake Kaori, Shindo Tomoko, Shibata Shinsuke, Matsumoto Morio, Nakamura Masaya, Okano HideyukiORCID
Abstract
AbstractBackgroundHuman induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC)-based cell transplantation has emerged as a groundbreaking method for replacing damaged neural cells and stimulating functional recovery, but its efficacy is strongly influenced by the state of the injured spinal microenvironment. This study evaluates the impact of a dual therapeutic intervention utilizing hepatocyte growth factor (HGF) and hiPSC-NS/PC transplantation on motor function restoration following spinal cord injury (SCI).MethodsSevere contusive SCI was induced in immunocompromised rats, followed by continuous administration of recombinant human HGF protein into the subarachnoid space immediately after SCI for two weeks. Acute-phase histological and RNA sequencing analyses were conducted. Nine days after the injury, hiPSC-NS/PCs were transplanted into the lesion epicenter of the injured spinal cord, and the functional and histological outcomes were determined.ResultsThe acute-phase HGF-treated group exhibited vascularization, diverse anti-inflammatory effects, and activation of endogenous neural stem cells after SCI, which collectively contributed to tissue preservation. Following cell transplantation into a favorable environment, the transplanted NS/PCs survived well, facilitating remyelination and neuronal regeneration in host tissues. These comprehensive effects led to substantial enhancements in motor function in the dual-therapy group compared to the single-treatment groups.ConclusionsWe demonstrate that the combined therapeutic approach of HGF preconditioning and hiPSC-NS/PC transplantation enhances locomotor functional recovery post-SCI, highlighting a highly promising therapeutic strategy for acute to subacute SCI.
Funder
Japan Agency for Medical Research and Development Japan Society for the Promotion of Science Orthopedic Research and Education Foundation
Publisher
Springer Science and Business Media LLC
Subject
Immunology,Immunology and Allergy
Reference52 articles.
1. Nori S, Okada Y, Yasuda A, Tsuji O, Takahashi Y, Kobayashi Y, et al. Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice. Proc Natl Acad Sci U S A. 2011;108(40):16825–30. 2. Kamata Y, Isoda M, Sanosaka T, Shibata R, Ito S, Okubo T, et al. A robust culture system to generate neural progenitors with gliogenic competence from clinically relevant induced pluripotent stem cells for treatment of spinal cord injury. Stem Cells Transl Med. 2021;10(3):398–413. 3. Kobayashi Y, Okada Y, Itakura G, Iwai H, Nishimura S, Yasuda A, et al. Pre-evaluated safe human iPSC-derived neural stem cells promote functional recovery after spinal cord injury in common marmoset without tumorigenicity. PLoS ONE. 2012;7(12): e52787. 4. Sugai K, Sumida M, Shofuda T, Yamaguchi R, Tamura T, Kohzuki T, et al. First-in-human clinical trial of transplantation of iPSC-derived NS/PCs in subacute complete spinal cord injury: study protocol. Regen Ther. 2021;18:321–33. 5. Lu P, Woodruff G, Wang Y, Graham L, Hunt M, Wu D, et al. Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron. 2014;83(4):789–96.
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