Intravenous administration of mesenchymal stem cell-derived exosome alleviates spinal cord injury by regulating NETs formation through exosomal miR-125a-3p

Friday, May 3, 2024

3:15 PM – 3:19 PM CT

Location: S401ab

Presenting Author(s)

Yutaka Morishima (he/him/his)

Under Graduate Student
Department of Neurosurgery, Graduate School of Medicine, Hokkaido University

Co-Author(s)

MF

Miki Fujimura, n/a

Professor
Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, United States
YF

Yoichiro Fujioka, n/a

Associate Professor
Department of Cell Physiology, Faculty of Medicine, Hokkaido University, United States
DH

Daigo Hashimoto, n/a

Associate Professor
Department of Hematology, Faculty of Medicine, Graduate School of Medicine, United States
MK

Masahito Kawabori, n/a

Lecturer
Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, Japan
YK

Yuji Kuge, n/a

Professor
Central Institute of Isotope Science, Hokkaido University, United States
SM

Sakiko Masuda, n/a

Lecturer
Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, United States
YM

Yuki Mizuno, n/a

Associate Professor
Central Institute of Isotope Science, Hokkaido University, United States
YN

Yo Nakahara, n/a

Research Assistant
Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, United States
YO

Yusuke Ohba, n/a

Professor
Department of Cell Physiology, Faculty of Medicine, Hokkaido University, United States
HS

Hajime Senjo, n/a

Medical Doctor
Department of Hematology, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, United States
ST

Soichiro Takamiya, n/a

Medical Doctor
Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, United States
SY

Sho Yamaguchi, n/a

Principal Investigator
Regenerative Medicine and Cell Therapy Laboratories, Kaneka Corporation, United States
KY

Kazuyoshi Yamazaki, n/a

Medical Doctor
Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, United States

Disclosure(s):

Yutaka Morishima: No financial relationships to disclose

Introduction: Spinal cord injuries (SCIs) present a significant clinical challenge with limited effective treatments. Stem cell therapy holds promise, with intravenous stem cell administration demonstrating therapeutic potential. However, the scarcity of detected stem cells within the injured cord suggests a potential role for stem cell-released exosomes in the healing process. While exosomes from stem cells have shown modulatory effects on microglial reactions and blood-brain barrier integrity, their impact on neutrophil deactivation, particularly concerning neutrophil extracellular traps (NETs), remains less explored.

Methods: Exosomes were isolated from amnion-derived mesenchymal stem cells (MSCs) using ultracentrifugation. A clip injury model induced SCIs in Sprague-Dawley rats, followed by intravenous administration of 100 μg of exosomes or PBS 24 hours post-injury. Motor function was serially assessed for 28 days. Spinal cord specimens were analyzed on Days 3 and 28 for injury extent and NETs formation. Flow cytometry evaluated circulating neutrophil NETs. Neutrophils were electroporated with exogenous miRNA to assess its impact on NETs formation. Biodistribution was assessed with 64Cu-labeled exosomes via positron emission tomography.

Results: Exosome-treated rats exhibited substantial motor function recovery and reduced injury size. Significantly decreased neutrophil infiltration and NETs formation within the spinal cord, along with a reduction in circulating neutrophils forming NETs, were observed. In vitro, exosomes localized near the nuclei of activated neutrophils. miR-125a-3p mimic diminished NETs formation, while miR-125a-3p inhibitor reversed this effect. PET studies indicated enhanced exosome presence in the damaged spinal cord compared to normal rats, despite predominant sequestration in the liver and spleen.

Conclusion : MSC-derived exosomes play a pivotal role in mitigating SCI, partially through deactivating neutrophil NETs formation via miR-125a-3p. These findings highlight the therapeutic potential of exosome-based interventions in SCI treatment.