Mesenchymal stem cell derived EVs mediate neuroprotection after spinal cord injury in rats via the microRNA-21-5p/FasL gene axis

Abstract Cell-based therapies are considered as promising strategies for spinal cord regeneration. However, a combinatorial cell therapeutic approach seems more beneficial as it can target various aspects of the injury. Here, we assessed the safety and feasibility of autologous mucosal Olfactory Ensheathing Cell (OEC) and bone marrow Mesenchymal Stem Cell (MSC) co-transplantation in patients with chronic, complete (American Spinal Injury Association (ASIA) classification A) Spinal Cord Injury (SCI). Three patients with the traumatic SCI of the thoracic level were enrolled. They received autologous OEC and MSC combination through the lumbar puncture. All adverse events and possible functional outcomes were documented performing pre- and post-operative general clinical examination, Magnetic Resonance Imaging (MRI), neurological assessment based on the International Standard of Neurological Classification for SCI (ISNCSCI), and functional evaluation using Spinal Cord Independence Measure version III (SCIM III). No serious safety issue was recorded during the two years of follow-up. MRI findings remained unchanged with no neoplastic tissue formation. ASIA impairment scale improved from A to B in one of the participants. SCIM III evaluation also showed some degrees of progress in this patient's quality of life. The two other patients had negligible or no improvement in their sensory scores without any changes in the ASIA impairment scale and SCIM III scores. No motor recovery was observed in any of the participants. Overall, this two-year trial was not associated with any adverse findings, which may suggest the safety of autologous OEC and bone marrow MSC combination for the treatment of human SCI.This study was registered at the Iranian Registry of Clinical Trials (IRCT registration number: IRCT20160110025930N2/ registration date: 2018-09-29).

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Adipose-Derived Mesenchymal Stem Cell Application Combined With Fibrin Matrix Promotes Structural and Functional Recovery Following Spinal Cord Injury in Rats

Frontiers in Pharmacology ◽

10.3389/fphar.2018.00343 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 21

Author(s):

Yana O. Mukhamedshina ◽

Elvira R. Akhmetzyanova ◽

Alexander A. Kostennikov ◽

Elena Y. Zakirova ◽

Luisa R. Galieva ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Functional Recovery ◽

Fibrin Matrix ◽

Cord Injury

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Adipose mesenchymal stem cell transplantation alleviates spinal cord injury-induced neuroinflammation partly by suppressing the Jagged1/Notch pathway

10.21203/rs.2.17540/v1 ◽

2019 ◽

Author(s):

Zhou Zhilai ◽

Tian Xiaobo ◽

Mo Biling ◽

Xu Huali ◽

Yao Shun ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Notch Signaling ◽

Signaling Pathway ◽

Notch Signaling Pathway ◽

Therapeutic Effects ◽

Mesenchymal Stem Cell Transplantation ◽

Cord Injury

Abstract Background The therapeutic effects of adipose-derived mesenchymal stem cell (ADSC) transplantation have been demonstrated in several models of central nervous system (CNS) injury and are thought to involve the modulation of the inflammatory response. However, the exact underlying molecular mechanism is poorly understood. Activation of the Jagged1/Notch signaling pathway is thought to involve inflammatory and gliotic events in the CNS. Here, we elucidated the effect of ADSC transplantation on the inflammatory reaction after spinal cord injury (SCI) and the potential mechanism mediated by Jagged1/Notch signaling pathway suppression.Methods Using a mouse model of compression SCI, ADSCs and Jagged1 small interfering RNA (siRNA) were injected into the spinal cord. Locomotor function, spinal cord tissue morphology and the levels of various proteins and transcripts were compared between groups.Results ADSC treatment resulted in significant downregulation of proinflammatory mediator expression and reduced ionized calcium binding adapter molecule 1 (Iba1) and ED1 staining in the injured spinal cord, promoting the survival of neurons. These changes were accompanied by improved functional recovery. The augmentation of the Jagged1/Notch signaling pathway after SCI was suppressed by ADSC transplantation. The inhibition of the Jagged1/Notch signaling pathway by Jagged1 siRNA resulted in a decrease in SCI-induced proinflammatory cytokines as well as the activation of microglia. Furthermore, Jagged1 knockdown suppressed the phosphorylation of JAK/STAT3 following SCI.Conclusion The results of this study demonstrated that the therapeutic effects of ADSCs in SCI mice were partly due to Jagged1/notch signaling pathway inhibition and a subsequent reduction in JAK/STAT3 phosphorylation.

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Mesenchymal Stem Cell Therapy for Apoptosis After Spinal Cord Injury

Advanced Understanding of Neurodegenerative Diseases ◽

10.5772/29332 ◽

2011 ◽

Cited By ~ 1

Author(s):

Venkata Ramesh ◽

Krishna Kumar ◽

Jasti S. ◽

Dan Fassett ◽

Dzung H.

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Cell Therapy ◽

Stem Cell Therapy ◽

Mesenchymal Stem Cell Therapy ◽

Cord Injury

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Mesenchymal stem cell therapy improves erectile dysfunction in experimental spinal cord injury

International Journal of Impotence Research ◽

10.1038/s41443-019-0168-1 ◽

2019 ◽

Vol 32 (3) ◽

pp. 308-316 ◽

Cited By ~ 5

Author(s):

Ömercan Albayrak ◽

Tarık Emre Şener ◽

Mehmet Erşahin ◽

Suna Özbaş-Turan ◽

Ceyda Ekentok ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Stem Cell ◽

Erectile Dysfunction ◽

Mesenchymal Stem Cell ◽

Cell Therapy ◽

Stem Cell Therapy ◽

Mesenchymal Stem Cell Therapy ◽

Experimental Spinal Cord Injury ◽

Cord Injury

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Targeted Delivery of Mesenchymal Stem Cell-Derived Nanovesicles for Spinal Cord Injury Treatment

International Journal of Molecular Sciences ◽

10.3390/ijms21114185 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4185

Author(s):

Ju-Ro Lee ◽

Jae Won Kyung ◽

Hemant Kumar ◽

Sung Pil Kwon ◽

Seuk Young Song ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Clinical Application ◽

Targeted Delivery ◽

Therapeutic Potential ◽

Systemic Injection ◽

Cord Injury ◽

Macrophage Membrane

Due to the safety issues and poor engraftment of mesenchymal stem cell (MSC) implantation, MSC-derived exosomes have been spotlighted as an alternative therapy for spinal cord injury (SCI). However, insufficient productivity of exosomes limits their therapeutic potential for clinical application. Moreover, low targeting ability of unmodified exosomes is a critical obstacle for their further applications as a therapeutic agent. In the present study, we fabricated macrophage membrane-fused exosome-mimetic nanovesicles (MF-NVs) from macrophage membrane-fused umbilical cord blood-derived MSCs (MF-MSCs) and confirmed their therapeutic potential in a clinically relevant mouse SCI model (controlled mechanical compression injury model). MF-NVs contained larger quantity of ischemic region-targeting molecules compared to normal MSC-derived nanovesicles (N-NVs). The targeting molecules in MF-NVs, which were derived from macrophage membranes, increased the accumulation of MF-NVs in the injured spinal cord after the in vivo systemic injection. Increased accumulation of MF-NVs attenuated apoptosis and inflammation, prevented axonal loss, enhanced blood vessel formation, decreased fibrosis, and consequently, improved spinal cord function. Synthetically, we developed targeting efficiency-potentiated exosome-mimetic nanovesicles and present their possibility of clinical application for SCI.

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