Safety and potential effects of intrathecal injection of allogeneic human umbilical cord mesenchymal stem cell-derived exosomes in complete subacute spinal cord injury: a first-in-human, single-arm, open-label, phase I clinical trial

Stem Cell Research & Therapy, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 26, 2024

Neurological and functional impairments are commonly observed in individuals with spinal cord injury (SCI) due to insufficient regeneration of damaged axons. Exosomes play a crucial role the paracrine effects mesenchymal stem cells (MSCs) have emerged as promising therapeutic approach for SCI. Thus, this study aimed evaluate safety potential intrathecal administration allogeneic exosomes derived from human umbilical MSCs (HUC-MSCs) patients complete subacute This was single-arm, open-label, phase I clinical trial 12-month follow-up period. HUC-MSCs were extracted tissue, isolated via ultracentrifugation. After injection, each participant underwent evaluation, including neurological assessment using American Spinal Injury Association (ASIA) scale, Cord Independence Measure (SCIM-III), neurogenic bowel dysfunction (NBD) NBD score, modified Ashworth scale (MAS), lower urinary tract function questionnaire. Nine SCI recruited. The injection HUC-MSCs-exosomes safe well tolerated. No early or late adverse event (AE) attributable intervention observed. Significant improvements ASIA pinprick (P-value = 0.039) light touch 0.038) scores, SCIM III total score 0.027), 0.042) also at after compared baseline. demonstrated that is Moreover, it seems therapy might be associated these patients. In regard, future larger II/III trials adequate power highly required. Iranian Registry Clinical Trials, IRCT20200502047277N1. Registered 2 October 2020, https://en.irct.ir/trial/48765 .

Language: Английский

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Exosome-mediated repair of spinal cord injury: a promising therapeutic strategy

Stem Cell Research & Therapy, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 2, 2024

Abstract Spinal cord injury (SCI) is a catastrophic to the central nervous system (CNS) that can lead sensory and motor dysfunction, which seriously affects patients' quality of life imposes major economic burden on society. The pathological process SCI divided into primary secondary injury, cascade amplified responses triggered by injury. Due complexity mechanisms SCI, there no clear effective treatment strategy in clinical practice. Exosomes, are extracellular vesicles endoplasmic origin with diameter 30–150 nm, play critical role intercellular communication have become an ideal vehicle for drug delivery. A growing body evidence suggests exosomes great potential repairing SCI. In this review, we introduce exosome preparation, functions, administration routes. addition, summarize effect mechanism various repair review efficacy combination other strategies Finally, challenges prospects use described.

Language: Английский

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Plant‐derived exosomes extracted from Lycium barbarum L. loaded with isoliquiritigenin to promote spinal cord injury repair based on 3D printed bionic scaffold

Bioengineering & Translational Medicine, Journal Year: 2024, Volume and Issue: 9(4)

Published: Jan. 30, 2024

Abstract Plant‐derived exosomes (PEs) possess an array of therapeutic properties, including antitumor, antiviral, and anti‐inflammatory capabilities. They are also implicated in defensive responses to pathogenic attacks. Spinal cord injuries (SCIs) regeneration represents a global medical challenge, with appropriate research concentration on three pivotal domains: neural promotion, inflammation inhibition, innovation application regenerative scaffolds. Unfortunately, the utilization PE SCI therapy remains unexplored. Herein, we isolated from traditional Chinese medicinal herb, Lycium barbarum L. discovered their inflammatory inhibition neuronal differentiation promotion Compared derived ectomesenchymal stem cells (EMSCs), demonstrated substantial enhancement differentiation. We encapsulated isoliquiritigenin (ISL)‐loaded plant‐derived (ISL@PE) within 3D‐printed bionic scaffold. The intricate construct modulated response following SCI, facilitating restoration damaged axons culminating ameliorated neurological function. This pioneering investigation proposes novel potential route for insoluble drug delivery via plant exosomes, as well repair. institutional animal care use committee number is UJS‐IACUC‐2020121602.

Language: Английский

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Stem Cell-Derived Extracellular Vesicle-Mediated Therapeutic Signaling in Spinal Cord Injury

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 723 - 723

Published: Jan. 16, 2025

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising therapeutic strategy for spinal cord injury (SCI). These nanosized possess unique properties such low immunogenicity and the ability to cross biological barriers, making them ideal carriers delivering bioactive molecules injured tissues. MSC-EVs been demonstrated exert multiple beneficial effects in SCI, including reducing inflammation, promoting neuroprotection, enhancing axonal regeneration. Recent studies delved into molecular mechanisms underlying MSC-EV-mediated effects. Exosomal microRNAs (miRNAs) identified key regulators of various cellular processes involved SCI pathogenesis repair. miRNAs can influence oxidative stress, apoptosis by modulating gene expression. This review summarized current state MSC-EV-based therapies highlighting potential clinical applications. We discussed challenges limitations translating these practice, inconsistent EV production, complex cargo composition, need targeted delivery strategies. Future research should focus on optimizing production characterization, identifying miRNAs, developing innovative systems maximize SCI.

Language: Английский

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Cerebrospinal fluid-derived extracellular vesicles after spinal cord injury promote vascular regeneration via PI3K/AKT signaling pathway

Journal of Orthopaedic Translation, Journal Year: 2023, Volume and Issue: 39, P. 124 - 134

Published: March 1, 2023

The cerebrospinal fluid (CSF), which surrounds the brain and spinal cord, is predominantly produced by choroid plexus of ventricle. Although CSF-derived extracellular vesicles (CSF-EVs) may be utilized as diagnostic prognostic indicators for illnesses central nervous system (CNS), it uncertain if CSF-EVs have an impact on neurological function after cord injury (SCI). Here, we isolated EVs using ultracentrifugation extracting CSF from Bama miniature pigs. We then combined with hydrogel put cord's surface. To determine had mice's neurofunctional recovery, behavioral evaluations were employed. Both in vitro vivo, effect angiogenesis was assessed. investigated whether stimulated PI3K/AKT pathway to alter PI3K inhibitor LY294002. successfully identified transmission electron microscope (TEM), nano-tracking analysis (NTA), western blot. could ingested vascular endothelial cells proved vivo imaging immunofluorescence. demonstrated that derived pigs SCI (SCI-EVs) showed a better promoting regeneration compared receiving laminectomy (Sham-EVs). Behavioral assessments SCI-EVs dramatically enhance motor sensory mice SCI. Western blot suggested promote activating signaling pathway, pro-angiogenetic attenuated application LY294002 (PI3K inhibitor). Our study revealed hence improving recovery SCI, offer potential novel therapeutic options acute This promotion exosomes, provide approach treatment injury.

Language: Английский

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Exosomes combined with biomaterials in the treatment of spinal cord injury

Frontiers in Bioengineering and Biotechnology, Journal Year: 2023, Volume and Issue: 11

Published: March 13, 2023

Spinal cord injury (SCI) is a serious and disabling disease with high mortality rate. It often leads to complete or partial sensory motor dysfunction accompanied by series of secondary outcomes, such as pressure sores, pulmonary infections, deep vein thrombosis in the lower extremities, urinary tract autonomic dysfunction. Currently, main treatments for SCI include surgical decompression, drug therapy, postoperative rehabilitation. Studies have shown that cell therapy plays beneficial role treatment SCI. Nonetheless, there controversy regarding therapeutic effect transplantation models. Meanwhile exosomes, new medium regenerative medicine, possess advantages small size, low immunogenicity, ability cross blood-spinal barrier. Certain studies stem cell-derived exosomes anti-inflammatory effects can play an irreplaceable In this case, it difficult single method effective repair neural tissue after The combination biomaterial scaffolds better transfer fix site improve their survival This paper first reviews current research status respectively, then describes application combined SCI, well challenges prospects.

Language: Английский

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Molecular Mechanisms and Clinical Application of Multipotent Stem Cells for Spinal Cord Injury

Cells, Journal Year: 2022, Volume and Issue: 12(1), P. 120 - 120

Published: Dec. 28, 2022

Spinal Cord Injury (SCI) is a common neurological disorder with devastating psychical and psychosocial sequelae. The majority of patients after SCI suffer from permanent disability caused by motor dysfunction, impaired sensation, neuropathic pain, spasticity as well urinary complications, small number experience complete recovery. Current standard treatment modalities the aim to prevent secondary injury provide limited recovery lost functions. Stem Cell Therapy (SCT) represents an emerging approach using differentiation, paracrine, self-renewal capabilities stem cells regenerate injured spinal cord. To date, multipotent including mesenchymal (MSCs), neural (NSCs), hematopoietic (HSCs) represent most investigated types for in preclinical clinical studies. microenvironment has significant impact on survival, proliferation, differentiation transplanted cells. Therefore, deep understanding pathophysiology molecular mechanisms through which act may help improve efficacy SCT find new therapeutic approaches such stem-cell-derived exosomes, gene-modified cells, scaffolds, nanomaterials. In this literature review, pathogenesis action MSCs, NSCs, HSCs are comprehensively described. Moreover, treatment, optimal protocol cell administration, recent based or combined also discussed.

Language: Английский

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Proteomic characterization of hUC-MSC extracellular vesicles and evaluation of its therapeutic potential to treat Alzheimer’s disease

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: March 12, 2024

Abstract In recent years, human umbilical cord mesenchymal stem cell (hUC-MSC) extracellular vesicles (EVs) have been used as a replacement therapy and shown to effectively overcome some of the disadvantages therapy. However, specific mechanism action EVs is still unclear, there no appropriate system for characterizing differences in molecular active substances produced by cells different physiological states. We data-independent acquisition (DIA) quantitative proteomics method identify quantify protein composition two generations from three donors analysed function possible proteins hUC-MSCs via bioinformatics. By comparative proteomic analysis, we characterized passages EVs. Furthermore, found that adaptor-related complex 2 subunit alpha 1 (AP2A1) beta (AP2B1) hUC-MSC-derived may play significant role treatment Alzheimer's disease (AD) regulating synaptic vesicle cycle signalling pathway. Our work provides direction batch-to-batch quality control their application AD treatment.

Language: Английский

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A tannic acid doped hydrogel with small extracellular vesicles derived from mesenchymal stem cells promotes spinal cord repair by regulating reactive oxygen species microenvironment

Materials Today Bio, Journal Year: 2022, Volume and Issue: 16, P. 100425 - 100425

Published: Sept. 16, 2022

Spinal cord injury (SCI) is a serious disease of the central nervous system that associated with poor prognosis; furthermore, existing clinical treatments cannot restore nerve function in an effective manner. Inflammatory responses and increased production reactive oxygen species (ROS) microenvironment lesion are major obstacles inhibit recovery SCI. Small extracellular vesicles (sEVs), derived from mesenchymal stem cells, suitable options for cell-free therapy have been shown to exert therapeutic effects SCI, thus providing potential strategy regulation. However, retention, controlled release, integration small into injured spinal tissue still challenge. Herein, we fabricated N-acryloyl glycinamide/gelatin methacrylate/Laponite/Tannic acid (NAGA/GelMA/LPN/TA, NGL/T) hydrogel sustainable sEV release (sEVs-NGL/T) promote motor after The newly developed functional sEVs-NGL/T exhibited excellent antioxidant properties H2O2-simulated peroxidative vitro. Implantation vivo could encapsulate sEVs, exhibiting efficient retention sustained thereby synergistically inducing significant restoration urinary preservation. These positive can be attributed mitigation inflammatory ROS microenvironment. Therefore, provides promising sEV-based treatment SCI by comprehensively regulating pathological

Language: Английский

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Current treatments after spinal cord injury: Cell engineering, tissue engineering, and combined therapies

Smart Medicine, Journal Year: 2022, Volume and Issue: 1(1)

Published: Dec. 1, 2022

Both traumatic and non-traumatic spinal cord injuries (SCIs) can be categorized as damages done to our central nervous system (CNS). The patients' physical mental health may suffer greatly because of SCI. With the widespread use motor vehicles increasingly aged population, occurrence SCI is more frequent than before, creating a considerable burden global public health. regeneration process hampered by series events that occur following like edema, hemorrhage, formation cystic cavities, ischemia. An effective strategy for treatment functional recovery still has not been discovered; however, recent advances have made in bioengineering fields therapies based on cells, biomaterials, biomolecules proved repair cord. In light worldwide importance treatments SCI, this article aims provide review first introducing physiology, etiology, epidemiology, mechanisms We then put emphasis widely used clinical strategies (cell-based, biomaterial-based, biomolecule-based) well challenges faced scientists currently. This provides clinicians with comprehensive outlook preclinical hoping help them find keys

Language: Английский

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