Engineered exosomes enriched in netrin-1 modRNA promote axonal growth in spinal cord injury by attenuating inflammation and pyroptosis

Biomaterials Research, Journal Year: 2023, Volume and Issue: 27(1)

Published: Jan. 17, 2023

Spinal cord injury (SCI) brings a heavy burden to individuals and society, there is no effective treatment at present. Exosomes (EX) are cell secreted vesicles containing molecules such as nucleic acids proteins, which hold promise for the of SCI. Netrin-1 an axon guidance factor that regulates neuronal growth. We investigated effects engineered EX enriched in netrin-1 chemically synthetic modified message RNA (modRNA) treating SCI attempt find novel therapeutic approach SCI.Netrin-1 modRNA was transfected into bone marrow mesenchymal stem cells obtain with (EX-netrin1). built inflammatory model vitro lipopolysaccharide (LPS) study effect EX-netrin1 on For experiments vitro, ELISA, CCK-8 assay, immunofluorescence staining, lactate dehydrogenase release test, real-time quantitative polymerase chain reaction, western blot were conducted. At same time, we constructed rat MRI, hematoxylin-eosin Nissl staining used assess extent rats.In showed had viability oligodendrocytes PC12 cells. could attenuate LPS-induced inflammation pyroptosis accelerate axonal/dentritic growth cells/oligodendrocytes. In addition, activate PI3K/AKT/mTOR signalling pathway upon binding its receptor unc5b. When Unc5b PI3K inhibited, weakened, be reversed by or mTOR activator. Our vivo indicated promote recovery rats SCI.We found regulated inflammation, via Unc5b/PI3K/AKT/mTOR pathway, provides new strategy

Language: Английский

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Pyroptosis: candidate key targets for mesenchymal stem cell-derived exosomes for the treatment of bone-related diseases

Stem Cell Research & Therapy, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 12, 2025

Bone-related diseases impact a large portion of the global population and, due to their high disability rates and limited treatment options, pose significant medical economic challenges. Mesenchymal stem cells (MSCs) can differentiate into multiple cell types offer strong regenerative potential, making them promising for treating various diseases. However, issues with immune response survival limit effectiveness transplantation. This has led increased interest in cell-free therapy, particularly use exosomes, which is most studied form this approach. Exosomes are extracellular vesicles that contain proteins, lipids, nucleic acids play key role communication material exchange. Pyroptosis, death involved innate immunity, also associated many Studies have shown MSC-derived exosomes therapeutic potential range conditions by regulating inflammation pyroptosis. study explored modulating pyroptosis improve bone-related

Language: Английский

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BMSC-Derived Exosomal CircHIPK3 Promotes Osteogenic Differentiation of MC3T3-E1 Cells via Mitophagy

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2785 - 2785

Published: Feb. 1, 2023

Exosome-based therapy is emerging as a promising strategy to promote bone regeneration due exosomal bioactive cargos, among which circular RNA (circRNA) has recently been recognized the key effector. The role of circRNA derived from marrow mesenchymal stem cells (BMSCs) not well-defined. present study aimed clarify regulatory function and molecular mechanism BMSC-derived in osteogenesis. Exosomes (BMSC-Exos) were isolated identified. BMSC-Exos' pro-osteogenic effect on MC3T3-E1 was validated by alkaline phosphatase (ALP) activity Alizarin Red staining. Through bioinformatic analysis experiments, circHIPK3 selected verified BMSC-Exos osteoblast differentiation cells. Mechanistically, acted an miR-29a-5p sponge functioned mitophagy via targeting PINK1. Additionally, we showed that level mediated BMSC-Exos, promoted osteogenic differentiation. Collectively, our results revealed important for These findings provide potentially effective therapeutic regeneration.

Language: Английский

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NLRP3 Inflammasome’s Activation in Acute and Chronic Brain Diseases—An Update on Pathogenetic Mechanisms and Therapeutic Perspectives with Respect to Other Inflammasomes

Biomedicines, Journal Year: 2023, Volume and Issue: 11(4), P. 999 - 999

Published: March 23, 2023

Increasingly prevalent acute and chronic human brain diseases are scourges for the elderly. Besides lack of therapies, these ailments share a neuroinflammation that is triggered/sustained by different innate immunity-related protein oligomers called inflammasomes. Relevant players such as microglia/monocytes typically exhibit strong NLRP3 inflammasome activation. Hence idea suppression might solve neurodegenerative ailments. Here we review recent Literature about this topic. First, update conditions mechanisms, including RNAs, extracellular vesicles/exosomes, endogenous compounds, ethnic/pharmacological agents/extracts regulating function. Second, pinpoint NLRP3-activating mechanisms known inhibition effects in (ischemia, stroke, hemorrhage), (Alzheimer’s disease, Parkinson’s Huntington’s MS, ALS), virus-induced (Zika, SARS-CoV-2, others) diseases. The available data show (i) disease-specific divergent activate (mainly animal) brains NLRP3; (ii) no evidence proves modifies (yet ad hoc trials ongoing); (iii) findings exclude concurrently activated other-than-NLRP3 inflammasomes functionally replace inhibited NLRP3. Finally, highlight among causes persistent therapies species difference problem disease models preference symptomatic over etiologic therapeutic approaches. Therefore, posit neural cell-based could drive etiological, pathogenetic, advances, NLRP3’s other inflammasomes’ regulation, while minimizing failure risks candidate drug trials.

Language: Английский

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Crosstalk among mitophagy, pyroptosis, ferroptosis, and necroptosis in central nervous system injuries

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 19(8), P. 1660 - 1670

Published: Nov. 8, 2023

Central nervous system injuries have a high rate of resulting in disability and mortality; however, at present, effective treatments are lacking. Programmed cell death, which is genetically determined form active ordered death with many types, has recently attracted increasing attention due to its functions determining the fate survival. A growing number studies suggested that programmed involved central plays an important role progression brain damage. In this review, we provide overview injuries, including pathways mitophagy, pyroptosis, ferroptosis, necroptosis, underlying mechanisms by mitophagy regulates necroptosis. We also discuss new direction therapeutic strategies targeting for treatment aim determine connection between identify therapies modulate following injury. conclusion, based on these properties effects, interventions could be developed as potential agents injury patients.

Language: Английский

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Hypoxic Bone Mesenchymal Stem Cell-Derived Exosomes Direct Schwann Cells Proliferation, Migration, and Paracrine to Accelerate Facial Nerve Regeneration via circRNA_Nkd2/miR-214-3p/MED19 Axis

International Journal of Nanomedicine, Journal Year: 2024, Volume and Issue: Volume 19, P. 1409 - 1429

Published: Feb. 1, 2024

Background: Facial nerves have the potential for regeneration following injury, but this process is often challenging and slow. Schwann cells (SCs) are pivotal in process. Bone mesenchymal stem (BMSC)-derived exosomes promote tissue repair through paracrine action, with hypoxic preconditioning enhancing their effects. The main purpose of study was to determine whether hypoxia-preconditioned BMSC-derived (Hypo-Exos) exhibit a greater therapeutic effect on facial nerve repair/regeneration reveal mechanism. Methods: CCK-8, EdU, Transwell, ELISA assays were used evaluate functions Hypo-Exos SCs. Histological analysis Vibrissae Movements (VMs) recovery effects rat model. circRNA array identify significantly differentially expressed exosomal circRNAs between normoxia-preconditioned (Nor-Exos) Hypo-Exos. miRDB, TargetScan, double luciferase assay, qRT-PCR WB predict cirRNA_Nkd2-complementary miRNAs its target gene. function circRNA_Nkd2 evaluated by cell animal experiments. Results: This confirmed that more effectively SCs proliferation, migration, function, accelerating injury (FNI) compared Nor-Exos. Furthermore, identified significant enrichment Exosomal positively regulates mediator complex subunit 19 (MED19) expression sponging rno-miR-214-3p. Conclusion: Our results demonstrated mechanism which enhanced FNI circRNA_Nkd2/miR-214-3p/Med19 axis. Hypoxic an effective promising method optimizing action FNI. Keywords: hypoxic, BMSCs, exosomes, cells,

Language: Английский

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The dual role of mesenchymal stem cells in apoptosis regulation

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(4)

Published: April 6, 2024

Abstract Mesenchymal stem cells (MSCs) are widely distributed pluripotent with powerful immunomodulatory capacity. MSCs transplantation therapy (MSCT) is used in the fields of tissue regeneration and repair, treatment inflammatory diseases. Apoptosis an important way for tissues to maintain cell renewal, but it also plays role various And many studies have shown that improves diseases by regulating apoptosis. The regulation on apoptosis double-sided. On one hand, significantly inhibit diseased cells. other promote tumor excessive immune Furthermore, regulate through multiple molecules pathways, including three classical apoptotic signaling pathways pathways. In this review, we summarize current evidence MSCs.

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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Engineering exosomes for bone defect repair

Frontiers in Bioengineering and Biotechnology, Journal Year: 2022, Volume and Issue: 10

Published: Dec. 7, 2022

Currently, bone defect repair is still an intractable clinical problem. Numerous treatments have been performed, but their results are unsatisfactory. As a key element of cell-free therapy, exosome becoming promising tool regeneration in recent decades, because its promoting osteogenesis and osteogenic differentiation function vivo vitro . However, low yield, weak activity, inefficient targeting ability, unpredictable side effects natural exosomes limited the application. To overcome weakness, various approaches applied to produce engineering by regulating production at present. In this review, we will focus on for repair. By summarizing exosomal cargos affecting osteogenesis, strategies properties exosome-integrated biomaterials, work provide novel insights into exploring advanced exosome-based therapy

Language: Английский

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Pyroptosis in spinal cord injury

Frontiers in Cellular Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: Nov. 17, 2022

Spinal cord injury (SCI) often brings devastating consequences to patients and their families. Pathophysiologically, the primary insult causes irreversible damage neurons glial cells initiates secondary cascade, further leading inflammation, ischemia, death. In SCI, release of various inflammatory mediators aggravates nerve injury. Pyroptosis is a new pro-inflammatory pattern regulated cell death (RCD), mainly mediated by caspase-1 or caspase-11/4/5. Gasdermins family are pore-forming proteins known as executor pyroptosis gasdermin D (GSDMD) best characterized. occurs in multiple central nervous system (CNS) types, especially plays vital role development SCI. We review here evidence for focus on different crosstalk between them. addition, we discuss interaction other forms RCD also summarize therapeutic strategies inhibition, so provide novel ideas improving outcomes following

Language: Английский

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