A paradigm shift in cell-free approach: the emerging role of MSCs-derived exosomes in regenerative medicine

Journal of Translational Medicine, Journal Year: 2021, Volume and Issue: 19(1)

Published: July 12, 2021

Abstract Recently, mesenchymal stem/stromal cells (MSCs) due to their pro-angiogenic, anti-apoptotic, and immunoregulatory competencies along with fewer ethical issues are presented as a rational strategy for regenerative medicine. Current reports have signified that the pleiotropic effects of MSCs not related differentiation potentials, but rather exerted through release soluble paracrine molecules. Being nano-sized, non-toxic, biocompatible, barely immunogenic, owning targeting capability organotropism, exosomes considered nanocarriers possible use in diagnosis therapy. Exosomes convey functional molecules such long non-coding RNAs (lncRNAs) micro-RNAs (miRNAs), proteins (e.g., chemokine cytokine), lipids from target cells. They participate intercellular interaction procedures enable repair damaged or diseased tissues organs. Findings evidenced alone liable beneficial influences myriad experimental models, suggesting MSC- can be utilized establish novel cell-free therapeutic treatment varied human disorders, encompassing myocardial infarction (MI), CNS-related musculoskeletal disorders (e.g. arthritis), kidney diseases, liver lung well cutaneous wounds. Importantly, compared MSCs, serve more steady entities reduced safety risks concerning injection live cells, microvasculature occlusion risk. In current review, we will discuss potential an innovative approach context medicine highlight recent knowledge on translational medicine, focusing vivo researches.

Language: Английский

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The role of autophagy in bone metabolism and clinical significance

Autophagy, Journal Year: 2023, Volume and Issue: 19(9), P. 2409 - 2427

Published: March 2, 2023

The skeletal system is the basis of vertebral body composition, which affords stabilization sites for muscle attachment, protects vital organs, stores mineral ions, supplies places to hematopoietic system, and participates in complex endocrine immune system. Not surprisingly, bones are constantly reabsorbed, formed, remodeled under physiological conditions. Once bone metabolic homeostasis interrupted (including inflammation, tumors, fractures, diseases), rapidly initiates regeneration maintain tissue structure quality. Macroautophagy/autophagy an essential process eukaryotic cells, maintains energy plays a role by controlling molecular degradation organelle renewal. One relatively new observation that mesenchymal osteoblasts, osteoclasts, osteocytes, chondrocytes, vascularization exhibit autophagy, mechanisms targets involved being explored updated. autophagy also emerging degenerative diseases (intervertebral disc degeneration [IVDD], osteoarthritis [OA], etc.) (osteoporosis [OP], osteitis deformans, osteosclerosis). use regulators modulate has benefited regeneration, including MTOR (mechanistic target rapamycin kinase) inhibitors, AMPK activators, phytochemicals. application biomaterials (especially nanomaterials) trigger attractive research direction, can exert superior therapeutic properties from material-loaded molecules/drugs or material's such as shape, roughness, surface chemistry, etc. All these have clinical significance with discovery associated signals, pathways, mechanisms, treatments future.Abbreviations: Δψm: mitochondrial transmembrane potential AMPK: AMP-activated protein kinase ARO: autosomal recessive osteosclerosis ATF4: activating transcription factor 4 ATG: autophagy-related β-ECD: β-ecdysone BMSC: marrow stem cell ER: endoplasmic reticulum FOXO: forkhead box O GC: glucocorticoid HIF1A/HIF-1α: hypoxia inducible 1 subunit alpha HSC: HSP: heat shock IGF1: insulin like growth IL1B/IL-1β: interleukin beta IVDD: intervertebral LPS: lipopolysaccharide MAPK: mitogen-activated MSC: MTOR: mechanistic NP: nucleus pulposus NPWT: negative pressure wound therapy OA: OP: osteoporosis PTH: parathyroid hormone ROS: reactive oxygen species SIRT1: sirtuin SIRT3: 3 SQSTM1/p62: sequestosome TNFRSF11B/OPG: TNF receptor superfamily member 11b TNFRSF11A/RANK: tumor necrosis superfamily, 11a TNFSF11/RANKL: (ligand) 11 TSC1: tuberous sclerosis ULK1: unc-51

Language: Английский

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Mesenchymal Stem Cell‐Derived Extracellular Vesicles with High PD‐L1 Expression for Autoimmune Diseases Treatment

Advanced Materials, Journal Year: 2021, Volume and Issue: 34(1)

Published: Oct. 8, 2021

Autoimmune diseases are the third most common disease influencing quality of life many patients. Here, a programmed cell death-ligand 1 + (PD-L1) mesenchymal stem (MSC) derived extracellular vesicles (MSC-sEVs-PD-L1) using lentivirus-mediated gene transfection technology is developed for reconfiguration local immune microenvironment affected tissue in autoimmune diseases. MSC-sEVs-PD-L1 exhibits an impressive ability to regulate various activated cells immunosuppressed state vitro. More importantly, dextran sulfate sodium-induced ulcerative colitis (UC) and imiquimod-induced psoriasis mouse models, significantly high accumulation observed inflamed tissues compared PD-L1+ MSCs. Therapeutic efficiency both UC models demonstrated reshape inflammatory ecosystem context. A as natural delivery platform treatment with clinical potential.

Language: Английский

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Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms

Theranostics, Journal Year: 2022, Volume and Issue: 12(6), P. 2722 - 2740

Published: Jan. 1, 2022

Aging is a natural process, which plays critical role in the pathogenesis of variety diseases, i.e., aging-related such as diabetes, osteoarthritis, Alzheimer disease, cardiovascular cancers, obesity and other metabolic abnormalities.Metformin, most widely used antidiabetic drug, has been reported to delay aging display protective effect on attenuating progression various diseases by impacting key hallmark events aging, including dysregulated nutrient sensing, loss proteostasis, mitochondrial dysfunction, altered intercellular communication, telomere attrition, genomic instability, epigenetic alterations, stem cell exhaustion cellular senescence.In this review, we provide updated information knowledge applications metformin prevention treatment diseases.We focus our discussions roles underlying mechanisms modulating treating diseases.

Language: Английский

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Preconditioning and Engineering Strategies for Improving the Efficacy of Mesenchymal Stem Cell-Derived Exosomes in Cell-Free Therapy

Stem Cells International, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 18

Published: May 14, 2022

Mesenchymal stem cells (MSCs) have been widely applied to regenerative medicine owing their multiple differentiation, self-renewal, and immunomodulatory abilities. Exosomes are cell-secreted natural nanovesicles thought be mediators of intercellular communication material transport. The therapeutic potential MSCs can largely attributed MSC-derived exosomes (MSC-exosomes). Emerging evidence suggests that the efficacy MSC-exosomes is highly dependent on status MSCs, optimization extracellular environment affects exosomal content. Pretreatment methods including three-dimensional cultures, hypoxia, other biochemical cues shown potentially enhance biological activity while maintaining or enhancing production. On hand, engineering means desired function has rapidly gaining attention. In particular, biologically active molecule encapsulation membrane modification alter functions targeting MSC-exosomes. this review, we summarize two possible strategies improve MSC-exosomes: preconditioning approaches exosomes. We also explore underlying mechanisms different discuss advantages limitations upcoming clinical applications.

Language: Английский

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Small extracellular vesicles derived from hypoxic mesenchymal stem cells promote vascularized bone regeneration through the miR-210-3p/EFNA3/PI3K pathway

Acta Biomaterialia, Journal Year: 2022, Volume and Issue: 150, P. 413 - 426

Published: July 16, 2022

Angiogenesis is closely coupled with osteogenesis and has equal importance. Thus, promoting angiogenesis during the bone repair process vital for ideal regeneration. As important mediators of cell-cell communication biological homeostasis, mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) have been proved to be highly involved in vascular Because hypoxia microenvironment promotes proangiogenic activity MSCs, present study, we investigate effect underlying molecular mechanisms sEVs from hypoxia-preconditioned MSCs (hypo-sEVs) on develop an effective strategy promote vascularized Compared normoxia (nor-sEVs), hypo-sEVs promoted proliferation, migration, HUVECs ultimately enhanced regeneration new blood vessel reconstruction a critical-size calvarial defect model. miRNA sequence verified results showed that miR-210-3p was increased via HIF-1α under hypoxia. The upregulated by downregulating EFNA3 expression enhancing phosphorylation PI3K/AKT pathway. this study suggests successful enhance utilizing miR-210-3p/EFNA3/PI3K/AKT Considering significance vascularization regeneration, strategies are required. Hypoxia can potential cells (MSCs). Nonetheless, therapeutic (sEVs) cranio-maxillofacial remains unknown, mechanism poorly understood. This shows significantly as well formation. Moreover, work indicates induce overexpression hypoxia, hinder subsequently activate application provides facile promising

Language: Английский

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Osteoinductive Dental Pulp Stem Cell-Derived Extracellular Vesicle-Loaded Multifunctional Hydrogel for Bone Regeneration

ACS Nano, Journal Year: 2024, Volume and Issue: 18(12), P. 8777 - 8797

Published: March 15, 2024

Stem cell-derived extracellular vesicles (EVs) show great potential for promoting bone tissue regeneration. However, normal EVs (Nor-EVs) have a limited ability to direct tissue-specific Therefore, it is necessary optimize the osteogenic capacity of EV-based systems repairing extensive defects. Herein, we that hydrogels loaded with osteoinductive dental pulp stem (Ost-EVs) enhanced remodeling, resulting in 2.23 ± 0.25-fold increase expression morphogenetic protein 2 (BMP2) compared hydrogel control group. Moreover, Ost-EVs led higher alkaline phosphatase (ALP) (1.88 0.16 relative Nor-EVs) and formation orange-red calcium nodules (1.38 0.10 vitro. RNA sequencing revealed showed significantly high miR-1246 expression. An ideal implant should also adhere surrounding moist tissues. In this study, were drawn mussel-inspired adhesive modification, where carrier was crafted from hyaluronic acid (HA) polyethylene glycol derivatives, showcasing impressive adhesion, self-healing capabilities, promote growth. The modified HA (mHA) responsive environmental stimuli, making an effective delivering EVs. ectopic osteogenesis animal model, Ost-EV/hydrogel system effectively alleviated inflammation, accelerated revascularization, promoted mineralization. We further used rat femoral condyle defect model evaluate situ Ost-EVs/hydrogel system. Collectively, our results suggest combined biomaterial-based hold promising treating

Language: Английский

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Extracellular vesicles derived from melatonin‐preconditioned mesenchymal stem cells containing USP29 repair traumatic spinal cord injury by stabilizing NRF2

Journal of Pineal Research, Journal Year: 2021, Volume and Issue: 71(4)

Published: Sept. 25, 2021

Spinal cord injury (SCI) is a devastating trauma that leads to irreversible motor and sensory dysfunction is, so far, without effective treatment. Recently, however, nano-sized extracellular vesicles derived from preconditioned mesenchymal stem cells (MSCs) have shown great promise in treating various diseases, including SCI. In this study, we investigated whether (MEVs) MSCs pretreated with melatonin (MT), which well recognized be useful Alzheimer's disease, non-small cell lung cancer, acute ischemia-reperfusion liver injury, chronic kidney SCI, are better able promote functional recovery mice after SCI than preconditioning (EVs). MEVs were found facilitate behavioral more EVs increase microglia/macrophages polarization M1-like M2-like mice. Experiments BV2 microglia RAW264.7 macrophages confirmed also showed they reduce the production of reactive oxygen species (ROS) regulate mitochondrial function. Proteomics analysis revealed ubiquitin-specific protease 29 (USP29) was markedly increased MEVs, knockdown USP29 (shUSP29-MEVs) abolished MEVs-mediated benefits vitro vivo. We then interacts with, deubiquitinates therefore stabilizes nuclear factor-like 2 (NRF2), thereby regulating polarization. NRF2 knockout mice, failed MT reduced global N6-methyladenosine (m6 A) modification levels m6 A "writer" methyltransferase-like 3 (METTL3). The stability mRNA enhanced by treatment MT, but inhibited overexpression METTL3. This study describes very promising vesicle-based approach for

Language: Английский

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Engineering Extracellular Vesicles Restore the Impaired Cellular Uptake and Attenuate Intervertebral Disc Degeneration

ACS Nano, Journal Year: 2021, Volume and Issue: 15(9), P. 14709 - 14724

Published: Sept. 3, 2021

Extracellular vesicles (EVs) are potential alternatives for mesenchymal stem cells (MSCs) in the treatment of musculoskeletal degenerative diseases, including intervertebral disc degeneration (IDD). Usually, EVs internalized and then deliver bioactive molecules that impart phenotypic changes recipient cells. For effective utilization IDD therapy, understanding mechanism EV uptake is vital importance. In this study, we found delivered antioxidant proteins to protect against pyroptosis nucleus pulposus (NPCs). particular, therapeutic effect decreased TNF-α-treated NPCs due impaired caveolae-mediated endocytosis pathway. Transcriptome sequencing functional verification revealed caveolae associated protein 2 (Cavin-2) played an important role process EVs. We constructed Cavin-2-modified engineering via gene-editing parental MSCs. These kinds modified presented improved rate NPCs, which effectively ameliorated cell death a three-dimensional hydrogel culture model retarded progression ex vivo organ model. Collectively, these findings illustrate explore application IDD.

Language: Английский

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Sustained gene delivery from inflammation-responsive anti-inflammatory hydrogels promotes extracellular matrix metabolism balance in degenerative nucleus pulposus

Composites Part B Engineering, Journal Year: 2022, Volume and Issue: 236, P. 109806 - 109806

Published: March 7, 2022

Language: Английский

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