Extracellular vesicles derived from mesenchymal stromal cells as nanotherapeutics for liver ischaemia–reperfusion injury by transferring mitochondria to modulate the formation of neutrophil extracellular traps

Lu, Tian; Zhang, Jiebin; Cai, Jianye; Xiao, Jiaqi; Sui, Xin; Yuan, Xiaofeng; Li, Rong; Li, Yang; Yao, Jia; Lv, Guo; Chen, Xiaoyan; Chen, Haitian; Zeng, Kaining; Liu, Yasong; Chen, Wenjie; Chen, Guihua; Yang, Yang; Zheng, Jun; Zhang, Yingcai

doi:10.1016/j.biomaterials.2022.121486

Cited by 67 publications

(32 citation statements)

References 63 publications

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“…Almost immediately, questions arose about the matching of the sizes of mitochondria and vesicles, the size dispersion of which in some cases did not allow the presence of mitochondria inside. Additionally, even those rare cases of demonstration mitochondrial presence inside large vesicles using electron microscopy, (e.g., [17,41,43]) did not exclude the possibility that these examples represent an early stage of lysosome formation, which added uncertainty and ambiguity to the conclusion of whether vesicles can contain functional mitochondria.…”

Section: General Discussion and Conclusionmentioning

confidence: 99%

Do Extracellular Vesicles Derived from Mesenchymal Stem Cells Contain Functional Mitochondria?

Zorova

Kovalchuk

Popkov

et al. 2022

IJMS

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Extracellular vesicles (EV) derived from stem cells have become an effective complement to the use in cell therapy of stem cells themselves, which has led to an explosion of research into the mechanisms of vesicle formation and their action. There is evidence demonstrating the presence of mitochondrial components in EV, but a definitive conclusion about whether EV contains fully functional mitochondria has not yet been made. In this study, two EV fractions derived from mesenchymal stromal stem cells (MSC) and separated by their size were examined. Flow cytometry revealed the presence of mitochondrial lipid components capable of interacting with mitochondrial dyes MitoTracker Green and 10-nonylacridine orange; however, the EV response to the probe for mitochondrial membrane potential was negative. Detailed analysis revealed components from all mitochondria compartments, including house-keeping mitochondria proteins and DNA as well as energy-related proteins such as membrane-localized proteins of complexes I, IV, and V, and soluble proteins from the Krebs cycle. When assessing the functional activity of mitochondria, high variability in oxygen consumption was noted, which was only partially attributed to mitochondrial respiratory activity. Our findings demonstrate that the EV contain all parts of mitochondria; however, their independent functionality inside EV has not been confirmed, which may be due either to the absence of necessary cofactors and/or the EV formation process and, probably the methodology of obtaining EV.

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Section: General Discussion and Conclusionmentioning

confidence: 99%

Do Extracellular Vesicles Derived from Mesenchymal Stem Cells Contain Functional Mitochondria?

Zorova

Kovalchuk

Popkov

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…For example, human umbilical cord‐derived MSC‐derived EVs (hUC‐MSC‐EVs) can prevent NET formation by delivering functional mitochondria, which preserve membrane potential and inhibit mitochondrial permeability transition pore initiation and mtROS and cytoplasmic mtDNA release in neutrophils. in vivo, such EV treatments protected liver function (reduced alanine transaminase, aspartate transaminase and lactate dehydrogenase levels) from ischemia‒reperfusion injury (IRI) (Lu et al., 2022 ). These studies provide insights into the links between mitochondrial damage and liver injury and suggest the potential of mitoEVs in the treatment of liver diseases.…”

Section: Clinical Translation Of Ev‐mediated Mitochondrial Deliverymentioning

confidence: 99%

MitoEVs: A new player in multiple disease pathology and treatment

Zhou

Liu

et al. 2023

J of Extracellular Vesicle

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Mitochondrial damage plays vital roles in the pathology of many diseases, such as cancers, neurodegenerative diseases, aging, metabolic diseases and many types of organ injury. However, the regulatory mechanism of mitochondrial functions among different cells or organs in vivo is still unclear, and efficient therapies for attenuating mitochondrial damage are urgently needed. Extracellular vesicles (EVs) are cell‐derived nanovesicles that can deliver bioactive cargoes among cells or organs. Interestingly, recent evidence shows that diverse mitochondrial contents are enriched in certain EV subpopulations, and such mitoEVs can deliver mitochondrial components to affect the functions of recipient cells under different conditions, which has emerged as a hot topic in this field. However, the overview and many essential questions with respect to this event remain elusive. In this review, we provide a global view of mitoEVs biology and mainly focus on the detailed sorting mechanisms, functional mitochondrial contents, and diverse biological effects of mitoEVs. We also discuss the pathogenic or therapeutic roles of mitoEVs in different diseases and highlight their potential as disease biomarkers or therapies in clinical translation. This review will provide insights into the pathology and drug development for various mitochondrial injury‐related diseases.

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“…Thirdly, MSC-Exos inhibits the formation of terminal complement complexes on neutrophils via CD59, thus attenuating neutrophil activation and inhibiting the release of NETs and IL-17 from neutrophils[ 124 ]. Besides, human umbilical cord blood-derived MSC-derived EVs (exosomes) can also repair and enhance neutrophil mitochondrial function by transferring functional mitochondria, then reducing the formation of NETs[ 125 ]. Of greater importance, Soni et al [ 72 ] further investigated the differences in the regulation of neutrophil function by exosomes from different sources of MSCs.…”

Section: Msc-exos Modulates Immune Response After Ismentioning

confidence: 99%

Immunomodulation: The next target of mesenchymal stem cell-derived exosomes in the context of ischemic stroke

Shan¹,

Luo²,

Chang³

et al. 2023

World J Stem Cells

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Ischemic stroke (IS) is the most prevalent form of brain disease, characterized by high morbidity, disability, and mortality. However, there is still a lack of ideal prevention and treatment measures in clinical practice. Notably, the transplantation therapy of mesenchymal stem cells (MSCs) has been a hot research topic in stroke. Nevertheless, there are risks associated with this cell therapy, including tumor formation, coagulation dysfunction, and vascular occlusion. Also, a growing number of studies suggest that the therapeutic effect after transplantation of MSCs is mainly attributed to MSC-derived exosomes (MSC-Exos). And this cell-free mediated therapy appears to circumvent many risks and difficulties when compared to cell therapy, and it may be the most promising new strategy for treating stroke as stem cell replacement therapy. Studies suggest that suppressing inflammation via modulation of the immune response is an additional treatment option for IS. Intriguingly, MSC-Exos mediates the inflammatory immune response following IS by modulating the central nervous system, the peripheral immune system, and immunomodulatory molecules, thereby promoting neurofunctional recovery after stroke. Thus, this paper reviews the role, potential mechanisms, and therapeutic potential of MSC-Exos in post-IS inflammation in order to identify new research targets.

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Extracellular vesicles derived from mesenchymal stromal cells as nanotherapeutics for liver ischaemia–reperfusion injury by transferring mitochondria to modulate the formation of neutrophil extracellular traps

Cited by 67 publications

References 63 publications

Do Extracellular Vesicles Derived from Mesenchymal Stem Cells Contain Functional Mitochondria?

Do Extracellular Vesicles Derived from Mesenchymal Stem Cells Contain Functional Mitochondria?

MitoEVs: A new player in multiple disease pathology and treatment

Immunomodulation: The next target of mesenchymal stem cell-derived exosomes in the context of ischemic stroke

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