Observing Extracellular Vesicles Originating from Endothelial Cells Demonstrates Improved Astrocyte Function Following Ischemic Stroke Via Aggregation-Induced Emission Luminogens

Overview

Journal ACS Nano

Publisher American Chemical Society

Specialty Biotechnology

Date 2023 Aug 3

PMID 37535897

Authors

Xiangyu Gao

Heqi Gao

Kangyi Yue

Xiuli Cao

ErWan Yang

Zhuoyuan Zhang

Yutao Huang

Xin Li

Dan Ding

Peng Luo

Xiaofan Jiang

Affiliations

Soon will be listed here.

Abstract

Extracellular vesicles (EVs) obtained from endothelial cells (ECs) have significant therapeutic potential in the clinical management of individuals with ischemic stroke (IS) because they effectively treat ischemic stroke in animal models. However, because molecular probes with both high labeling efficiency and tracer stability are lacking, monitoring the actions of EC-EVs in the brain remains difficult. The specific intracellular targets in the brain that EC-EVs act on to produce their protective effects are still unknown, greatly impeding their use in clinical settings. For this research, we created a probe that possessed aggregation-induced emission (AIE) traits (namely, TTCP), enabling the effective labeling of EC-EVs while preserving their physiological properties. , TTCP simultaneously had a higher EC-EV labeling efficiency and better tracer stability than the commercial EV tags PKH-67 and DiI. , TTCP precisely tracked the actions of EC-EVs in a mouse IS model without influencing their protective effects. Furthermore, through the utilization of TTCP, it was determined that astrocytes were the specific cells affected by EC-EVs and that EC-EVs exhibited a safeguarding impact on astrocytes following cerebral ischemia-reperfusion (I/R) injury. These protective effects encompassed the reduction of the inflammatory reaction and apoptosis as well as the enhancement of cell proliferation. Further analysis showed that miRNA-155-5p carried by EC-EVs is responsible for these protective effects via regulation of the c-Fos/AP-1 pathway; this information provided a strategy for IS therapy. In conclusion, TTCP has a high EC-EV labeling efficiency and favorable tracer stability during IS therapy. Moreover, EC-EVs are absorbed by astrocytes during cerebral I/R injury and promote the restoration of neurological function through the regulation of the c-Fos/AP-1 signaling pathway.

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References

Madhu L, Attaluri S, Kodali M, Shuai B, Upadhya R, Gitai D . Neuroinflammation in Gulf War Illness is linked with HMGB1 and complement activation, which can be discerned from brain-derived extracellular vesicles in the blood. Brain Behav Immun. 2019; 81:430-443. DOI: 10.1016/j.bbi.2019.06.040. View

Mei J, Hong Y, Lam J, Qin A, Tang Y, Tang B . Aggregation-induced emission: the whole is more brilliant than the parts. Adv Mater. 2014; 26(31):5429-79. DOI: 10.1002/adma.201401356. View

Shi X, Luo L, Wang J, Shen H, Li Y, Mamtilahun M . Stroke subtype-dependent synapse elimination by reactive gliosis in mice. Nat Commun. 2021; 12(1):6943. PMC: 8626497. DOI: 10.1038/s41467-021-27248-x. View

Baudin B, Bruneel A, Bosselut N, Vaubourdolle M . A protocol for isolation and culture of human umbilical vein endothelial cells. Nat Protoc. 2007; 2(3):481-5. DOI: 10.1038/nprot.2007.54. View

Xiao B, Chai Y, Lv S, Ye M, Wu M, Xie L . Endothelial cell-derived exosomes protect SH-SY5Y nerve cells against ischemia/reperfusion injury. Int J Mol Med. 2017; 40(4):1201-1209. PMC: 5593464. DOI: 10.3892/ijmm.2017.3106. View

Cai X, Liu B . Aggregation-Induced Emission: Recent Advances in Materials and Biomedical Applications. Angew Chem Int Ed Engl. 2020; 59(25):9868-9886. DOI: 10.1002/anie.202000845. View

Zhou X, Chen J, Tao H, Cai Y, Huang L, Zhou H . Intranasal Delivery of miR-155-5p Antagomir Alleviates Acute Seizures Likely by Inhibiting Hippocampal Inflammation. Neuropsychiatr Dis Treat. 2020; 16:1295-1307. PMC: 7251485. DOI: 10.2147/NDT.S247677. View

Hill A . Extracellular Vesicles and Neurodegenerative Diseases. J Neurosci. 2019; 39(47):9269-9273. PMC: 6867808. DOI: 10.1523/JNEUROSCI.0147-18.2019. View

Liu S, Wang B, Yu Y, Liu Y, Zhuang Z, Zhao Z . Cationization-Enhanced Type I and Type II ROS Generation for Photodynamic Treatment of Drug-Resistant Bacteria. ACS Nano. 2022; 16(6):9130-9141. DOI: 10.1021/acsnano.2c01206. View

10.

Zgorzynska E, Stulczewski D, Dziedzic B, Su K, Walczewska A . Docosahexaenoic fatty acid reduces the pro-inflammatory response induced by IL-1β in astrocytes through inhibition of NF-κB and AP-1 transcription factor activation. BMC Neurosci. 2021; 22(1):4. PMC: 7839194. DOI: 10.1186/s12868-021-00611-w. View

11.

DSouza A, Dave K, Stetler R, Manickam D . Targeting the blood-brain barrier for the delivery of stroke therapies. Adv Drug Deliv Rev. 2021; 171:332-351. DOI: 10.1016/j.addr.2021.01.015. View

12.

. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015; 386(9995):743-800. PMC: 4561509. DOI: 10.1016/S0140-6736(15)60692-4. View

13.

Venkat P, Cui C, Chopp M, Zacharek A, Wang F, Landschoot-Ward J . MiR-126 Mediates Brain Endothelial Cell Exosome Treatment-Induced Neurorestorative Effects After Stroke in Type 2 Diabetes Mellitus Mice. Stroke. 2019; 50(10):2865-2874. PMC: 6756941. DOI: 10.1161/STROKEAHA.119.025371. View

14.

Luo D, Zhang Y, Yuan X, Pan Y, Yang L, Zhao Y . Oleoylethanolamide inhibits glial activation via moudulating PPARα and promotes motor function recovery after brain ischemia. Pharmacol Res. 2019; 141:530-540. DOI: 10.1016/j.phrs.2019.01.027. View

15.

Wang J, Zhang L, Li Z . Aggregation-Induced Emission Luminogens with Photoresponsive Behaviors for Biomedical Applications. Adv Healthc Mater. 2021; 10(24):e2101169. DOI: 10.1002/adhm.202101169. View

16.

Athauda D, Gulyani S, Karnati H, Li Y, Tweedie D, Mustapic M . Utility of Neuronal-Derived Exosomes to Examine Molecular Mechanisms That Affect Motor Function in Patients With Parkinson Disease: A Secondary Analysis of the Exenatide-PD Trial. JAMA Neurol. 2019; 76(4):420-429. PMC: 6459135. DOI: 10.1001/jamaneurol.2018.4304. View

17.

Dehghani M, Gulvin S, Flax J, Gaborski T . Systematic Evaluation of PKH Labelling on Extracellular Vesicle Size by Nanoparticle Tracking Analysis. Sci Rep. 2020; 10(1):9533. PMC: 7293335. DOI: 10.1038/s41598-020-66434-7. View

18.

He W, Zhang T, Bai H, Kwok R, Lam J, Tang B . Recent Advances in Aggregation-Induced Emission Materials and Their Biomedical and Healthcare Applications. Adv Healthc Mater. 2021; 10(24):e2101055. DOI: 10.1002/adhm.202101055. View

19.

Rong Y, Liu W, Wang J, Fan J, Luo Y, Li L . Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy. Cell Death Dis. 2019; 10(5):340. PMC: 6472377. DOI: 10.1038/s41419-019-1571-8. View

20.

Lai X, Wang Y, Wang X, Liu B, Rong L . miR-146a-5p-modified hUCMSC-derived exosomes facilitate spinal cord function recovery by targeting neurotoxic astrocytes. Stem Cell Res Ther. 2022; 13(1):487. PMC: 9524140. DOI: 10.1186/s13287-022-03116-3. View