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Anti-CHAC1 exosomes for nose-to-brain delivery of miR-760-3p in cerebral ischemia/reperfusion injury mice inhibiting neuron ferroptosis

Wang, Yong, Niu, Huicong, Li, Luyu, Han, Jing, Liu, Zhuohang, Chu, Min, Sha, Xianyi, Zhao, Jing·2023·Journal of Nanobiotechnology
DOI 10.1186/s12951-023-01862-xPMC PMC10041751
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Abstract

Ferroptosis plays a critical role in ischemic stroke, and anti-ferroptosis strategies were regarded as potentially effective measures. Based on ferroptosis-related mechanisms, this study aims to design and prepare anti-ferroptosis exosomes from adipose-derived mesenchymal stem cells (ADSC-Exo) for treating ischemic brain injury via intranasal (IN) administration. According to the bioinformatic analysis, CHAC1 was a key gene in the progress of ferroptosis in ischemic stroke. miR-760-3p can inhibit the expression of CHAC1 and may be abundant in ADSC-Exo. Therefore, ADSC-Exo were successfully isolated and the immunofluorescence showed that they can be efficiently delivered to the brain via IN administration. Additionally, IN administration of ADSC-Exo can effectively improve the neurobehavior function of mice after I/R, and improve the ferroptosis-related outcomes. As the immunofluorescence showed the co-localization of NeuN with CHAC1 obviously, we further evaluated the systematic effect of ADSC-Exo in an oxygen–glucose deprivation (OGD) mouse neuroblastoma cell line N2a model. The results showed that miR-760-3p in ADSC‐Exo contributed to their function in inhibiting ferroptosis by targeting CHAC1 in neurons. Collectively, the present study successfully designed and prepared anti-CHAC1 ADSC-Exo and suggested a promising exosome-based strategy for anti-ferroptosis therapy in cerebral ischemia/reperfusion injury. Graphical abstract

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Figures

Fig. 1 Identification of ferroptosis-related Different Expression Genes (DEGs) in ischemic stroke and prediction of ADSC-Exo as a suitable anti-ferroptosis agent based on the content of DEGs’ target miRNAs. A The volcano plot revealed 43 upregulated genes and 38 down‐regulated genes in the infarct core compared to healthy contralateral areas. B The ferroptosis-related DEGs were identified by a Venn diagram. C The CHAC1 expression in infarct core and healthy contralateral areas from a human dataset. D The CHAC1 expression of brain tissues at MCAO and control groups from a mouse dataset. E The CHAC1 expression of serum at the ischemic stroke and healthy groups from a human dataset. F The target miRNAs of CHAC1 predicted by starBase v2.0. G The cross miRNAs in ADSC-Exo and starBase-predicted miRNAs were identified by a Venn diagram. H The candidate target miRNAs in human ADSC-Exo were ranked. I The miR-760 expression in infarct core and healthy contralateral areas from a human dataset. J The miR-760-3p expression of brain tissues at MCAO and control groups from a mouse dataset. K The CHAC1 expression of brain tissues at MCAO and sham groups in mice, n = 5 L The miR-760-3p expression of brain tissues at MCAO and sham groups in mice, n = 5 M. The CHAC1 expression of serum from ischemic stroke and healthy people, n = 5. N The miR-760 expression of serum from ischemic stroke and healthy people, n = 5
Fig. 1 Identification of ferroptosis-related Different Expression Genes (DEGs) in ischemic stroke and prediction of ADSC-Exo as a suitable anti-ferroptosis agent based on the content of DEGs’ target miRNAs. A The volcano plot revealed 43 upregulated genes and 38 down‐regulated genes in the infarct core compared to healthy contralateral areas. B The ferroptosis-related DEGs were identified by a Venn diagram. C The CHAC1 expression in infarct core and healthy contralateral areas from a human dataset. D The CHAC1 expression of brain tissues at MCAO and control groups from a mouse dataset. E The CHAC1 expression of serum at the ischemic stroke and healthy groups from a human dataset. F The target miRNAs of CHAC1 predicted by starBase v2.0. G The cross miRNAs in ADSC-Exo and starBase-predicted miRNAs were identified by a Venn diagram. H The candidate target miRNAs in human ADSC-Exo were ranked. I The miR-760 expression in infarct core and healthy contralateral areas from a human dataset. J The miR-760-3p expression of brain tissues at MCAO and control groups from a mouse dataset. K The CHAC1 expression of brain tissues at MCAO and sham groups in mice, n = 5 L The miR-760-3p expression of brain tissues at MCAO and sham groups in mice, n = 5 M. The CHAC1 expression of serum from ischemic stroke and healthy people, n = 5. N The miR-760 expression of serum from ischemic stroke and healthy people, n = 5CC BY · PubMed Central
Fig. 2 Characterization of ADSCs and ADSC-Exo. A Flow cytometric analysis of ADSCs surface markers CD44 and CD105, and negative markers CD45 and CD34. B Oil Red O staining showed a large number of red oil droplets in the cytoplasm (white arrows). Scale bars = 50 μm C. Alizarin red staining showed the red calcium nodules (white arrows) formed in cells. Scale bars = 100 μm D Representative TEM image of ADSC-Exo (white arrows). Scale bars = 200 nm. E Expressions of the ADSC-Exo markers CD63 and TSG101 were confirmed by Western blot. F Size distribution of ADSC-Exo measured by NanoFCM. G PKH‐26 labeled ADSC-Exo (Red) were detected around the nucleus (Blue) in the ipsilateral hemisphere of MCAO mice brain. Scale bars = 20 μm
Fig. 2 Characterization of ADSCs and ADSC-Exo. A Flow cytometric analysis of ADSCs surface markers CD44 and CD105, and negative markers CD45 and CD34. B Oil Red O staining showed a large number of red oil droplets in the cytoplasm (white arrows). Scale bars = 50 μm C. Alizarin red staining showed the red calcium nodules (white arrows) formed in cells. Scale bars = 100 μm D Representative TEM image of ADSC-Exo (white arrows). Scale bars = 200 nm. E Expressions of the ADSC-Exo markers CD63 and TSG101 were confirmed by Western blot. F Size distribution of ADSC-Exo measured by NanoFCM. G PKH‐26 labeled ADSC-Exo (Red) were detected around the nucleus (Blue) in the ipsilateral hemisphere of MCAO mice brain. Scale bars = 20 μmCC BY · PubMed Central
Fig. 3 Ferroptosis occurred in ischemic stroke mice and patients. A Representative photomicrographs of laser speckle imaging for ischemic stroke mice. B Representative photomicrographs of brain coronal sections stained with triphenyl tetrazolium chloride (TTC) staining for ischemic mice at 24 h after MCAO. C Western blot analysis of ferroptosis markers ACSL4 and GPX4 at different time points after MCAO in mice, n = 3. D Quantification of the protein expression of ACSL4, n = 3. E Quantification of the protein expression of GPX4, n = 3. F Quantification of the malondialdehyde (MDA) at different time points after MCAO in mice, n = 5. G, H The mRNA expression levels of ACSL4 and GPX4 were detected by RT-qPCR in the serum from healthy volunteers and ischemic stroke patients, n = 5. I The amount of MDA detected in the serum from healthy volunteers and ischemic stroke patients, n = 5
Fig. 3 Ferroptosis occurred in ischemic stroke mice and patients. A Representative photomicrographs of laser speckle imaging for ischemic stroke mice. B Representative photomicrographs of brain coronal sections stained with triphenyl tetrazolium chloride (TTC) staining for ischemic mice at 24 h after MCAO. C Western blot analysis of ferroptosis markers ACSL4 and GPX4 at different time points after MCAO in mice, n = 3. D Quantification of the protein expression of ACSL4, n = 3. E Quantification of the protein expression of GPX4, n = 3. F Quantification of the malondialdehyde (MDA) at different time points after MCAO in mice, n = 5. G, H The mRNA expression levels of ACSL4 and GPX4 were detected by RT-qPCR in the serum from healthy volunteers and ischemic stroke patients, n = 5. I The amount of MDA detected in the serum from healthy volunteers and ischemic stroke patients, n = 5CC BY · PubMed Central
Fig. 4 Intranasal administration of ADSC-Exo improved neurobehavior function and inhibit ferroptosis after ischemic stroke in mice. A Experimental schedule. ADSC-Exo intranasal administration was performed daily for 1–3 days after MCAO. B The neurological deficits were assessed by mNSS evaluation before MCAO and 1, 3, 7, 14, and 28 days after the operation, n = 10. C The grasping function of mice’s affected limbs before MCAO and 14 and 28 days after the operation was assessed by foot fault test, n = 10. D The motor function before MCAO and 7, 14, and 28 days after the operation was assessed by open-field test, n = 10. E The coordination function before MCAO and 3, 7, 14, and 28 days after the operation was assessed by the rotarod test, n = 10. F Ferroptosis-related protein markers ACSL4 and GPX4 expression detected by Western blot, n = 5. G Quantification of the protein expression of ACSL4, n = 5. H Quantification of the protein expression of GPX4, n = 5. I Quantification of the malondialdehyde (MDA), n = 5. J Quantification of ferrous iron level (Fe2+), n = 5. **p < 0.01, ***p < 0.001, ****p < 0.0001
Fig. 4 Intranasal administration of ADSC-Exo improved neurobehavior function and inhibit ferroptosis after ischemic stroke in mice. A Experimental schedule. ADSC-Exo intranasal administration was performed daily for 1–3 days after MCAO. B The neurological deficits were assessed by mNSS evaluation before MCAO and 1, 3, 7, 14, and 28 days after the operation, n = 10. C The grasping function of mice’s affected limbs before MCAO and 14 and 28 days after the operation was assessed by foot fault test, n = 10. D The motor function before MCAO and 7, 14, and 28 days after the operation was assessed by open-field test, n = 10. E The coordination function before MCAO and 3, 7, 14, and 28 days after the operation was assessed by the rotarod test, n = 10. F Ferroptosis-related protein markers ACSL4 and GPX4 expression detected by Western blot, n = 5. G Quantification of the protein expression of ACSL4, n = 5. H Quantification of the protein expression of GPX4, n = 5. I Quantification of the malondialdehyde (MDA), n = 5. J Quantification of ferrous iron level (Fe2+), n = 5. **p < 0.01, ***p < 0.001, ****p < 0.0001CC BY · PubMed Central
Fig. 5 CHAC1 was up-regulated in mouse neurons at 3d after MCAO and ADSC-Exo were taken up by neurons in vivo and in vitro. A The immunofluorescence showed the co-localization of NeuN with CHAC1 obviously, while no co-localization of CHAC1 with IBA1 or GFAP was identified. White arrows indicated the co-localization of NeuN with CHAC1. Scale bars = 20 μm. B Immunofluorescence imaging showed the uptake of ADSC-Exo by neurons in vivo. PKH26 labeled ADSC-Exo (Red) were intranasally administered to the mouse at 24 h after MCAO. The internalization of ADSC-Exo by NeuN + neuron (Green) was detected 6 h after the administration. The white circle indicated ADSC-Exo internalized by neuron. Scale bar = 50 μm. C PKH‐26 labeled ADSC-Exo (Red) were taken up by NeuN + N2a cells (Green). PKH‐26 labeled ADSC-Exo were incubated with N2a cells for 6 h. Scale bar = 20 μm
Fig. 5 CHAC1 was up-regulated in mouse neurons at 3d after MCAO and ADSC-Exo were taken up by neurons in vivo and in vitro. A The immunofluorescence showed the co-localization of NeuN with CHAC1 obviously, while no co-localization of CHAC1 with IBA1 or GFAP was identified. White arrows indicated the co-localization of NeuN with CHAC1. Scale bars = 20 μm. B Immunofluorescence imaging showed the uptake of ADSC-Exo by neurons in vivo. PKH26 labeled ADSC-Exo (Red) were intranasally administered to the mouse at 24 h after MCAO. The internalization of ADSC-Exo by NeuN + neuron (Green) was detected 6 h after the administration. The white circle indicated ADSC-Exo internalized by neuron. Scale bar = 50 μm. C PKH‐26 labeled ADSC-Exo (Red) were taken up by NeuN + N2a cells (Green). PKH‐26 labeled ADSC-Exo were incubated with N2a cells for 6 h. Scale bar = 20 μmCC BY · PubMed Central
Fig. 6 CHAC1 was verified as a downstream target gene of miR-760-3p in N2a cells. A A luciferase reporter assay verified the miR-760-3p could bind to the 3′-UTR of the CHAC1 mRNA, n = 3. (B) The miR-760-3p mimic elevated miR-760-3p levels in N2a cells by RT-qPCR, n = 3. (C) The miR-760-3p inhibitor suppressed miR-760-3p levels in N2a cells by RT-qPCR, n = 3. (D) The CHAC1 mRNA expression was assessed by RT-qPCR, n = 3. (E, F) The CHAC1 protein expression was assessed by Western blot, n = 3
Fig. 6 CHAC1 was verified as a downstream target gene of miR-760-3p in N2a cells. A A luciferase reporter assay verified the miR-760-3p could bind to the 3′-UTR of the CHAC1 mRNA, n = 3. (B) The miR-760-3p mimic elevated miR-760-3p levels in N2a cells by RT-qPCR, n = 3. (C) The miR-760-3p inhibitor suppressed miR-760-3p levels in N2a cells by RT-qPCR, n = 3. (D) The CHAC1 mRNA expression was assessed by RT-qPCR, n = 3. (E, F) The CHAC1 protein expression was assessed by Western blot, n = 3CC BY · PubMed Central
Fig. 7 miR-760-3p inhibitor reversed the effects of ADSC-Exo on CHAC1 protein downregulation and ferroptosis inhibition. A Successfully established of OGD model of N2a cells confirmed by CCK-8 assay, n = 7. B, C The CHAC1 protein expression of OGD-treated N2a cells in different groups was assessed by Western blot, n = 3. D The survival rate of OGD-treated N2a cells in different groups was assessed by CCK-8 assay, n = 3. E, F The lipid peroxidation of OGD-treated N2a cells in different groups was assessed by the C11-BODIPY probe, n = 3. G The ferrous iron level (Fe2+) of OGD-treated N2a cells in different groups was assessed by the FerroOrange probe, n = 3
Fig. 7 miR-760-3p inhibitor reversed the effects of ADSC-Exo on CHAC1 protein downregulation and ferroptosis inhibition. A Successfully established of OGD model of N2a cells confirmed by CCK-8 assay, n = 7. B, C The CHAC1 protein expression of OGD-treated N2a cells in different groups was assessed by Western blot, n = 3. D The survival rate of OGD-treated N2a cells in different groups was assessed by CCK-8 assay, n = 3. E, F The lipid peroxidation of OGD-treated N2a cells in different groups was assessed by the C11-BODIPY probe, n = 3. G The ferrous iron level (Fe2+) of OGD-treated N2a cells in different groups was assessed by the FerroOrange probe, n = 3CC BY · PubMed Central
Fig. 8 CHAC1 overexpression reversed the effects of ADSC-Exo on ferroptosis inhibition. A Transfection efficiency of the lentivirus virus was detected by fluorescence microscopy, Scale bars = 50 μm. B Overexpression of CHAC1 in N2a cells confirmed by RT-qPCR, n = 3. C The survival rate of OGD-treated N2a cells in different groups was assessed by CCK-8 assay, n = 3. D, E The lipid peroxidation of OGD-treated N2a cells in different groups was assessed by the C11-BODIPY probe, n = 3. F The ferrous iron level (Fe2+) of OGD-treated N2a cells at different groups was assessed by the FerroOrange probe, n = 3. G The GSH level of OGD-treated N2a cells in different groups was assessed by Glutathione Assay Kit, n = 3
Fig. 8 CHAC1 overexpression reversed the effects of ADSC-Exo on ferroptosis inhibition. A Transfection efficiency of the lentivirus virus was detected by fluorescence microscopy, Scale bars = 50 μm. B Overexpression of CHAC1 in N2a cells confirmed by RT-qPCR, n = 3. C The survival rate of OGD-treated N2a cells in different groups was assessed by CCK-8 assay, n = 3. D, E The lipid peroxidation of OGD-treated N2a cells in different groups was assessed by the C11-BODIPY probe, n = 3. F The ferrous iron level (Fe2+) of OGD-treated N2a cells at different groups was assessed by the FerroOrange probe, n = 3. G The GSH level of OGD-treated N2a cells in different groups was assessed by Glutathione Assay Kit, n = 3CC BY · PubMed Central

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Metadata

Authors
Wang, Y., Niu, H., Li, L., Han, J., Liu, Z., Chu, M., Sha, X., & Zhao, J.
Venue
Journal of Nanobiotechnology
Publisher
Springer Science and Business Media LLC
Published
2023-03-27
Volume
21
Issue
1
ISSN
1477-3155
DOI
10.1186/s12951-023-01862-x
PMC
PMC10041751
Cited by
172
References
5
Language
en
Licence
Funders
  • National Key Research and Development Program of China (2022YFC2304303)
  • National Natural Science Foundation of China (81973157)

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