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Cited by 125Extracellular vesicles in diseaseMesenchymal stem cell researchLiver physiology and pathology

Huc-MSC-derived exosomes modified with the targeting peptide of aHSCs for liver fibrosis therapy

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Lin, Yan, Yan, Mengchao, Bai, Zhongtian, Xie, Ye, Ren, Longfei, Wei, Jiayun, Zhu, Dan, Wang, Haiping +3 more·2022·Journal of Nanobiotechnology
DOI 10.1186/s12951-022-01636-xPMC PMC9526331
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Abstract

Background: Effective therapeutics to stop or reverse liver fibrosis have not emerged, because these potential agents cannot specifically target activated hepatic stellate cells (aHSCs) or are frequently toxic to parenchymal cells. Human umbilical cord mesenchymal stem cell (Huc-MSC)-derived exosomes show promise in nanomedicine for the treatment of liver fibrosis. However, systemic injection showed that unmodified exosomes were mainly taken up by the mononuclear phagocyte system. The discovery of ligands that selectively bind to a specific target plays a crucial role in clinically relevant diagnostics and therapeutics. Herein, we aimed to identify the targeting peptide of aHSCs by screening a phage-displayed peptide library, and modify Huc-MSC-derived exosomes with the targeting peptide. Results: In this study, we screened a phage-displayed peptide library by biopanning for peptides preferentially bound to HSC-T6 cells. The identified peptide, HSTP1, also exhibited better targeting ability to aHSCs in pathological sections of fibrotic liver tissues. Then, HSTP1 was fused with exosomal enriched membrane protein (Lamp2b) and was displayed on the surface of exosomes through genetic engineering technology. The engineered exosomes (HSTP1-Exos) could be more efficiently internalized by HSC-T6 cells and outperformed both unmodified exosomes (Blank-Exos) and Lamp2b protein overexpressed exosomes (Lamp2b + Exos) in enhancing the ability of exosomes to promote HSC-T6 reversion to a quiescent phenotype. In vivo results showed HSTP1-Exos could specifically target to the aHSC region after intravenous administration, as demonstrated by coimmunofluorescence with the typical aHSCs marker α-SMA, and enhance the therapeutic effect on liver fibrosis. Conclusion: These results suggest that HSTP1 is a reliable targeting peptide that can specifically bind to aHSCs and that HSTP1-modified exosomes realize the precise treatment for aHSCs in complex liver tissue. We provide a novel strategy for clinical liver fibrosis therapy. Graphical Abstract:

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  • HSTP1-modified MSC-Exos regulated M2 polarization by suppressing CCL2 secretion from aHSCs, resulting in attenuated fibrosis.

    “Lin et al. used HSTP1, a targeting peptide of aHSCs, to modify MSC-Exos, which regulated M2 polarization by suppressing CCL2 secretion from aHSCs, resulting in attenuated fibrosis [256].”

    From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [256]

    The Results section ('Regulation of HSTP1-exos on macrophage'; page unavailable) says HSTP1-Exos regulated M2 polarization by inhibiting CCL2 secretion from activated hepatic stellate cells. The Discussion reports reduced liver fibrosis in vivo, but says CCL2 inhibition may be one reason for that effect; it does not establish the claimed causal link as fact. (LLM, conf=0.85)

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References 53 · Cited by 125

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  1. [1]Moon AM Singal AG Tapper EB Contemporary epidemiology of chronic liver disease and cirrhosis Clin Gastroenterol Hepatol 2020 18 12 2650 2666 31401364 PMC7007353
  2. [2]Du XS Li HD Yang XJ Li JJ Xu JJ Chen Y Xu QQ Yang L He CS Huang C Wogonin attenuates liver fibrosis via regulating hepatic stellate cell activation and apoptosis Int Immunopharmacol 2019 75 105671 31377590
  3. [3]Devaraj E Perumal E Subramaniyan R Mustapha N Liver fibrosis: extracellular vesicles mediated intercellular communication in perisinusoidal space Hepatology 2021 10.1002/hep.32239 34773651 · DOI
  4. [4]Mejias M Gallego J Naranjo-Suarez S Ramirez M Pell N Manzano A Suñer C Bartrons R Mendez R Fernandez M Cpeb4 increases expression of PFKFB3 to induce glycolysis and activate mouse and human hepatic stellate cells, promoting liver fibrosis Gastroenterology 2020 159 1 273 288 32169429
  5. [5]Ji D Wang Q Zhao Q Tong H Yu M Wang M Lu T Jiang C Co-delivery of miR-29b and germacrone based on cyclic RGD-modified nanoparticles for liver fibrosis therapy J Nanobiotechnology 2020 18 1 86 32513194 PMC7281922
  6. [6]Luo N Li J Wei Y Lu J Dong R Hepatic stellate cell: a double-edged sword in the liver Physiol Res 2021 70 6 821 829 34717063 PMC8815467
  7. [7]Haaker MW Vaandrager AB Helms JB Retinoids in health and disease: a role for hepatic stellate cells in affecting retinoid levels Biochim Biophys Acta Mol Cell Biol Lipids 2020 1865 6 158674 32105672
  8. [8]Schinagl M Tomin T Gindlhuber J Honeder S Pfleger R Schittmayer M Trauner M Birner-Gruenberger R Proteomic changes of activated hepatic stellate cells Int J Mol Sci 2021 22 23 12782 34884585 PMC8657869
  9. [9]Yan J Tung HC Li S Niu Y Garbacz WG Lu P Bi Y Li Y He J Xu M Aryl hydrocarbon receptor signaling prevents activation of hepatic stellate cells and liver fibrogenesis in mice Gastroenterology 2019 157 3 793 806.e714 31170413 PMC6707837
  10. [10]Kisseleva T Cong M Paik Y Scholten D Jiang C Benner C Iwaisako K Moore-Morris T Scott B Tsukamoto H Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis Proc Natl Acad Sci U S A 2012 109 24 9448 9453 22566629 PMC3386114
  11. [11]Kannan S Viswanathan P Gupta PK Kolkundkar UK Characteristics of pooled wharton's jelly mesenchymal stromal cells (WJ-MSCs) and their potential role in rheumatoid arthritis treatment Stem Cell Rev Rep 2022 10.1007/s12015-022-10344-w 35113368 · DOI
  12. [12]Zhou Q Gu T Zhang Y Li H Zhuansun X Xu S Kuang Y Human umbilical cord mesenchymal stem cells ameliorate hepatic stellate cell activation and liver fibrosis by upregulating microRNA-455-3p through suppression of p21-activated kinase-2 Biomed Res Int 2021 2021 6685605 33708992 PMC7932777
  13. [13]Dong L Pu Y Chen X Qi X Zhang L Xu L Li W Ma Y Zhou S Zhu J hUCMSC-extracellular vesicles downregulated hepatic stellate cell activation and reduced liver injury in S. japonicum-infected mice Stem Cell Res Ther 2020 11 1 21 31918749 PMC6953150
  14. [15]Lou G Chen Z Zheng M Liu Y Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases Exp Mol Med 2017 49 6 e346 28620221 PMC5519012
  15. [16]Heo JS Kim S Human adipose mesenchymal stem cells modulate inflammation and angiogenesis through exosomes Sci Rep 2022 12 1 2776 35177768 PMC8854709
  16. [17]Guy R Offen D Promising opportunities for treating neurodegenerative diseases with mesenchymal stem cell-derived exosomes Biomolecules 2020 10 9 1320 PMC7564210 32942544
  17. [18]Kim J Lee C Shin Y Wang S Han J Kim M Kim JM Shin SC Lee BJ Kim TJ sEVs from tonsil-derived mesenchymal stromal cells alleviate activation of hepatic stellate cells and liver fibrosis through miR-486-5p Mol Ther 2021 29 4 1471 1486 33348053 PMC8058446
  18. [19]Wan Z Zhao L Lu F Gao X Dong Y Zhao Y Wei M Yang G Xing C Liu L Mononuclear phagocyte system blockade improves therapeutic exosome delivery to the myocardium Theranostics 2020 10 1 218 230 31903116 PMC6929612
  19. [20]Parada N Romero-Trujillo A Georges N Alcayaga-Miranda F Camouflage strategies for therapeutic exosomes evasion from phagocytosis J Adv Res 2021 31 61 74 34194832 PMC8240105
  20. [21]Higashi T Friedman SL Hoshida Y Hepatic stellate cells as key target in liver fibrosis Adv Drug Deliv Rev 2017 121 27 42 28506744 PMC5682243
  21. [22]Shang L Hosseini M Liu X Kisseleva T Brenner DA Human hepatic stellate cell isolation and characterization J Gastroenterol 2018 53 1 6 17 29094206
  22. [23]Terkelsen MK Bendixen SM Hansen D Scott EAH Moeller AF Nielsen R Mandrup S Schlosser A Andersen TL Sorensen GL Transcriptional dynamics of hepatic sinusoid-associated cells after liver injury Hepatology 2020 72 6 2119 2133 32145072 PMC7820956
  23. [24]Lin Y Lu Y Li X Biological characteristics of exosomes and genetically engineered exosomes for the targeted delivery of therapeutic agents J Drug Target 2020 28 2 129 141 31280623
  24. [26]Zhang J Li Y Liu Q Huang Y Li R Wu T Zhang Z Zhou J Huang H Tang Q Sirt6 alleviated liver fibrosis by deacetylating conserved lysine 54 on smad2 in hepatic stellate cells Hepatology 2021 73 3 1140 1157 32535965 PMC8048913
  25. [27]Yang W He H Wang T Su N Zhang F Jiang K Zhu J Zhang C Niu K Wang L Single-cell transcriptomic analysis reveals a hepatic stellate cell-activation roadmap and myofibroblast origin during liver fibrosis in mice Hepatology 2021 74 5 2774 2790 34089528 PMC8597108
  26. [28]Gurung S Khan F Gunassekaran GR Yoo JD Poongkavithai Vadevoo SM Permpoon U Kim SH Kim HJ Kim IS Han H Phage display-identified PD-L1-binding peptides reinvigorate T-cell activity and inhibit tumor progression Biomaterials 2020 247 119984 32278214
  27. [29]Saw PE Song EW Phage display screening of therapeutic peptide for cancer targeting and therapy Protein Cell 2019 10 11 787 807 31140150 PMC6834755
  28. [30]Wang X Chen Y Zhao Z Meng Q Yu Y Sun J Yang Z Chen Y Li J Ma T Engineered exosomes with ischemic myocardium-targeting peptide for targeted therapy in myocardial infarction J Am Heart Assoc 2018 7 15 e008737 30371236 PMC6201471
  29. [31]Bakhshinejad B Zade HM Shekarabi HS Neman S Phage display biopanning and isolation of target-unrelated peptides: in search of nonspecific binders hidden in a combinatorial library Amino Acids 2016 48 12 2699 2716 27650972
  30. [32]Lou G Chen L Xia C Wang W Qi J Li A Zhao L Chen Z Zheng M Liu Y MiR-199a-modified exosomes from adipose tissue-derived mesenchymal stem cells improve hepatocellular carcinoma chemosensitivity through mTOR pathway J Exp Clin Cancer Res 2020 39 1 4 31898515 PMC6941283
  31. [33]Chen J Huang T Liu R Wang C Jiang H Sun H Congenital microtia patients: the genetically engineered exosomes released from porous gelatin methacryloyl hydrogel for downstream small RNA profiling, functional modulation of microtia chondrocytes and tissue-engineered ear cartilage regeneration J Nanobiotechnology 2022 20 1 164 35346221 PMC8962601
  32. [34]Rong X Liu J Yao X Jiang T Wang Y Xie F Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/β-catenin pathway Stem Cell Res Ther 2019 10 1 98 30885249 PMC6421647
  33. [35]Li T Yan Y Wang B Qian H Zhang X Shen L Wang M Zhou Y Zhu W Li W Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis Stem Cells Dev 2013 22 6 845 854 23002959 PMC3585469
  34. [36]Hyun J Wang S Kim J Kim GJ Jung Y MicroRNA125b-mediated Hedgehog signaling influences liver regeneration by chorionic plate-derived mesenchymal stem cells Sci Rep 2015 5 14135 26370741 PMC4569897
  35. [37]Tian T Zhang HX He CP Fan S Zhu YL Qi C Huang NP Xiao ZD Lu ZH Tannous BA Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy Biomaterials 2018 150 137 149 29040874
  36. [38]Du K Hyun J Premont RT Choi SS Michelotti GA Swiderska-Syn M Dalton GD Thelen E Rizi BS Jung Y Hedgehog-YAP signaling pathway regulates glutaminolysis to control activation of hepatic stellate cells Gastroenterology 2018 154 5 1465 1479.e1413 29305935 PMC5880682
  37. [39]Qin L Qin J Zhen X Yang Q Huang L Curcumin protects against hepatic stellate cells activation and migration by inhibiting the CXCL12/CXCR4 biological axis in liver fibrosis: a study in vitro and in vivo Biomed Pharmacother 2018 101 599 607 29518606
  38. [41]Mastoridou EM Goussia AC Glantzounis GK Kanavaros P Charchanti AV Autophagy and exosomes: cross-regulated pathways playing major roles in hepatic stellate cells activation and liver fibrosis Front Physiol 2021 12 801340 35185602 PMC8850693
  39. [42]Guo Z Li D Peng H Kang J Jiang X Xie X Sun D Jiang H Specific hepatic stellate cell-penetrating peptide targeted delivery of a KLA peptide reduces collagen accumulation by inducing apoptosis J Drug Target 2017 25 8 715 723 28447897
  40. [43]Qiao JB Fan QQ Xing L Cui PF He YJ Zhu JC Wang L Pang T Oh YK Zhang C Vitamin A-decorated biocompatible micelles for chemogene therapy of liver fibrosis J Control Release 2018 283 113 125 29857004
  41. [45]Jeon M Kim G Lee W Baek S Jung HN Im HJ Development of theranostic dual-layered Au-liposome for effective tumor targeting and photothermal therapy J Nanobiotechnology 2021 19 1 262 34481489 PMC8418714
  42. [46]Choi J Kim G Cho SB Im HJ Radiosensitizing high-Z metal nanoparticles for enhanced radiotherapy of glioblastoma multiforme J Nanobiotechnology 2020 18 1 122 32883290 PMC7470617
  43. [48]Xi S Zheng X Li X Jiang Y Wu Y Gong J Jie Y Li Z Cao J Sha L Activated hepatic stellate cells induce infiltration and formation of CD163(+) macrophages via CCL2/CCR2 pathway Front Med (Lausanne) 2021 8 627927 33614685 PMC7893116
  44. [49]Sahin D Taflan SO Yartas G Ashktorab H Smoot DT Screening and identification of peptides specifically targeted to gastric cancer cells from a phage display peptide library Asian Pac J Cancer Prev 2018 19 4 927 932 29693344 PMC6031796
  45. [50]Zhang F Guo J Zhang Z Qian Y Wang G Duan M Zhao H Yang Z Jiang X Mesenchymal stem cell-derived exosome: a tumor regulator and carrier for targeted tumor therapy Cancer Lett 2022 526 29 40 34800567
  46. [51]Ramaraju H Miller SJ Kohn DH Dual-functioning peptides discovered by phage display increase the magnitude and specificity of BMSC attachment to mineralized biomaterials Biomaterials 2017 134 1 12 28453953 PMC5492996
  47. [52]Zhang H Wu J Wu J Fan Q Zhou J Wu J Liu S Zang J Ye J Xiao M Exosome-mediated targeted delivery of miR-210 for angiogenic therapy after cerebral ischemia in mice J Nanobiotechnology 2019 17 1 29 30782171 PMC6379944

Authors
Lin, Y., Yan, M., Bai, Z., Xie, Y., Ren, L., Wei, J., Zhu, D., Wang, H., Liu, Y., Luo, J., & Li, X.
Affiliations
  • Lanzhou University (CN)
  • First Hospital of Lanzhou University (CN)
  • South China University of Technology (CN)
  • Shanxi Medical University (CN)
Corresponding author
Li, Xun
ORCID
Venue
Journal of Nanobiotechnology
Publisher
Springer Science and Business Media LLC
Published
2022-10-01
Volume
20
Issue
1
Pages
432-432
ISSN
1477-3155 (ISSN-L)
DOI
10.1186/s12951-022-01636-x
PMC
PMC9526331
OpenAlex
W4298620989
Cited by
125
References
53
Citations by year
2026: 26 · 2025: 46 · 2024: 42 · 2023: 10 · 2022: 1
FWCI
8.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Nanobiotechnology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Natural Science Foundation of Gansu province (Grant No.21JR1RA072)
  • National Natural Science Foundation of China (82060119)
  • Health Scientific Research Plan Projects of Gansu Province (GSWSKY-2015-49)
  • Special Fund for Basic Scientific Research of Lanzhou University (lzujbky-2021-kb37)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
liver fibrosis, exosomes, mesenchymal stem cell-derived exosomes, human umbilical cord mesenchymal stem cells, activated hepatic stellate cells, targeting peptides, phage display, Lamp2b, exosome surface modification, HSC-T6 cells, exosome internalization, alpha-smooth muscle actin, nanomedicine
MeSH terms
Humans, Liver Cirrhosis, Membrane Proteins, Peptides, Umbilical Cord, Peptide Library, Hepatic Stellate Cells, Exosomes

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