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Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma

Lou, Guohua, Song, Xiuli, Yang, Fan, Wu, Shanshan, Wang, Jing, Chen, Zhi, Liu, Yanning·2015·Journal of Hematology & Oncology
DOI 10.1186/s13045-015-0220-7PMC PMC4627430
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Fig. 1 Identification of human adipose tissue-derived mesenchymal stem cells (AMSCs). a Flow cytometry analysis of the surface markers in AMSCs. b Cellular morphology of AMSCs in culture. c Oil Red O staining in AMSCs cultured in adipogenesis differentiation medium for 14 days. d Alcian Blue staining in AMSCs cultured in chondrogenesis differentiation medium for 21 days. Scale bar = 50 μm
Fig. 1 Identification of human adipose tissue-derived mesenchymal stem cells (AMSCs). a Flow cytometry analysis of the surface markers in AMSCs. b Cellular morphology of AMSCs in culture. c Oil Red O staining in AMSCs cultured in adipogenesis differentiation medium for 14 days. d Alcian Blue staining in AMSCs cultured in chondrogenesis differentiation medium for 21 days. Scale bar = 50 μmCC BY · PubMed Central
Fig. 2 Exosome-mediated miR-122 communication between AMSCs and HepG2 cells. a Western blot for CD9, CD63, and CD81 expression in AMSC-derived exosomes. b–d Real-time PCR detection of miR-122 expression in AMSCs (b), AMSC-derived exosomes (c), and exosome-treated HepG2 cells (d). e, f Confocal images of AMSC-122 stained with DilC16(3), a phospholipid membrane dye. Transfer of fluorescent exosomes from AMSC-122 is apparent in HepG2 cell membranes and cytoplasm. Data are presented as means ± SE. (*p < 0.05, n = 3). AMSC-122 miR-122-transfected AMSC, AMSC-67 cel-miR-67-transfected AMSC, Media precipitates from AMSC-conditioned media, Exo naïve AMSC-derived exosomes, 122-Exo AMSC-122-derived exosomes, 67-Exo AMSC-67-derived exosomes. Scale bar = 20 μm
Fig. 2 Exosome-mediated miR-122 communication between AMSCs and HepG2 cells. a Western blot for CD9, CD63, and CD81 expression in AMSC-derived exosomes. b–d Real-time PCR detection of miR-122 expression in AMSCs (b), AMSC-derived exosomes (c), and exosome-treated HepG2 cells (d). e, f Confocal images of AMSC-122 stained with DilC16(3), a phospholipid membrane dye. Transfer of fluorescent exosomes from AMSC-122 is apparent in HepG2 cell membranes and cytoplasm. Data are presented as means ± SE. (*p < 0.05, n = 3). AMSC-122 miR-122-transfected AMSC, AMSC-67 cel-miR-67-transfected AMSC, Media precipitates from AMSC-conditioned media, Exo naïve AMSC-derived exosomes, 122-Exo AMSC-122-derived exosomes, 67-Exo AMSC-67-derived exosomes. Scale bar = 20 μmCC BY · PubMed Central
Fig. 3 122-Exo alters miR-122-target genes expression in HepG2 cells. a mRNA expression levels of miR-122-targeted genes in HepG2 cells treated with exosomes. b Western blot analysis of miR-122-targeted genes in HepG2 cells treated with exosomes. c–e Relative protein expression levels of CCNG1, ADAM10, and IGF1R in exosome-treated HepG2 cells. Data are presented as means ± SE. (*p < 0.05, n = 3). U.T untreated, 122-Exo AMSC-122-derived exosomes, 67-Exo AMSC-67-derived exosomes
Fig. 3 122-Exo alters miR-122-target genes expression in HepG2 cells. a mRNA expression levels of miR-122-targeted genes in HepG2 cells treated with exosomes. b Western blot analysis of miR-122-targeted genes in HepG2 cells treated with exosomes. c–e Relative protein expression levels of CCNG1, ADAM10, and IGF1R in exosome-treated HepG2 cells. Data are presented as means ± SE. (*p < 0.05, n = 3). U.T untreated, 122-Exo AMSC-122-derived exosomes, 67-Exo AMSC-67-derived exosomesCC BY · PubMed Central
Fig. 4 122-Exo sensitizes HCC cells to chemotherapeutic agents. a Cell viability assay on HepG2 and Huh7 cells by combined treatment with chemotherapeutic agents and AMSC-derived exosomes. b FITC-Annexin V/PI assay in exosome-treated HCC cells after 5-FU treatment. c FC analysis for Annexin V revealed an increase in apoptotic cells in 122-Exo-treated HCC cells after 5-FU or sorafenib exposure. d, e Cell cycle analysis revealed an increase in G0/G1 population in 122-Exo-treated HepG2 cells after 5-FU or sorafenib exposure. Data are presented as means ± SE. (*p < 0.05, **p < 0.01, n = 3). U.T untreated, 122-Exo AMSC-122-derived exosomes, 67-Exo AMSC-67-derived exosomes
Fig. 4 122-Exo sensitizes HCC cells to chemotherapeutic agents. a Cell viability assay on HepG2 and Huh7 cells by combined treatment with chemotherapeutic agents and AMSC-derived exosomes. b FITC-Annexin V/PI assay in exosome-treated HCC cells after 5-FU treatment. c FC analysis for Annexin V revealed an increase in apoptotic cells in 122-Exo-treated HCC cells after 5-FU or sorafenib exposure. d, e Cell cycle analysis revealed an increase in G0/G1 population in 122-Exo-treated HepG2 cells after 5-FU or sorafenib exposure. Data are presented as means ± SE. (*p < 0.05, **p < 0.01, n = 3). U.T untreated, 122-Exo AMSC-122-derived exosomes, 67-Exo AMSC-67-derived exosomesCC BY · PubMed Central
Fig. 5 Intra-tumor injection of 122-Exo sensitizes HCC cells to sorafenib in vivo. a, b Tumor volume a and weight b measurement of HepG2 xenograft tumors at 35 days post-implantation (28 days after exosome administration combined with sorafenib treatment). c Imaging of mice at 35 days post-implantation. d, e Real-time PCR (d) and Western blot (e) analyses of miR-122-targeted gene expression in tumor samples at 35 days post-implantation. f Western blot analysis of apoptosis-related gene expression in the above tumor samples. Data are presented as means ± SE. (*p < 0.05, n = 5). Exo naïve AMSC-derived exosomes, 122-Exo AMSC-122-derived exosomes, 67-Exo AMSC-67-derived exosomes
Fig. 5 Intra-tumor injection of 122-Exo sensitizes HCC cells to sorafenib in vivo. a, b Tumor volume a and weight b measurement of HepG2 xenograft tumors at 35 days post-implantation (28 days after exosome administration combined with sorafenib treatment). c Imaging of mice at 35 days post-implantation. d, e Real-time PCR (d) and Western blot (e) analyses of miR-122-targeted gene expression in tumor samples at 35 days post-implantation. f Western blot analysis of apoptosis-related gene expression in the above tumor samples. Data are presented as means ± SE. (*p < 0.05, n = 5). Exo naïve AMSC-derived exosomes, 122-Exo AMSC-122-derived exosomes, 67-Exo AMSC-67-derived exosomesCC BY · PubMed Central
Fig. 6 Treatment with AMSC-derived exosomes alone has no effect on HCC growth in vivo. a, b Nude mice were inoculated subcutaneously with HepG2 cells. After 7 days of tumor growth, AMSC-derived exosomes were directly administered via intra-tumor injection. Tumor volume (a) and weight (b) measurement of HepG2 xenograft tumors at 35 days post-implantation (28 days after exosome administration). c Imaging of mice at 28 days after sole exosome treatment. Data are presented as means ± SE (n = 5). Exo naïve AMSC-derived exosomes, 122-Exo AMSC-122-derived exosomes, 67-Exo AMSC-67-derived exosomes
Fig. 6 Treatment with AMSC-derived exosomes alone has no effect on HCC growth in vivo. a, b Nude mice were inoculated subcutaneously with HepG2 cells. After 7 days of tumor growth, AMSC-derived exosomes were directly administered via intra-tumor injection. Tumor volume (a) and weight (b) measurement of HepG2 xenograft tumors at 35 days post-implantation (28 days after exosome administration). c Imaging of mice at 28 days after sole exosome treatment. Data are presented as means ± SE (n = 5). Exo naïve AMSC-derived exosomes, 122-Exo AMSC-122-derived exosomes, 67-Exo AMSC-67-derived exosomesCC BY · PubMed Central

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Metadata

Authors
Lou, G., Song, X., Yang, F., Wu, S., Wang, J., Chen, Z., & Liu, Y.
Venue
Journal of Hematology & Oncology
Publisher
Springer Science and Business Media LLC
Published
2015-10-29
Volume
8
Issue
1
ISSN
1756-8722
DOI
10.1186/s13045-015-0220-7
PMC
PMC4627430
Cited by
651
References
0
Language
en
Funders
  • National Natural Science Fund (81000730, 81201782)
  • International Science and Technology Cooperation Project (re-innovation industrialization) (2012C14028)
  • Medical and Health science and technology project in Zhejiang province (2014KYB085)

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