Inducible Costimulator Gene-Transduced Bone Marrow-Derived Mesenchymal Stem Cells Attenuate the Severity of Acute Graft-Versus-Host Disease in Mouse Models
In murine allogeneic transplantation models, ICOS gene-transduced bone marrow-derived mesenchymal stem cells (MSCs ICOS-EGFP ) were evaluated for their effects on GvHD severity and long-term survival. Lethally irradiated BALB/c or first filial generation of BALB/c and C57BL/6 (CB6F1) mice were trans...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2015-09-01
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| Series: | Cell Transplantation |
| Online Access: | https://doi.org/10.3727/096368914X684592 |
| _version_ | 1818454690714615808 |
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| author | Dan Yang Li-Ping Wang Hong Zhou Hui Cheng Xiao-Chen Bao Sheng Xu Wei-Ping Zhang Jian-Min Wang |
| author_facet | Dan Yang Li-Ping Wang Hong Zhou Hui Cheng Xiao-Chen Bao Sheng Xu Wei-Ping Zhang Jian-Min Wang |
| author_sort | Dan Yang |
| collection | DOAJ |
| description | In murine allogeneic transplantation models, ICOS gene-transduced bone marrow-derived mesenchymal stem cells (MSCs ICOS-EGFP ) were evaluated for their effects on GvHD severity and long-term survival. Lethally irradiated BALB/c or first filial generation of BALB/c and C57BL/6 (CB6F1) mice were transplanted with bone marrow cells and splenocytes from C57BL/6 mice to establish acute GvHD models. Recipient mice were injected with MSCs ICOS-EGFP , MSCs, MSCs EGFP , ICOS-Ig fusion protein, MSCs + ICOS-Ig, or PBS (control group). Long-term survival, GvHD rates and severity, CD4 + T-cell apoptosis and proliferation, and Th1/Th2/ Th17 effecter cell polarization were evaluated. In the C57BL/6 → CB6F1 HSCT model, the long-term survival in the MSC ICOS-EGFP group was higher than that in the GvHD group (74.29 ± 7.39% vs. 0, p < 0.01), and this survival rate was also higher than that in the MSC, ICOS-Ig, or MSC + ICOS-Ig groups (42.86 ± 8.36%, p = 0.004; 48.57 ± 8.45%, p = 0.03; or 50.43 ± 8.45% p = 0.04, respectively). The survival advantages of MSC ICOS-EGFP -treated group were confirmed in the C57BL/6 → BALB/c HSCT model. In both HSCT models, the low mortality in the MSC ICOS-EGFP group was associated with lower incidence and severity of acute GvHD. Treatment with MSCs ICOS-EGFP induced more CD4 + T-cell apoptosis compared with that in the GvHD group. The effect on CD4 + T cells was shown as early as day 2 and maintained until day 14 ( p < 0.05 on days 2, 3, 7, and 14). Furthermore, we demonstrated that MSCs ICOS-EGFP were able to suppress Th1 and Th17 polarization and promote Th2 polarization on both protein expression and gene transcription levels. Higher serum levels of IL-4, IL-10, and lower levels of IFN-γ, IL-2, IL-12, and IL-17A were detected in the MSC ICOS-EGFP group. The MSCs ICOS-EGFP could also induce GATA-3, STAT6 expression and inhibit T-bet, STAT4, ROR-gt expression. Our results showed that injection of MSCs ICOS-EGFP is a promising strategy for acute GvHD prevention and treatment. It provides synergistic benefits of MSC immune modulation and ICOS-B7h pathway blockage. |
| first_indexed | 2024-12-14T21:58:54Z |
| format | Article |
| id | doaj.art-abb68dc12e77444b8592ab1a7df9ba60 |
| institution | Directory Open Access Journal |
| issn | 0963-6897 1555-3892 |
| language | English |
| last_indexed | 2024-12-14T21:58:54Z |
| publishDate | 2015-09-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Cell Transplantation |
| spelling | doaj.art-abb68dc12e77444b8592ab1a7df9ba602022-12-21T22:46:03ZengSAGE PublishingCell Transplantation0963-68971555-38922015-09-012410.3727/096368914X684592Inducible Costimulator Gene-Transduced Bone Marrow-Derived Mesenchymal Stem Cells Attenuate the Severity of Acute Graft-Versus-Host Disease in Mouse ModelsDan Yang0Li-Ping Wang1Hong Zhou2Hui Cheng3Xiao-Chen Bao4Sheng Xu5Wei-Ping Zhang6Jian-Min Wang7Institute of Hematology, Changhai Hospital, the Second Military Medical University, Shanghai, ChinaInstitute of Hematology, Changhai Hospital, the Second Military Medical University, Shanghai, ChinaInstitute of Hematology, Changhai Hospital, the Second Military Medical University, Shanghai, ChinaInstitute of Hematology, Changhai Hospital, the Second Military Medical University, Shanghai, ChinaInstitute of Hematology, Changhai Hospital, the Second Military Medical University, Shanghai, ChinaInstitute of Hematology, Changhai Hospital, the Second Military Medical University, Shanghai, ChinaInstitute of Hematology, Changhai Hospital, the Second Military Medical University, Shanghai, ChinaInstitute of Hematology, Changhai Hospital, the Second Military Medical University, Shanghai, ChinaIn murine allogeneic transplantation models, ICOS gene-transduced bone marrow-derived mesenchymal stem cells (MSCs ICOS-EGFP ) were evaluated for their effects on GvHD severity and long-term survival. Lethally irradiated BALB/c or first filial generation of BALB/c and C57BL/6 (CB6F1) mice were transplanted with bone marrow cells and splenocytes from C57BL/6 mice to establish acute GvHD models. Recipient mice were injected with MSCs ICOS-EGFP , MSCs, MSCs EGFP , ICOS-Ig fusion protein, MSCs + ICOS-Ig, or PBS (control group). Long-term survival, GvHD rates and severity, CD4 + T-cell apoptosis and proliferation, and Th1/Th2/ Th17 effecter cell polarization were evaluated. In the C57BL/6 → CB6F1 HSCT model, the long-term survival in the MSC ICOS-EGFP group was higher than that in the GvHD group (74.29 ± 7.39% vs. 0, p < 0.01), and this survival rate was also higher than that in the MSC, ICOS-Ig, or MSC + ICOS-Ig groups (42.86 ± 8.36%, p = 0.004; 48.57 ± 8.45%, p = 0.03; or 50.43 ± 8.45% p = 0.04, respectively). The survival advantages of MSC ICOS-EGFP -treated group were confirmed in the C57BL/6 → BALB/c HSCT model. In both HSCT models, the low mortality in the MSC ICOS-EGFP group was associated with lower incidence and severity of acute GvHD. Treatment with MSCs ICOS-EGFP induced more CD4 + T-cell apoptosis compared with that in the GvHD group. The effect on CD4 + T cells was shown as early as day 2 and maintained until day 14 ( p < 0.05 on days 2, 3, 7, and 14). Furthermore, we demonstrated that MSCs ICOS-EGFP were able to suppress Th1 and Th17 polarization and promote Th2 polarization on both protein expression and gene transcription levels. Higher serum levels of IL-4, IL-10, and lower levels of IFN-γ, IL-2, IL-12, and IL-17A were detected in the MSC ICOS-EGFP group. The MSCs ICOS-EGFP could also induce GATA-3, STAT6 expression and inhibit T-bet, STAT4, ROR-gt expression. Our results showed that injection of MSCs ICOS-EGFP is a promising strategy for acute GvHD prevention and treatment. It provides synergistic benefits of MSC immune modulation and ICOS-B7h pathway blockage.https://doi.org/10.3727/096368914X684592 |
| spellingShingle | Dan Yang Li-Ping Wang Hong Zhou Hui Cheng Xiao-Chen Bao Sheng Xu Wei-Ping Zhang Jian-Min Wang Inducible Costimulator Gene-Transduced Bone Marrow-Derived Mesenchymal Stem Cells Attenuate the Severity of Acute Graft-Versus-Host Disease in Mouse Models Cell Transplantation |
| title | Inducible Costimulator Gene-Transduced Bone Marrow-Derived Mesenchymal Stem Cells Attenuate the Severity of Acute Graft-Versus-Host Disease in Mouse Models |
| title_full | Inducible Costimulator Gene-Transduced Bone Marrow-Derived Mesenchymal Stem Cells Attenuate the Severity of Acute Graft-Versus-Host Disease in Mouse Models |
| title_fullStr | Inducible Costimulator Gene-Transduced Bone Marrow-Derived Mesenchymal Stem Cells Attenuate the Severity of Acute Graft-Versus-Host Disease in Mouse Models |
| title_full_unstemmed | Inducible Costimulator Gene-Transduced Bone Marrow-Derived Mesenchymal Stem Cells Attenuate the Severity of Acute Graft-Versus-Host Disease in Mouse Models |
| title_short | Inducible Costimulator Gene-Transduced Bone Marrow-Derived Mesenchymal Stem Cells Attenuate the Severity of Acute Graft-Versus-Host Disease in Mouse Models |
| title_sort | inducible costimulator gene transduced bone marrow derived mesenchymal stem cells attenuate the severity of acute graft versus host disease in mouse models |
| url | https://doi.org/10.3727/096368914X684592 |
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