Upregulation of IDO gene expression reduces the immunogenicity of epidermal cells and strengthens the immune protection of epidermal cells during transplantation treatment of wounds
Copyright © 2024. Published by Elsevier B.V..
BACKGROUND: Epidermal cell transplantation is a feasible treatment option for large wounds; however, sources of autologous epidermal cells are often limited. Allogeneic epidermal cells can be cultured conveniently; however, related immune rejection needs to be addressed. Herein, we hypothesized that the immunogenicity of epidermal cells with high indoleamine 2,3-dioxygenase (IDO) expression may be reduced by gene transfection.
METHODS/RESULTS: To test this hypothesis, we obtained stable transfectants by transfecting epidermal stem cells with a lentiviral vector encoding the IDO gene and screening them for puromycin resistance (a marker for successful transfection). The phenotype tested using cell counting kit -8 and Transwell assays confirmed that IDO-transfected epidermal cells maintained their characteristics. Co-culture of IDO-transfected epidermal cells with allogeneic CD4+ T cells in vitro showed that the upregulation of IDO expression in epidermal cells inhibited the proliferation of CD4+ T cells (P < 0.001, P < 0.001, and P < 0.001, respectively) and promoted their apoptosis (P = 0.00028, P = 0.0006, and P = 0.00247, respectively) and transformation into functional regulatory T cells (Tregs) (P = 0.0051, P = 0.0132, and P = 0.0248, respectively) compared with Con, NC, and 1-MT groups. The increased proportion of Tregs may be related to the overexpression of IDO, which promoted the expression of transforming growth factor beta (TGF-β) (P = 0.0001, P = 0.0013, and, P = 0.0009) and interleukin (IL) 10 (IL-10) (P = 0.0062, P = 0.0058, and P = 0.0119) while inhibited the expression of IL-2 (P = 0.0012, P = 0.0126, and P = 0.0066). We further verified these effects in vivo as transplanted IDO-transfected epidermal stem cells were effective in treating wounds in mice. On days 5 and 7, wounds treated with IDO cells healed faster than those in the other groups (day 5: P = 0.012 and P = 0.0136; day 7: P = 0.0242 and P = 0.0187, respectively), whereas this effect was significantly inhibited by 1-methyltryptophan (1-MT) (day 5: P = 0.0303; day 7: P = 0.0105). Immunofluorescence staining detected IDO and CD4+ Foxp3+ Tregs in the transplanted wounds, which may promote Foxp3+ Tregs in the wound tissue (day 5: P < 0.0001, P < 0.0001, and P < 0.0001; day 7: P < 0.0001, P < 0.0001, and P < 0.0001), respectively) and decrease CD4+ T cells (day 5: P < 0.0001, P < 0.0001, and P < 0.0001; day 7: P < 0.0001, P < 0.0001, and P < 0.0001).
CONCLUSION: Our results suggest that the upregulation of IDO expression in epidermal stem cells can reduce their immunogenicity by promoting Tregs, thus inducing the immune protection of epidermal stem cells.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:82 |
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| Enthalten in: |
Transplant immunology - 82(2024) vom: 08. Feb., Seite 101987 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Kun [VerfasserIn] |
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| Links: |
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| Themen: |
Epidermal cells |
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| Anmerkungen: |
Date Completed 29.01.2024 Date Revised 06.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.trim.2024.101987 |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Upregulation of IDO gene expression reduces the immunogenicity of epidermal cells and strengthens the immune protection of epidermal cells during transplantation treatment of wounds |
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| 500 | |a Date Revised 06.03.2024 | ||
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| 520 | |a Copyright © 2024. Published by Elsevier B.V. | ||
| 520 | |a BACKGROUND: Epidermal cell transplantation is a feasible treatment option for large wounds; however, sources of autologous epidermal cells are often limited. Allogeneic epidermal cells can be cultured conveniently; however, related immune rejection needs to be addressed. Herein, we hypothesized that the immunogenicity of epidermal cells with high indoleamine 2,3-dioxygenase (IDO) expression may be reduced by gene transfection | ||
| 520 | |a METHODS/RESULTS: To test this hypothesis, we obtained stable transfectants by transfecting epidermal stem cells with a lentiviral vector encoding the IDO gene and screening them for puromycin resistance (a marker for successful transfection). The phenotype tested using cell counting kit -8 and Transwell assays confirmed that IDO-transfected epidermal cells maintained their characteristics. Co-culture of IDO-transfected epidermal cells with allogeneic CD4+ T cells in vitro showed that the upregulation of IDO expression in epidermal cells inhibited the proliferation of CD4+ T cells (P < 0.001, P < 0.001, and P < 0.001, respectively) and promoted their apoptosis (P = 0.00028, P = 0.0006, and P = 0.00247, respectively) and transformation into functional regulatory T cells (Tregs) (P = 0.0051, P = 0.0132, and P = 0.0248, respectively) compared with Con, NC, and 1-MT groups. The increased proportion of Tregs may be related to the overexpression of IDO, which promoted the expression of transforming growth factor beta (TGF-β) (P = 0.0001, P = 0.0013, and, P = 0.0009) and interleukin (IL) 10 (IL-10) (P = 0.0062, P = 0.0058, and P = 0.0119) while inhibited the expression of IL-2 (P = 0.0012, P = 0.0126, and P = 0.0066). We further verified these effects in vivo as transplanted IDO-transfected epidermal stem cells were effective in treating wounds in mice. On days 5 and 7, wounds treated with IDO cells healed faster than those in the other groups (day 5: P = 0.012 and P = 0.0136; day 7: P = 0.0242 and P = 0.0187, respectively), whereas this effect was significantly inhibited by 1-methyltryptophan (1-MT) (day 5: P = 0.0303; day 7: P = 0.0105). Immunofluorescence staining detected IDO and CD4+ Foxp3+ Tregs in the transplanted wounds, which may promote Foxp3+ Tregs in the wound tissue (day 5: P < 0.0001, P < 0.0001, and P < 0.0001; day 7: P < 0.0001, P < 0.0001, and P < 0.0001), respectively) and decrease CD4+ T cells (day 5: P < 0.0001, P < 0.0001, and P < 0.0001; day 7: P < 0.0001, P < 0.0001, and P < 0.0001) | ||
| 520 | |a CONCLUSION: Our results suggest that the upregulation of IDO expression in epidermal stem cells can reduce their immunogenicity by promoting Tregs, thus inducing the immune protection of epidermal stem cells | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Epidermal cells | |
| 650 | 4 | |a Immune protection | |
| 650 | 4 | |a Indoleamine 2,3-dioxygenase(IDO) | |
| 650 | 7 | |a Forkhead Transcription Factors |2 NLM | |
| 650 | 7 | |a Indoleamine-Pyrrole 2,3,-Dioxygenase |2 NLM | |
| 700 | 1 | |a Liu, Xinzhu |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zhisheng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Hongqing |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Dawei |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zhaoxing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Bohan |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Chuanan |e verfasserin |4 aut | |
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