Knockout of beta-2 microglobulin enhances cardiac repair by modulating exosome imprinting and inhibiting stem cell-induced immune rejection
Background and aims Allogeneic human umbilical mesenchymal stem cells (alloUMSC) are convenient cell source for stem cell-based therapy. However, immune rejection is a major obstacle for clinical application of alloUMSC for cardiac repair after myocardial infarction (MI). The immune rejection is due to the presence of human leukocyte antigen (HLA) class I molecule which is increased during MI. The aim of this study was to knockout HLA light chain $ β_{2} $-microglobulin (B2M) in UMSC to enhance stem cell engraftment and survival after transplantation. Methods and results We developed an innovative strategy using CRISPR/Cas9 to generate UMSC with B2M deletion ($ B2M^{–} $UMSC). AlloUMSC injection induced $ CD8^{+} $ T cell-mediated immune rejection in immune competent rats, whereas no $ CD8^{+} $ T cell-mediated killing against $ B2M^{–} $UMSC was observed even when the cells were treated with IFN-γ. Moreover, we demonstrate that UMSC-derived exosomes can inhibit cardiac fibrosis and restore cardiac function, and exosomes derived from $ B2M^{–} $UMSC are more efficient than those derived from UMSC, indicating that the beneficial effect of exosomes can be enhanced by modulating exosome’s imprinting. Mechanistically, microRNA sequencing identifies miR-24 as a major component of the exosomes from $ B2M^{–} $UMSCs. Bioinformatics analysis identifies Bim as a putative target of miR-24. Loss-of-function studies at the cellular level and gain-of-function approaches in exosomes show that the beneficial effects of $ B2M^{–} $UMSCs are mediated by the exosome/miR-24/Bim pathway. Conclusion Our findings demonstrate that modulation of exosome’s imprinting via B2M knockout is an efficient strategy to prevent the immune rejection of alloUMSCs. This study paved the way to the development of new strategies for tissue repair and regeneration without the need for HLA matching..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:77 |
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| Enthalten in: |
Cellular and molecular life sciences - 77(2019), 5 vom: 16. Juli, Seite 937-952 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shao, Lianbo [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| BKL: | |
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| Themen: |
Cytotoxicity |
| doi: |
10.1007/s00018-019-03220-3 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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SPR039014738 |
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| 520 | |a Background and aims Allogeneic human umbilical mesenchymal stem cells (alloUMSC) are convenient cell source for stem cell-based therapy. However, immune rejection is a major obstacle for clinical application of alloUMSC for cardiac repair after myocardial infarction (MI). The immune rejection is due to the presence of human leukocyte antigen (HLA) class I molecule which is increased during MI. The aim of this study was to knockout HLA light chain $ β_{2} $-microglobulin (B2M) in UMSC to enhance stem cell engraftment and survival after transplantation. Methods and results We developed an innovative strategy using CRISPR/Cas9 to generate UMSC with B2M deletion ($ B2M^{–} $UMSC). AlloUMSC injection induced $ CD8^{+} $ T cell-mediated immune rejection in immune competent rats, whereas no $ CD8^{+} $ T cell-mediated killing against $ B2M^{–} $UMSC was observed even when the cells were treated with IFN-γ. Moreover, we demonstrate that UMSC-derived exosomes can inhibit cardiac fibrosis and restore cardiac function, and exosomes derived from $ B2M^{–} $UMSC are more efficient than those derived from UMSC, indicating that the beneficial effect of exosomes can be enhanced by modulating exosome’s imprinting. Mechanistically, microRNA sequencing identifies miR-24 as a major component of the exosomes from $ B2M^{–} $UMSCs. Bioinformatics analysis identifies Bim as a putative target of miR-24. Loss-of-function studies at the cellular level and gain-of-function approaches in exosomes show that the beneficial effects of $ B2M^{–} $UMSCs are mediated by the exosome/miR-24/Bim pathway. Conclusion Our findings demonstrate that modulation of exosome’s imprinting via B2M knockout is an efficient strategy to prevent the immune rejection of alloUMSCs. This study paved the way to the development of new strategies for tissue repair and regeneration without the need for HLA matching. | ||
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| 700 | 1 | |a Zhang, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Pan, Xiangbin |e verfasserin |4 aut | |
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| 700 | 1 | |a Liang, Chun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yuqing |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yanli |e verfasserin |4 aut | |
| 700 | 1 | |a Yan, Bing |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Wenping |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Zhenya |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Xi-Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yangxin |e verfasserin |4 aut | |
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