Downregulating human leucocyte antigens on mesenchymal stromal cells by epigenetically repressing a β2-microglobulin super-enhancer
Immune rejection caused by mismatches in human leucocyte antigens (HLAs) remains a major obstacle to the success of allogeneic cell therapies. Current strategies for the generation of ‘universal’ immune-compatible cells, particularly the editing of HLA class I (HLA-I) genes or the modulation of prot...
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| Veröffentlicht in: | Nature biomedical engineering 2024-12, Vol.8 (12), p.1682-1699 |
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| creator | Wang, Fei Li, Ran Xu, Jing Yi Bai, Xiaoxia Wang, Ying Chen, Xu Ri Pan, Chen Chen, Shen Zhou, Ke Heng, Boon Chin Wu, Xuewei Guo, Wei Song, Zhe Jin, Shu Cheng Zhou, Jing Zou, Xiao Hui Ouyang, Hong Wei Liu, Hua |
| description | Immune rejection caused by mismatches in human leucocyte antigens (HLAs) remains a major obstacle to the success of allogeneic cell therapies. Current strategies for the generation of ‘universal’ immune-compatible cells, particularly the editing of HLA class I (HLA-I) genes or the modulation of proteins that inhibit natural killer cells, often result in genomic instability or cellular cytotoxicity. Here we show that a β
2
-microglobulin super-enhancer (B2M-SE) that is responsive to interferon-γ is a critical regulator of the expression of HLA-I on mesenchymal stromal cells (MSCs). Targeted epigenetic repression of B2M-SE in MSCs reduced the surface expression of HLA-I below the threshold required to activate allogenic T cells while maintaining levels sufficient to evade cytotoxicity mediated by natural killer cells. In a humanized mouse model, the epigenetically edited MSCs demonstrated improved survival by evading the immune system, allowing them to exert enhanced therapeutic effects on LPS-induced acute lung injury. Targeted epigenetic repression of B2M-SE may facilitate the development of off-the-shelf cell sources for allogeneic cell therapy.
The targeted epigenetic repression of a β
2
-microglobulin super-enhancer downregulates the expression of human leucocyte antigens on mesenchymal stromal cells, making the cells suitable for allogeneic cell therapy. |
| doi_str_mv | 10.1038/s41551-024-01264-w |
| format | Article |
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2
-microglobulin super-enhancer (B2M-SE) that is responsive to interferon-γ is a critical regulator of the expression of HLA-I on mesenchymal stromal cells (MSCs). Targeted epigenetic repression of B2M-SE in MSCs reduced the surface expression of HLA-I below the threshold required to activate allogenic T cells while maintaining levels sufficient to evade cytotoxicity mediated by natural killer cells. In a humanized mouse model, the epigenetically edited MSCs demonstrated improved survival by evading the immune system, allowing them to exert enhanced therapeutic effects on LPS-induced acute lung injury. Targeted epigenetic repression of B2M-SE may facilitate the development of off-the-shelf cell sources for allogeneic cell therapy.
The targeted epigenetic repression of a β
2
-microglobulin super-enhancer downregulates the expression of human leucocyte antigens on mesenchymal stromal cells, making the cells suitable for allogeneic cell therapy.</description><identifier>ISSN: 2157-846X</identifier><identifier>EISSN: 2157-846X</identifier><identifier>DOI: 10.1038/s41551-024-01264-w</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/100 ; 13/105 ; 13/107 ; 13/31 ; 13/51 ; 13/89 ; 14/1 ; 14/19 ; 14/5 ; 14/63 ; 38/23 ; 38/39 ; 38/77 ; 38/91 ; 42/109 ; 42/41 ; 45/41 ; 631/1647/1511 ; 631/532/2074 ; 631/61/2320 ; 64/60 ; Antigens ; Biocompatibility ; Biomedical and Life Sciences ; Biomedical Engineering/Biotechnology ; Biomedicine ; Cell survival ; Cell therapy ; Cytotoxicity ; Epigenetics ; Genomic instability ; Histocompatibility antigen HLA ; Immune system ; Leukocytes ; Lymphocytes ; Lymphocytes T ; Mesenchymal stem cells ; Natural killer cells ; Stromal cells ; Toxicity ; β2 Microglobulin ; γ-Interferon</subject><ispartof>Nature biomedical engineering, 2024-12, Vol.8 (12), p.1682-1699</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2024 Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>Copyright Nature Publishing Group Dec 2024</rights><rights>2024. The Author(s), under exclusive licence to Springer Nature Limited.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c233t-e1a2e426e35d658ab2ba908587ef072b1fa8f41b50bd2a549a39fa3fea7fa36b3</cites><orcidid>0000-0002-0922-4209 ; 0000-0002-2226-2613 ; 0000-0001-9563-0301 ; 0000-0001-6712-3468 ; 0000-0001-7729-1246</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41551-024-01264-w$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41551-024-01264-w$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,778,782,27907,27908,41471,42540,51302</link.rule.ids></links><search><creatorcontrib>Wang, Fei</creatorcontrib><creatorcontrib>Li, Ran</creatorcontrib><creatorcontrib>Xu, Jing Yi</creatorcontrib><creatorcontrib>Bai, Xiaoxia</creatorcontrib><creatorcontrib>Wang, Ying</creatorcontrib><creatorcontrib>Chen, Xu Ri</creatorcontrib><creatorcontrib>Pan, Chen</creatorcontrib><creatorcontrib>Chen, Shen</creatorcontrib><creatorcontrib>Zhou, Ke</creatorcontrib><creatorcontrib>Heng, Boon Chin</creatorcontrib><creatorcontrib>Wu, Xuewei</creatorcontrib><creatorcontrib>Guo, Wei</creatorcontrib><creatorcontrib>Song, Zhe</creatorcontrib><creatorcontrib>Jin, Shu Cheng</creatorcontrib><creatorcontrib>Zhou, Jing</creatorcontrib><creatorcontrib>Zou, Xiao Hui</creatorcontrib><creatorcontrib>Ouyang, Hong Wei</creatorcontrib><creatorcontrib>Liu, Hua</creatorcontrib><title>Downregulating human leucocyte antigens on mesenchymal stromal cells by epigenetically repressing a β2-microglobulin super-enhancer</title><title>Nature biomedical engineering</title><addtitle>Nat. Biomed. Eng</addtitle><description>Immune rejection caused by mismatches in human leucocyte antigens (HLAs) remains a major obstacle to the success of allogeneic cell therapies. Current strategies for the generation of ‘universal’ immune-compatible cells, particularly the editing of HLA class I (HLA-I) genes or the modulation of proteins that inhibit natural killer cells, often result in genomic instability or cellular cytotoxicity. Here we show that a β
2
-microglobulin super-enhancer (B2M-SE) that is responsive to interferon-γ is a critical regulator of the expression of HLA-I on mesenchymal stromal cells (MSCs). Targeted epigenetic repression of B2M-SE in MSCs reduced the surface expression of HLA-I below the threshold required to activate allogenic T cells while maintaining levels sufficient to evade cytotoxicity mediated by natural killer cells. In a humanized mouse model, the epigenetically edited MSCs demonstrated improved survival by evading the immune system, allowing them to exert enhanced therapeutic effects on LPS-induced acute lung injury. Targeted epigenetic repression of B2M-SE may facilitate the development of off-the-shelf cell sources for allogeneic cell therapy.
The targeted epigenetic repression of a β
2
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Li, Ran ; Xu, Jing Yi ; Bai, Xiaoxia ; Wang, Ying ; Chen, Xu Ri ; Pan, Chen ; Chen, Shen ; Zhou, Ke ; Heng, Boon Chin ; Wu, Xuewei ; Guo, Wei ; Song, Zhe ; Jin, Shu Cheng ; Zhou, Jing ; Zou, Xiao Hui ; Ouyang, Hong Wei ; Liu, Hua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c233t-e1a2e426e35d658ab2ba908587ef072b1fa8f41b50bd2a549a39fa3fea7fa36b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>13/100</topic><topic>13/105</topic><topic>13/107</topic><topic>13/31</topic><topic>13/51</topic><topic>13/89</topic><topic>14/1</topic><topic>14/19</topic><topic>14/5</topic><topic>14/63</topic><topic>38/23</topic><topic>38/39</topic><topic>38/77</topic><topic>38/91</topic><topic>42/109</topic><topic>42/41</topic><topic>45/41</topic><topic>631/1647/1511</topic><topic>631/532/2074</topic><topic>631/61/2320</topic><topic>64/60</topic><topic>Antigens</topic><topic>Biocompatibility</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical Engineering/Biotechnology</topic><topic>Biomedicine</topic><topic>Cell survival</topic><topic>Cell therapy</topic><topic>Cytotoxicity</topic><topic>Epigenetics</topic><topic>Genomic instability</topic><topic>Histocompatibility antigen HLA</topic><topic>Immune system</topic><topic>Leukocytes</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Mesenchymal stem cells</topic><topic>Natural killer cells</topic><topic>Stromal cells</topic><topic>Toxicity</topic><topic>β2 Microglobulin</topic><topic>γ-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Fei</creatorcontrib><creatorcontrib>Li, Ran</creatorcontrib><creatorcontrib>Xu, Jing Yi</creatorcontrib><creatorcontrib>Bai, Xiaoxia</creatorcontrib><creatorcontrib>Wang, Ying</creatorcontrib><creatorcontrib>Chen, Xu Ri</creatorcontrib><creatorcontrib>Pan, Chen</creatorcontrib><creatorcontrib>Chen, Shen</creatorcontrib><creatorcontrib>Zhou, Ke</creatorcontrib><creatorcontrib>Heng, Boon Chin</creatorcontrib><creatorcontrib>Wu, Xuewei</creatorcontrib><creatorcontrib>Guo, Wei</creatorcontrib><creatorcontrib>Song, Zhe</creatorcontrib><creatorcontrib>Jin, Shu Cheng</creatorcontrib><creatorcontrib>Zhou, Jing</creatorcontrib><creatorcontrib>Zou, Xiao Hui</creatorcontrib><creatorcontrib>Ouyang, Hong Wei</creatorcontrib><creatorcontrib>Liu, Hua</creatorcontrib><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Nature biomedical engineering</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Fei</au><au>Li, Ran</au><au>Xu, Jing Yi</au><au>Bai, Xiaoxia</au><au>Wang, Ying</au><au>Chen, Xu Ri</au><au>Pan, Chen</au><au>Chen, Shen</au><au>Zhou, Ke</au><au>Heng, Boon Chin</au><au>Wu, Xuewei</au><au>Guo, Wei</au><au>Song, Zhe</au><au>Jin, Shu Cheng</au><au>Zhou, Jing</au><au>Zou, Xiao Hui</au><au>Ouyang, Hong Wei</au><au>Liu, Hua</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Downregulating human leucocyte antigens on mesenchymal stromal cells by epigenetically repressing a β2-microglobulin super-enhancer</atitle><jtitle>Nature biomedical engineering</jtitle><stitle>Nat. Biomed. Eng</stitle><date>2024-12-01</date><risdate>2024</risdate><volume>8</volume><issue>12</issue><spage>1682</spage><epage>1699</epage><pages>1682-1699</pages><issn>2157-846X</issn><eissn>2157-846X</eissn><abstract>Immune rejection caused by mismatches in human leucocyte antigens (HLAs) remains a major obstacle to the success of allogeneic cell therapies. Current strategies for the generation of ‘universal’ immune-compatible cells, particularly the editing of HLA class I (HLA-I) genes or the modulation of proteins that inhibit natural killer cells, often result in genomic instability or cellular cytotoxicity. Here we show that a β
2
-microglobulin super-enhancer (B2M-SE) that is responsive to interferon-γ is a critical regulator of the expression of HLA-I on mesenchymal stromal cells (MSCs). Targeted epigenetic repression of B2M-SE in MSCs reduced the surface expression of HLA-I below the threshold required to activate allogenic T cells while maintaining levels sufficient to evade cytotoxicity mediated by natural killer cells. In a humanized mouse model, the epigenetically edited MSCs demonstrated improved survival by evading the immune system, allowing them to exert enhanced therapeutic effects on LPS-induced acute lung injury. Targeted epigenetic repression of B2M-SE may facilitate the development of off-the-shelf cell sources for allogeneic cell therapy.
The targeted epigenetic repression of a β
2
-microglobulin super-enhancer downregulates the expression of human leucocyte antigens on mesenchymal stromal cells, making the cells suitable for allogeneic cell therapy.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><doi>10.1038/s41551-024-01264-w</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0002-0922-4209</orcidid><orcidid>https://orcid.org/0000-0002-2226-2613</orcidid><orcidid>https://orcid.org/0000-0001-9563-0301</orcidid><orcidid>https://orcid.org/0000-0001-6712-3468</orcidid><orcidid>https://orcid.org/0000-0001-7729-1246</orcidid></addata></record> |
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| subjects | 13/100 13/105 13/107 13/31 13/51 13/89 14/1 14/19 14/5 14/63 38/23 38/39 38/77 38/91 42/109 42/41 45/41 631/1647/1511 631/532/2074 631/61/2320 64/60 Antigens Biocompatibility Biomedical and Life Sciences Biomedical Engineering/Biotechnology Biomedicine Cell survival Cell therapy Cytotoxicity Epigenetics Genomic instability Histocompatibility antigen HLA Immune system Leukocytes Lymphocytes Lymphocytes T Mesenchymal stem cells Natural killer cells Stromal cells Toxicity β2 Microglobulin γ-Interferon |
| title | Downregulating human leucocyte antigens on mesenchymal stromal cells by epigenetically repressing a β2-microglobulin super-enhancer |
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