Downregulating human leucocyte antigens on mesenchymal stromal cells by epigenetically repressing a β2-microglobulin super-enhancer

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 β2-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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access

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Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS MESENCHYMAL STEM CELLS TRANSFER MITOCHONDRIA TO ALLOGENEIC TREGS IN AN HLA-DEPENDENT MANNER IMPROVING THEIR IMMUNOSUPPRESSIVE

ACTIVITY Article Open access 14 February 2022 MESENCHYMAL STROMAL CELL APOPTOSIS IS REQUIRED FOR THEIR THERAPEUTIC FUNCTION Article Open access 11 November 2021 EXTRA-HEMATOPOIETIC

IMMUNOMODULATORY ROLE OF THE GUANINE-EXCHANGE FACTOR DOCK2 Article Open access 15 November 2022 DATA AVAILABILITY The main data supporting the results in this study are available within the

article and its Supplementary Information. The RNA-seq, ChIP–seq and ATAC–seq datasets generated during the study are available from the Genome Sequence Archive for Human

(https://ngdc.cncb.ac.cn/gsa-human, HRA003235). The raw and analysed datasets generated during the study are available for research purposes from the corresponding authors on reasonable

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Download references ACKNOWLEDGEMENTS We thank Y. Huang, Y. Xing, Y. Li and J. Wang from the Core Facility, Zhejiang University School of Medicine for their technical support. We thank Y. J.

Wang from the Blood Center of Zhejiang Province for technical support. We thank J. L. Jia, W. L. Liu, L. R. Lu, X. Chen, Z. Yin, S. F. Zhang, Y. Ping, Y. Shen, Q. Sun and Y. Gu for helpful

discussions. We thank Z. J. Cai for providing the K562 cell line. H.L. discloses support for the research described in this study from the National Key Research and Development Program of

China (grant number 2023YFB3813003) and the National Natural Science Foundation of China (grant number 32371424). H.W.O. discloses support for the research described in this study from the

National Natural Science Foundation of China (grant numbers T2121004 and 92268203). X.H.Z. discloses support for the publication of this study from the Zhejiang Province Science and

Technology Innovation Talent Plan (grant number 2023R5238), the Zhejiang Province Key Research and Development Program (grant number 2023C03099) and the National Natural Science Foundation

of China (grant number 92049117). AUTHOR INFORMATION Author notes * These authors contributed equally: Fei Wang, Ran Li, Jing Yi Xu, Xiaoxia Bai. AUTHORS AND AFFILIATIONS * Department of

Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China Fei Wang, Jing Zhou, Hong Wei Ouyang & Hua Liu * Dr.

Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China Fei Wang, Jing Yi Xu, Ying Wang, Xu Ri Chen, Ke Zhou, 

Zhe Song, Shu Cheng Jin, Jing Zhou, Hong Wei Ouyang & Hua Liu * Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, Hangzhou City University School of

Medicine, Hangzhou, China Ran Li & Chen Pan * The Women’s Hospital, Zhejiang University School of Medicine and Key Laboratory of Women’s Reproduction Health of Zhejiang Province,

Hangzhou, China Xiaoxia Bai * Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China Shen Chen * Central Laboratories, Peking University School of

Stomatology, Beijing, China Boon Chin Heng * Zhejiang University–University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, China Xuewei Wu, Wei Guo & Hong Wei

Ouyang * Central laboratory, The First Affiliated Hospital School of Medicine, Zhejiang University, Hangzhou, China Xiao Hui Zou * China Orthopedic Regenerative Medicine Group (CORMed),

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Google Scholar * Hua Liu View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS H.L., H.W.O. and X.H.Z. were responsible for the conception,

supervision, interpretation and financial support of the project, and wrote the article with the assistance of all the co-authors. F.W. designed and performed the majority of the

experiments, analysed the data and prepared the figures and article. R.L. led the bioinformatic analysis and annotated the B2M-SE with cooperation from F.W., H.L. and C.P. J.Y.X. performed

the molecular experiments with assistance from S.C.J. X.X.B., Y.W. and Z.S. constructed the humanized mouse model and performed animal experiments with assistance from X.W. and W.G. X.R.C.

performed the ALI experiments with assistance from S.C. K.Z. performed the differentiation experiments of ES cells into MSCs and identified the MSCs. B.C.H. prepared the article. J.Z.

supervised the study. All authors have approved the article for submission and publication. CORRESPONDING AUTHORS Correspondence to Xiao Hui Zou, Hong Wei Ouyang or Hua Liu. ETHICS

DECLARATIONS COMPETING INTERESTS China National Intellectual Property Administration has filed for patent protection on the technology described in this study (CN113801881B and CN113846063B;

with authors H.L., F.W. and R.L). The other authors declare no competing interests. PEER REVIEW PEER REVIEW INFORMATION _Nature Biomedical Engineering_ thanks the anonymous reviewers for

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Raw data for Supplementary Fig. 4. SUPPLEMENTARY DATA 6 Raw data for Supplementary Fig. 5. SUPPLEMENTARY DATA 7 Raw data for Supplementary Fig. 6. SUPPLEMENTARY TABLE 1 List of

oligonucleotide sequences. SUPPLEMENTARY TABLE 2 Key resources list. SOURCE DATA SOURCE DATA FIG. 2 Source data. SOURCE DATA FIG. 3 Source data. SOURCE DATA FIG. 4 Source data. SOURCE DATA

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Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Wang, F., Li, R., Xu, J.Y. _et al._ Downregulating human leucocyte antigens on mesenchymal stromal cells by epigenetically

repressing a β2-microglobulin super-enhancer. _Nat. Biomed. Eng_ 8, 1682–1699 (2024). https://doi.org/10.1038/s41551-024-01264-w Download citation * Received: 01 December 2022 * Accepted: 13

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