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

Nature Biomedical Engineering volume 8, pages 1682–1699 (2024)Cite this article

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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.

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Fig. 1: Discovery of an IFNγ-responsive B2M-SE in MSCs.
Fig. 2: One-shot epigenetic repression of B2M-SE at specific sites effectively reduced the responsiveness of B2M to IFNγ.
Fig. 3: Goldilocks-level of β2m expression enabled MSCs to evade the immune responses of allogeneic T and NK cells in vitro.
Fig. 4: GLOBES barely elicited immune activation and immune memory in HSC-humanized mice.
Fig. 5: GLOBES persisted for an extended duration and exerted effective therapy in LPS-induced ALI.
Fig. 6: Schematic establishing GLOBES with immune compatibility by B2M-SE editing.

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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 request. Source data are provided with this paper.

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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).

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  1. These authors contributed equally: Fei Wang, Ran Li, Jing Yi Xu, Xiaoxia Bai.

Authors and Affiliations

  1. 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

  2. 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

  3. 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

  4. The Women’s Hospital, Zhejiang University School of Medicine and Key Laboratory of Women’s Reproduction Health of Zhejiang Province, Hangzhou, China

    Xiaoxia Bai

  5. Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China

    Shen Chen

  6. Central Laboratories, Peking University School of Stomatology, Beijing, China

    Boon Chin Heng

  7. Zhejiang University–University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, China

    Xuewei Wu, Wei Guo & Hong Wei Ouyang

  8. Central laboratory, The First Affiliated Hospital School of Medicine, Zhejiang University, Hangzhou, China

    Xiao Hui Zou

  9. China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China

    Hong Wei Ouyang

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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.

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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.

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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

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