Generation of hypoimmunogenic human pluripotent stem cells
Open accessAbstract
Significance: To enable cell therapy on a broader scale, the development of universal donor stem cell products that can be administered to multiple patients in need has been proposed, yet a strategy controlling both adaptive and innate immune rejection has not been reported. In this study, we employed multiplex genome editing to selectively ablate the highly polymorphic HLA class Ia and class II molecules and introduced the immunoregulatory factors PD-L1, HLA-G, and CD47 to control T cell- and NK cell-mediated immune responses and macrophage engulfment in vitro and in vivo. Our strategy demonstrates the power of cell engineering and informs future studies aiming to generate “off-the-shelf” universal cell products that may make cell therapy available to a larger pool of patients.
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hPSCs with CRISPR/Cas9 removal of HLA-A, B, and C and CIITA, and overexpression of PD-L1, HLA-G, and CD47, differentiated into endothelial cells or vascular smooth muscle cells and demonstrated improved survival in co-cultures with T-cells, NK cells, and macrophages.
“These cells could be differentiated into endothelial cells or vascular smooth muscle cells and demonstrated improved survival in co-cultures with T-cells, NK cells, and macrophages.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [119]
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Genetically engineered hypoimmunogenic cell therapy
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Generation of universal and hypoimmunogenic human pluripotent stem cells
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“The cytotoxicity assay using HLA-reactive CD8 + T cells was performed according to published literature [10].”
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“Several groups have employed genetic engineering to alter the expression of key immune genes on stem cell-derived tissues, including polymorphic HLA molecules and immune checkpoint inhibitors to evade allo-genic immune rejection 29,30,43–45 to overcome immune rejection.”
Self-citationBogomiakova, M., Sekretova, E. K., Anufrieva, K. S., Khabarova, P. O., Kazakova, A. N., Bobrovsky, P. A., Grigoryeva, T. V., Eremeev, A., Lebedeva, O., Bogomazova, A., et al. (2023) · Stem cell research & therapeutics · doi:10.1186/s13287-023-03308-5 · Cited by 36 · see citing works
“The vascular smooth muscle cells (VSMCs) derived from HLA-ABC−/− ESCs triggered degranulation and NK-cell-mediated cytotoxicity to the same extent as wild-type VSMCs [23].”
BackgroundInfluentialGaykema, L., van Nieuwland, R. V., Dekkers, M. C., van Essen, M. V., Heidt, S., Zaldumbide, A., van den Berg, C. W., Rabelink, T., & van Kooten, C. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1058763 · Cited by 36 · see citing works
Macrophages derived from pluripotent stem cells: prospective applications and research gaps
Lyadova, I. V., & Vasiliev, A. V. (2022) · Cell & Bioscience · doi:10.1186/s13578-022-00824-4 · Cited by 37 · see citing works
Human iPSCs and Genome Editing Technologies for Precision Cardiovascular Tissue Engineering
Gähwiler, E. K. N., Motta, S. E., Martin, M., Nugraha, B., Hoerstrup, S. P., & Emmert, M. Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.639699 · Cited by 42 · see citing works
Lu, Z., Yao, X., Lyu, P., Yadav, M., Yoo, K. W., Atala, A., & Lu, B. (2021) · The CRISPR Journal · doi:10.1089/crispr.2020.0106 · Cited by 31 · see citing works
Tsai, H., Kao, H., Kuo, M.-W., Lin, C., Chang, C.-M., Chen, Y., Chen, H., Kwok, P., Yu, A. L.-T., & Yu, J. (2023) · Nature Communications · doi:10.1038/s41467-023-40901-x · Cited by 34 · see citing works
“Recently,severalstudiesshowedthathuman iPSCs lost immunogenicity when MHC class I and II genes were inactivated, and CD47 was overexpressed by CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9) genome editing 7 – 10 .”
BackgroundModeling human T1D-associated autoimmune processes
Maharlooei, M. K., Madley, R., Borsotti, C., Ferreira, L. M. R., Sharp, R. C., Brehm, M. A., Greiner, D. L., Parent, A. V., Anderson, M. S., Sykes, M., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101417 · Cited by 42 · see citing works
Self-citationImmune Editing: Overcoming Immune Barriers in Stem Cell Transplantation
Meissner, T. B., Schulze, H. S., & Dale, S. M. (2022) · Current Stem Cell Reports · doi:10.1007/s40778-022-00221-0 · Cited by 39 · see citing works
Self-citationType 1 diabetes and engineering enhanced islet transplantation
Jeyagaran, A., Lu, C., Zbinden, A., Birkenfeld, A. L., Brucker, S. Y., & Layland, S. L. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114481 · Cited by 41 · see citing works
Generation of hypoimmunogenic universal iPS cells through HLA-type gene knockout
Kim, J., Nam, Y., Jeon, D., Choi, Y., Choi, S., Hong, C. P., Kim, S., Jung, H., Park, N., Sohn, Y., et al. (2025) · Experimental and Molecular Medicine · doi:10.1038/s12276-025-01422-3 · Cited by 32 · see citing works
“2b – d).”
Feng, L., Chao, J.-F., Ye, P., Luong, Q., Sun, G.-Q., Liu, W., Cui, Q., Flores, S., Jackson, N., Shayento, A. N. H., et al. (2023) · Advancement of science · doi:10.1002/advs.202206910 · Cited by 32 · see citing works
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“However, single knockins were only partially effective, and further studies proposed to combine the above strategies, knocking in HLA-G, PD-L1, and CD47 in an MHC-I-null stem cell line (Han et al., 2019).”
BackgroundLi, Y., Wu, Y. P., Federzoni, E. A., Wang, X., Dharmawan, A., Hu, X., Wang, H., Hawley, R. J., Stevens, S. G., Sykes, M., et al. (2022) · eLife · doi:10.7554/elife.73677 · Cited by 36 · see citing works
“More recently, transgenic overexpression of CD47 was also applied for reducing allogenicity and generating hypoimmunogenic pluripotent stem cells (Han et al., 2019, Deuse et al., 2019).”
BackgroundMethodInfluentialGenetic Engineering of Immune Evasive Stem Cell-Derived Islets
Sackett, S. D., Kaplan, S. J., Mitchell, S. A., Brown, M. E., Burrack, A. L., Grey, S., Huangfu, D., & Odorico, J. (2022) · Transplant International · doi:10.3389/ti.2022.10817 · Cited by 32 · see citing works
“To this end, Gornalusse et al. developed a B2MHLA-E (a minimally polymorphic) fusion protein after complete B2M deletion in hPSCs (38) while Shi et al. similarly expressed a B2M-HLA-G fusion construct to stabilize theMHC and allow cell surface expression in B2M KO hPSC cells and showed hypoimmunogenicity and reduced N…”
BackgroundInfluentialNetsrithong, R., García-Pérez, L., & Themeli, M. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1325209 · Cited by 33 · see citing works
Cell therapy for liver disorders: past, present and future
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Modulation of Stem Cells as Therapeutics for Severe Mental Disorders and Cognitive Impairments
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“Universal donor cells or hypoimmunogenic cells, a promising solution, come from pluripotent PSC and differentiate into various cell types that are ready for being tested against a vast number of chronic and genetic diseases (58).”
BackgroundCell therapy for type 1 diabetes
Loretelli, C., Assi, E., Seelam, A., Nasr, M. B., & Fiorina, P. (2020) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2020.1748596 · Cited by 29 · see citing works
Update on islet cell transplantation
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How to repair a broken heart with pluripotent stem cell-derived cardiomyocytes
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Chen, Y., Zhu, Y., Kramer, A. B., Fang, Y., Wilson, M., Li, Y.-R., & Yang, L. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1135468 · Cited by 26 · see citing works
“Current pre-clinical and clinical research has focused on HSCs and iPSCs as the initial source for engineered allogeneic cell products.”
BackgroundInfluentialSelvakumar, D., Reyes, L., & Chong, J. J. H. (2022) · Current Cardiology Reports · doi:10.1007/s11886-022-01666-9 · Cited by 28 · see citing works
Ho, B. X., Teo, A. K. K., & Ng, N. H. J. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1375177 · Cited by 32 · see citing works
“( (93) and primary human islets (85) resulted in ablation of cytotoxic CD8 + and CD4 + helper T cell responses.”
BackgroundInfluentialFurukawa, Y., Ishii, M., Ando, J., Ikeda, K., Igarashi, K. J., Kinoshita, S., Azusawa, Y., Toyota, T., Honda, T., Nakanishi, M., et al. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101327 · Cited by 25 · see citing works
“25 To study NK cell responses in detail, we used HPV-rejTs and overexpressed HLA-A24, which is found in several populations around the world.”
BackgroundMethodInfluentialChallenges and perspectives of tendon-derived cell therapy for tendinopathy: from bench to bedside
Chen, Z., Chen, P., Zheng, M., Gao, J., Liu, D., Wang, P. A., Zheng, Q., Leys, T., Tai, A. C. P., & Zheng, M. (2022) · Stem Cell Research & Therapy · doi:10.1186/s13287-022-03113-6 · Cited by 30 · see citing works
“IPSCs can become hypoimmunogenic by knocking out of B2M, HLA subtypes or/and overexpression of CD47 [202, 203], as these strategies could affect the antigen presentation to T cells and trigger T cell response and thus lead to the surface-epitope masking.”
BackgroundPavan, C., Davidson, K. C., Payne, N. L., Frausin, S., Hunt, C. J., Moriarty, N., Rubio, M. Á. B., Elahi, Z., Quattrocchi, A. T., Abu-Bonsrah, K. D., et al. (2025) · Cell stem cell · doi:10.1016/j.stem.2025.03.008 · Cited by 24 · see citing works
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Universal cell donor lines: A review of the current research
Simpson, A., Hewitt, A. W., & Fairfax, K. A. (2023) · Stem Cell Reports · doi:10.1016/j.stemcr.2023.09.010 · Cited by 24 · see citing works
The need for more research into reproductive health and disease
Mercuri, N., & Cox, B. (2022) · eLife · doi:10.7554/elife.75061 · Cited by 24 · see citing works
“In regenerative medicine, the immune-modulating genes used by the placenta ( Szekeres-Bartho, 2002 ) are repurposed to generate universally trans-plantable stem cells and tissues ( Han et al., 2019 ).”
Karpov, D. S., Sosnovtseva, A. O., Pylina, S. V., Bastrich, A., Petrova, D. A., Kovalev, M. A., Shuvalova, A. I., Константиновна, Е. А., & Mokrysheva, N. G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417320 · Cited by 29 · see citing works
“The efficient insertion and expression of transgenes is achieved using different approaches: lentiviral particle [117,231], transposon [176], recombining AAV [114], and CRISPR/Cas9 [121,128,169].”
BackgroundMethodGaykema, L., van Nieuwland, R. V., Lievers, E., Moerkerk, W. B. J., de Klerk, J. A., Dumas, S. J., Kers, J., Zaldumbide, A., van den Berg, C. W., & Rabelink, T. (2023) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szad069 · Cited by 23 · see citing works
“40 This can be prevented by selective maintenance of certain HLA subtypes, especially HLA-C, 25 induced expression of minimally polymorphic HLA molecules, 26,43,51 or induced expression of an inhibitory ligand such as CD47.”
Dashnau, J. L., Xue, Q., Nelson, M., Law, E., Cao, L., & Hei, D. J. (2022) · Cytotherapy · doi:10.1016/j.jcyt.2022.08.001 · Cited by 30 · see citing works
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Gene editing in dermatology: Harnessing CRISPR for the treatment of cutaneous disease
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- Authors
- Han, X., Wang, M., Duan, S., Franco, P. J., Kenty, J. H.-R., Hedrick, P., Xia, Y., Allen, A., Ferreira, L. M. R., Strominger, J. L., Melton, D. A., Meissner, T. B., & Cowan, C. A.
- Affiliations
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- Broad Institute (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-04-30
- Volume
- 116
- Issue
- 21
- Pages
- 10441-10446
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6535035
- OpenAlex
- W2943378944
- Cited by
- 363
- References
- 0
- Citations by year
- 2026: 45 · 2025: 52 · 2024: 49 · 2023: 62 · 2022: 58 · 2021: 53 · 2020: 34 · 2019: 10
- FWCI
- 12.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Harvard University | Harvard Stem Cell Institute (DP-0155-16-00)
- Blavatnik Biomedical Accelerator (no number)
- JDRF (3-SRA-2017-363-S-B)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Keywords
- human pluripotent stem cells, multiplex genome editing, PD-L1, HLA-G, CD47, macrophage engulfment, cell therapy
- MeSH terms
- Cell Line, Genes, MHC Class II, Genes, MHC Class I, Genetic Engineering, Humans, Pluripotent Stem Cells, Gene Knockout Techniques, CRISPR-Cas Systems
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