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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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“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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Cited by
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Design Approaches for Generating Organ Constructs
Xia, Y. F., & Belmonte, J. C. I. (2019) · Cell stem cell · doi:10.1016/j.stem.2019.05.016 · Cited by 32
Self-citationFang, M., Allen, A. G., Luo, C., & Finn, J. D. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1457629 · Cited by 26
“An alternative approach to avoid CD8+ T cell HvG while minimizing the induction of NK “ missing-self ” is to speci fi cally delete the HLA-A, HLA-B, and HLA-C genes while leaving B2M and HLA-E intact to engage NKG2A on patient NK cells (72).”
BackgroundSelf-citationIsenberg, J. S., & Montero, E. (2024) · Clinical and Translational Medicine · doi:10.1002/ctm2.1584 · Cited by 31
Zheng, Y., Gallegos, C. M., Xue, H., Li, S., Kim, D., Zhou, H., Xia, X., Liu, Y., & Cao, Q. (2022) · Cells · doi:10.3390/cells11172765 · Cited by 31
The progress of pluripotent stem cell-derived pancreatic β-cells regeneration for diabetic therapy
Wang, X., Gao, M., Wang, Y., & Zhang, Y. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.927324 · Cited by 20
“The emergence of CRISPRCas9 also revolutionizes the field by ablating HLA-A/-B/-C and HLA class II in PSCs to generate immune tolerant b-cells (98).”
BackgroundAdvances in Adoptive Cell Therapy Using Induced Pluripotent Stem Cell-Derived T Cells
Netsrithong, R., & Wattanapanitch, M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.759558 · Cited by 24
Gheibi, S., Singh, T., da Cunha, J. P. M. C. M., Fex, M., & Mulder, H. (2020) · Cells · doi:10.3390/cells9112465 · Cited by 29
“In addition, the CRISPR-Cas9 system for gene editing enables the ablation of the highly polymorphic HLA class I and class II molecules, as well as expressing immunomodulatory factors, such as PD-L1, HLA-G, and CD47 [253,254].”
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“To prevent NK cell mediated rejection, some groups expressed HLAE or HLA-G in B2M knockout iPSC.(103,105) In addition, immune checkpoint PD-L1 and macrophage “don’t-eat me” signal CD47 were employed to create universal and hypoimmunogenic hiPSCs.”
BackgroundEngineering human pluripotent stem cell lines to evade xenogeneic transplantation barriers
Pizzato, H. A., Alonso‐Guallart, P., Woods, J., Jóhannesson, B., Connelly, J. P., Fehniger, T. A., Atkinson, J. P., Pruett‐Miller, S. M., Monsma, F. J., & Bhattacharya, D. (2024) · Stem Cell Reports · doi:10.1016/j.stemcr.2023.12.003 · Cited by 28
Chen, Y., Zhou, Y., Zhou, Z., Fang, Y., Ma, L., Zhang, X., Xiong, J., & Liu, L. (2023) · Stem Cell Research & Therapy · doi:10.1186/s13287-022-03233-z · Cited by 22
Inducible Pluripotent Stem Cells as a Potential Cure for Diabetes
Verhoeff, K. K., Henschke, S., Marfil‐Garza, B. A., Dadheech, N., & Shapiro, A. M. J. (2021) · Cells · doi:10.3390/cells10020278 · Cited by 34
Human pluripotent stem cells: A toolbox to understand and treat retinal degeneration
Morizur, L., Herardot, E., Monville, C., & M’Barek, K. B. (2020) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2020.103523 · Cited by 29
Chen, S., Wang, W., Shen, L., Liu, H., Luo, J. C., Ren, Y., Cui, S., Ye, Y., Shi, G., Cheng, F., et al. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.122947 · Cited by 19
Cell therapy strategies for COVID-19: Current approaches and potential applications
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Cardiovascular Tissue Engineering and Regeneration: A Plead for Further Knowledge Convergence
Bouten, C. V. C., Cheng, C., Vermue, I. M., Gawlitta, D., & Passier, R. C. (2022) · Tissue Engineering Part A · doi:10.1089/ten.tea.2021.0231 · Cited by 27
Song, C.-C., Wang, L., Li, Q.-Y., Liao, B., Qiao, W.-H., Li, Q., Dong, N.-G., & Li, L.-P. (2022) · Stem cell research & therapeutics · doi:10.1186/s13287-022-02720-7 · Cited by 19
“[40] employed multiplex genome editing to specifically ablate the expression of the highly polymorphic HLA-A/-B/-C via cleavage of HLA-I gene fragments as well as of HLA class II via CIITA KO in PSCs.”
MethodBeneath the radar: immune-evasive cell sources for stroke therapy
Buil, B. A., Rentsch, N. H., Weber, R., Rickenbach, C., Halliday, S., Hotta, A., Tackenberg, C., & Rust, R. (2024) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2023.12.004 · Cited by 20
HLA-based banking of induced pluripotent stem cells in Saudi Arabia
Alowaysi, M., Lehmann, R., Al-Shehri, M., Baadhaim, M., Alzahrani, H., Aboalola, D., Zia, A., Malibari, D., Daghestani, M., Alghamdi, K., et al. (2023) · Stem cell research & therapeutics · doi:10.1186/s13287-023-03612-0 · Cited by 18
“To evade detection and subsequent attacks by NK cells, the ectopic expression of immune-modifying molecules like HLA-E, HLA-G, and CD47 could be introduced, which adds to the complexity of achieving the sought after hypoimmu-nogenic line [44, 45].”
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Caldara, R., Tomajer, V., Monti, P., Sordi, V., Citro, A., Chimienti, R., Gremizzi, C., Catarinella, D., Tentori, S., Paloschi, V., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1323439 · Cited by 19
Santini-González, J., Castro-Gutiérrez, R., Becker, M. W., Rancourt, C., Russ, H. A., & Phelps, E. A. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.989815 · Cited by 26
Masuda, K., & Kawamoto, H. (2021) · Inflammation and Regeneration · doi:10.1186/s41232-020-00150-7 · Cited by 18
“have reported the production of PSCs in which HLA class I and II were deleted while HLA-G, CD47, and PD-L1 were knocked-in [24] (Fig.”
BackgroundBenabdallah, B., Désaulniers-Langevin, C., Colas, C., Li, Y.-Y., Rousseau, G., Guimond, J., Haddad, É., & Beauséjour, C. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02580 · Cited by 17
Choi, J., Kang, S., Kim, B., So, S., Han, J., Kim, G., Lee, M., Roh, S., Lee, J. Y., Oh, S. J., et al. (2021) · Stem Cell Research & Therapy · doi:10.1186/s13287-021-02470-y · Cited by 17
“molecules, such as PD-L1, HLA-E, and CD47, have also been recently identified supporting and describing the lack of immunorecognition upon transplantation in allogenic and xenogenic settings [57].”
Bogomiakova, M., Sekretova, E. K., Eremeev, A., Shuvalova, L. D., Bobrovsky, P. A., Zerkalenkova, E. A., Lebedeva, O., & Lagarkova, M. (2021) · Stem Cell Research · doi:10.1016/j.scr.2021.102451 · Cited by 16
Gao, Y., & Pu, J. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.658088 · Cited by 22
In vitro oxygen imaging of acellular and cell-loaded beta cell replacement devices
Kotecha, M., Wang, L., Hameed, S., Viswakarma, N., Ma, M., Stabler, C. L., Hoesli, C. A., & Epel, B. (2023) · Scientific Reports · doi:10.1038/s41598-023-42099-w · Cited by 17
Hypoimmunogenic Human Pluripotent Stem Cells as a Powerful Tool for Liver Regenerative Medicine
Trionfini, P., Romano, E., Varinelli, M., Longaretti, L., Rizzo, P., Giampietro, R., Caroli, A., Aiello, S., Todeschini, M., Casiraghi, F., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411810 · Cited by 17
“In light of these findings, we reasoned that we could avoid overexpressing CD47, a common strategy used by many researchers to compensate for the loss of HLA-I [6,7].”
BackgroundWszola, M., Nitarska, D., Cywoniuk, P., Gomółka, M., & Klak, M. (2021) · Cells · doi:10.3390/cells10061544 · Cited by 20
“Modified cells remained unrecognized by the immune system for a long time after transplantation to mice and retained pluripotent properties [193,194].”
BackgroundTriolo, T. M., & Bellin, M. D. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.636824 · Cited by 19
“Advances in genome engineering using CRISPR/ Cas9 allows for modification of hPSCs (71) and can knock out HLA surface molecules implicated in autoimmunity (72, 73).”
MethodHuman iPS Cell-derived Tissue Engineered Vascular Graft: Recent Advances and Future Directions
Shi, X., He, L., Zhang, S., & Luo, J. (2020) · Stem Cell Reviews and Reports · doi:10.1007/s12015-020-10091-w · Cited by 18
“, 2019 [55] • Ablated the highly polymorphic HLA-A, B and C and class II molecules”
BackgroundPluripotent stem cell-based gene therapy approach: human de novo synthesized chromosomes
Sinenko, S. A., Ponomartsev, S. V., & Tomilin, A. N. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03653-1 · Cited by 16
McCallion, O., Du, W., Glaser, V., Milward, K. F., Short, S., Bilici, M., Cross, A. R., Stark, H. L., Franke, C., Kath, J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-64945-3 · Cited by 22
“The development of hypoimmunogenic, gene-edited ‘ off-the-shelf ’ cellular therapies has been proposed for tissue replacement 24,42 , anti-tumor cell therapy with conventional T cells 25,43 – 45 , and now, allogeneic Treg applications.”
Karaoğlu, İ. C., Duymaz, D., Rashid, M. M., & Kızılel, S. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1618086 · Cited by 15
“PD-L1 is a ligand for PD-1; its overexpression on beta cells can “ turn off ” exhausted or activated T cells by engaging PD-1, reducing their proliferation and cytotoxicity (39).”
InfluentialGraft survival of major histocompatibility complex deficient stem cell-derived retinal cells
Ishida, M., Masuda, T., Sakai, N., Nakai-Futatsugi, Y., Kamao, H., Shiina, T., Takahashi, M., & Sugita, S. (2024) · Communications Medicine · doi:10.1038/s43856-024-00617-5 · Cited by 14
Abe, K., & Tsumaki, N. (2023) · Inflammation and Regeneration · doi:10.1186/s41232-023-00307-0 · Cited by 15
“Recent studies have established that human iPSCs lack HLA class I and II molecules and suppress NK cell attack by HLA-E transduction, CD47 overexpression, or PVR knockout [63–67].”
BackgroundThongsin, N., & Wattanapanitch, M. (2021) · Methods in molecular biology · doi:10.1007/7651_2021_352 · Cited by 14
Engineering Strategies for Generating Hypoimmunogenic Cells with High Clinical and Commercial Value
Malik, N. N., Jenkins, A. M., Mellon, J., & Bailey, G. (2019) · Regenerative Medicine · doi:10.2217/rme-2019-0117 · Cited by 20
Mu-u-min, R., Diané, A., Allouch, A., & Al-Siddiqi, H. (2025) · Biomedicines · doi:10.3390/biomedicines13020383 · Cited by 14
Liu, X.-R., Yang, J., Yan, Y., Li, Q.-F., & Huang, R.-L. (2024) · Theranostics · doi:10.7150/thno.93919 · Cited by 13
“The employment of CRISPR-Cas9 to eliminate human leukocyte antigen expressions and ex vivo interferon-γ stimulation to induce endogenous PD-L1 expressions show promise in solving immune issues [143,164].”
BackgroundMethodNew Prospects for Retinal Pigment Epithelium Transplantation
Gullapalli, V. K., & Zarbin, M. A. (2022) · Asia-Pacific Journal of Ophthalmology · doi:10.1097/apo.0000000000000521 · Cited by 13
Is hypoimmunogenic stem cell therapy safe in times of pandemics?
Matheus, F., Raveh, T. B., Oro, A. E., Wernig, M., & Drukker, M. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2022.02.014 · Cited by 15
Current Challenges and Solutions to Tissue Engineering of Large-scale Cardiac Constructs
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“However, the complete elimination of HLA-I on the cell surface could provoke ‘missing-self’ lysis, which is mediated by NK cells in other independent studies 10,11 .”
Immunosuppressant therapy averts rejection of allogeneic FKBP1A-disrupted CAR-T cells
Maldini, C. R., Messana, A., Bendet, P. B., Camblin, A. J., Musenge, F. M., White, M. L., Rocha, J. J., Coholan, L. J., Karaca, C., Li, F., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.06.022 · Cited by 18
Pluripotent stem cell strategies for rebuilding the human brain
Limone, F., Klim, J. R., & Mordes, D. A. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.1017299 · Cited by 15
“This tactic proposes to use genetic engineering to reduce immunogenicity by removing the MHC molecules from the surface of the cells while also introducing well-established tolerance-inducing molecules (Riolobos et al., 2013; Han et al., 2019).”
Ding, Z., Pan, X., Wang, X., Xie, H., & Ye, Q. (2021) · Smart Materials in Medicine · doi:10.1016/j.smaim.2021.07.002 · Cited by 14
Tissue-engineered vocal fold replacement in swine: Methods for functional and structural analysis
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“However, ASCs are known to have immunosuppressive properties which may partially protect them from rejection [40].”
BackgroundAdvances in Cellular Reprogramming-Based Approaches for Heart Regenerative Repair
He, X., Liang, J., Paul, C., Huang, W. C., Dutta, S., & Wang, Y. (2022) · Cells · doi:10.3390/cells11233914 · Cited by 15
““Universal” or “hypoimmunogenic” hiPSCs were designed through CRISPR/Cas9 gene-editing techniques by knocking out these immune-related genes/factors, which could effectively enhance immune compatibility [55].”
MethodVoynova, E., & Kovalovsky, D. (2021) · Cells · doi:10.3390/cells10112845 · Cited by 15
“To prevent this immune attack, iPSCs were modified to delete HLA I and II molecules and have also incorporated PD-L1, HLA-G and CD47 to control, T and NK cellmediated responses as well as macrophage engulfment [74].”
BackgroundGarbern, J. C., Escalante, G. O., & Lee, R. T. (2020) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2020.01.002 · Cited by 12
Hypoimmunogenic Human iPSCs for Repair and Regeneration in the CNS
Zhang, H.-W., Zhou, H.-X., Xia, X.-G., Cao, Q.-L., & Liu, Y. (2025) · Cells · doi:10.3390/cells14161248 · Cited by 10
“As a result, only two separate gene edits are required to eliminate the expression of all three classical HLA class I molecules [9].”
Islet Transplantation: Microencapsulation, Nanoencapsulation, and Hypoimmune Engineering
Lee, K., Vargas, A. A., Bottino, R., & Wang, Y. (2025) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.70016 · Cited by 12
“Another group also knocked out both HLA class I and HLA class II genes, but uniquely retained HLA-E expression (Han et al. 2019).”
InfluentialCRISPR-Cas9 immune-evasive hESCs are rejected following transplantation into immunocompetent mice
Frederiksen, H. R. S., Glantz, A., Vøls, K. K., Skov, S., Tveden‐Nyborg, P., Freude, K., & Doehn, U. (2024) · Frontiers in Genome Editing · doi:10.3389/fgeed.2024.1403395 · Cited by 9
“Hence, many tactics have been explored to reduce NK killing by either preserving the expression of less polymorphic MHC molecules (Taylor et al., 2012; Gornalusse et al., 2017; Han et al., 2019; Shi et al., 2020; An et al., 2022) or by overexpressing PDL-1 (Han et al., 2019) or CD47 (Deuse et al., 2019; Han et al., 20…”
BackgroundFeng, X., Zhang, H., Yang, S., Cui, D., Wu, Y., Qi, X., & Su, Z. (2024) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-024-04999-x · Cited by 13
“…studies have utilized immune engineering to circumvent allogenic rejection, and these strategies aim to produce immune-privileged hPSCs by removing antigen-presenting proteins such as human leukocyte antigen (HLA) or overexpressing immune checkpoint inhibitors such as PD-L1 and CD47 [118–121].”
Kawamoto, H., & Masuda, K. (2024) · International Immunology · doi:10.1093/intimm/dxad051 · Cited by 11
“• A method for forced expression of CD47, PD-L1, and HLA-G in HLA-deficient cells (21) (Fig.”
MethodCell reprogramming therapy for Parkinson’s disease
Dong, W., Liu, S., Li, S., & Wang, Z. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.390965 · Cited by 21
“…to knock in HLA-E genes at the B2M locus in hiPSCs (Gornalusse et al., 2017), selective deletion of HLA genes using clustered regularly interspaced short palindromic repeats (CRISPR-Cas9) (Xu et al., 2019), and other gene editing methods to generate suitable HLA cell lines (Han et al., 2019).”
MethodLarge animal models for cardiac remuscularization studies: A methodological review
Yu, Y., Tham, S. K., Roslan, F. F., Shaharuddin, B., Yong, Y. K., Zhikun, G., & Tan, J. J. (2023) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2023.1011880 · Cited by 9
“Cowen’s laboratory also suggested the removal of CIITA in human PSCs but they proposed selective deletion of HLA-A/-B/-C instead of B2M to preserve the expression of HLA-E and HLA-G, the HLA class Ib molecules that retain the tolerance to natural killer (NK) cells (116).”
BackgroundStem cell-based multi-tissue platforms to model human autoimmune diabetes
Leavens, K. F., Alvarez‐Dominguez, J. R., Vo, L. T., Russ, H. A., & Parent, A. V. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101610 · Cited by 18
“In this approach, HLA genes causing allogeneic responses in hPSCs are inactivated while antigen presentation capability is conserved through retention of HLA alleles relevant to T1D [137,140].”
BackgroundPendse, S., Vaidya, A., & Kale, V. P. (2022) · Regenerative Medicine · doi:10.2217/rme-2022-0045 · Cited by 11
Optimizing Generation of Stem Cell-Derived Islet Cells
Verhoeff, K. K., Cuesta‐Gomez, N., Jasra, I. T., Marfil‐Garza, B. A., Dadheech, N., & Shapiro, A. M. J. (2022) · Stem Cell Reviews and Reports · doi:10.1007/s12015-022-10391-3 · Cited by 11
“Genetically modifying hESCs to express immunotolerant molecules such as IL-10 or PD-L1 [40, 146], or eliminating HLA class 1 molecule expression has been accomplished and shown reduced T cell and macrophage reactivity, and minimal NK cellmediated death [34, 48, 116].”
BackgroundEngineering of human mesenchymal stem cells resistant to multiple natural killer subtypes
Zheng, D.-J., Wang, X.-Y., Zhang, Z., Li, E.-Q., Yeung, C.-K., Borkar, R., Qin, G., Wu, Y.-J., & Xu, R.-H. (2022) · International Journal on Biological Sciences · doi:10.7150/ijbs.64640 · Cited by 10
“Moreover, HLA-G expression in HLA-Ia-depleted hESCs also protect against NK cell-mediated lysis [15].”
BackgroundResultKim, A., Lee, K., Kwon, Y., Lee, K.-I., Yang, H.-M., Habib, O., Kim, J., Kim, S. J., Kim, J., Kim, J., et al. (2020) · Stem Cell Reviews and Reports · doi:10.1007/s12015-020-10113-7 · Cited by 17
Harnessing the immunomodulatory properties of HLA-G for advanced immunotherapies
Beli, X., Savvopoulos, N., Kefala, D., Lysandrou, M., Liga, M., & Spyridonidis, A. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1716778 · Cited by 9
Hypoimmune stem cells and islets: hype or a true breakthrough in diabetes treatment?
Shalaby, K. E., & Abdelalim, E. M. (2025) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-025-00786-8 · Cited by 10
“Further in vitro assays involve testing the immune evasion capabilities of the modified stem cells using co-culture systems with immune cells to measure T cell, NK cell, dendritic cell, and macrophage immunogenic activities [112–115 , 118– 120].”
Zhang, Q., Xia, C., Weng, Q., Zhang, L., Wang, Y., Liu, Y., Zheng, X., Lin, Y., Chen, Y., Shen, Y., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1504459 · Cited by 8
Regenerative medicine in cardiovascular disease
Goto, T., Nakamura, Y., Ito, Y., & Miyagawa, S. (2024) · Regenerative Therapy · doi:10.1016/j.reth.2024.09.004 · Cited by 9
“Additionally, iPSC-derived cardiomyocytes and vascular endothelial cells overexpressing CD47, which is the inhibitory ligand of NK cells, evaded rejection by NK cells after transplantation, and long-term engraftment was achieved [64].”
Backgroundda Silva, L. H. A., Heuer, R. A., Roque, C. B., Mcguire, T. L., Hosoya, T., Kimura, H., Tamura, K., & Matsuoka, A. (2023) · Stem cell research & therapeutics · doi:10.1186/s13287-023-03304-9 · Cited by 9
“Future studies will also address strategies to overexpress and sustain the expression of genes that play roles in immune evasion, such as CD47 [15, 16].”
BackgroundFabricating 3-dimensional human brown adipose microtissues for transplantation studies
Wang, O., Li, H., Lin, H., Tian, M., Zhang, S., Duan, B., Chung, S., Zhang, C., Lian, X. L., Wang, Y., et al. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.10.022 · Cited by 12
Disease modeling and stem cell immunoengineering in regenerative medicine using CRISPR/Cas9 systems
Antao, A. M., Karapurkar, J. K., Lee, D. R., Kim, K.-S., & Ramakrishna, S. (2020) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2020.11.026 · Cited by 14
Benabdallah, B., Désaulniers-Langevin, C., Goyer, M.-L., Colas, C., Maltais, C., Li, Y.-Y., Guimond, J., Tremblay, J., Haddad, É., & Beauséjour, C. (2020) · Stem Cells Translational Medicine · doi:10.1002/sctm.19-0452 · Cited by 9
Hypoimmunogenic pluripotent stem cells: A game-changer in cell-based regenerative medicine
Sarabi, P. A., Rismani, E., Shabanpouremam, M., Hendi, Z., Nikoubin, B., Rahimi, S., Taleb, M., Khosravi, A., Zarrabi, A., Hassan, M., et al. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115134 · Cited by 7
Beta cells deficient for Renalase counteract autoimmunity by shaping natural killer cell activity
Bode, K., Wei, S., Gruber, I., Li, J., Kissler, S., & Peng, Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1403752 · Cited by 8
Hang, S., Wang, N., & Sugimura, R. (2023) · Differentiation · doi:10.1016/j.diff.2023.01.001 · Cited by 8
Morizane, A., & Takahashi, J. B. (2021) · Journal of Parkinson s Disease · doi:10.3233/jpd-212608 · Cited by 12
“Accordingly, to protect transplanted cells from T cell and NK cell responses, researchers have knocked out HLA-A, -B, -C genes while overexpressing HLA-G gene [17].”
BackgroundSung, T.-C., Jiang, Y.-P., Hsu, J.-Y., Ling, Q.-D., Chen, H., Kumar, S., Chang, Y., Hsu, S.-T., Ye, Q., & Higuchi, A. (2021) · Cell Proliferation · doi:10.1111/cpr.12995 · Cited by 8
Stealth designs to overcome allorejection in engineered cell therapy
Li, Y.-R., Chen, Y., & Yang, L. (2026) · Trends in Immunology · doi:10.1016/j.it.2026.02.008 · Cited by 9
Selective agonists of KIR and NKG2A to evade missing self response of natural killer cells
Hiura, S., Kuwasaki, Y., Nishikawa, Y., Kimura, T., Yoshida, S., Nakayama, M., Makino, T., & Ueno, S. (2025) · Scientific Reports · doi:10.1038/s41598-025-18394-z · Cited by 6
Naffaa, M. M. (2025) · Regenerative medicine reports . · doi:10.4103/regenmed.regenmed-d-25-00013 · Cited by 5
Hypoimmunogenic hPSC-derived cardiac organoids for immune evasion and heart repairPreprint
Silver, S. E., Howells, A. R., Arhontoulis, D. C., Randolph, L. N., Hyams, N. A., Barrs, R. W., Li, M., Kerr, C. M., Robino, R. A., Morningstar, J. E., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.09.648007 · Cited by 6
“To overcome this, NK cell inhibitory molecules, such as CD47 and HLA-E, and HLA-G, have been introduced into B2M -/- cells to generate hypoimmunogenic cells 39-42 ( Fig.”
Self-citationLv, Y., Li, Q.-Y., Duan, P., Zhang, M.-F., Liu, B., Li, S., Zhao, T.-T., Wang, H., Liu, Y., & Yin, Z. (2025) · Stem Cell Reports · doi:10.1016/j.stemcr.2025.102424 · Cited by 7
Harnessing Global HLA Data for Enhanced Patient Matching in iPSC Haplobanks
Maiers, M., Sullivan, S. R., Mcclain, C., Leonhard-Melief, C., Turner, M. L., & Turner, D. (2024) · bioRxiv · doi:10.1101/2024.10.15.618361 · Cited by 7
“…iPSC cell lines representing common HLA types to enable some degree of matching with patients (haplobanking) (Sullivan, Fairchild, et al. 2020), or the creation of hypoimmunogenic lines where the expression of immune stimulating molecules have been down regulated or eliminated (Han et al. 2019).”
BackgroundRetinal transplant immunology and advancements
Perez, V. L., Mousa, H., Miyagishima, K. J., Reed, A. A., Su, A.-J. A., Greenwell, T. N., & Washington, K. (2024) · Stem Cell Reports · doi:10.1016/j.stemcr.2024.04.007 · Cited by 7
Ma, C., Cao, H., Sun, Z., Deng, Q., Liu, W., Xin, Y., Qiao, S., Cen, J., Shu, Y., Qi, K., et al. (2023) · American Journal of Transplantation · doi:10.1016/j.ajt.2023.07.020 · Cited by 10
Replacing renal function using bioengineered tissues
Little, M., & Rabelink, T. (2023) · Nature Reviews Bioengineering · doi:10.1038/s44222-023-00066-0 · Cited by 7
Cardiac Regeneration Using Pluripotent Stem Cells and Controlling Immune Responses
Ichimura, H., Chino, S., & Shiba, Y. (2023) · Heart Lung and Circulation · doi:10.1016/j.hlc.2022.12.014 · Cited by 7
Immortal orexin cell transplants restore motor-arousal synchrony during cataplexy
Pintwala, S. K., Fraigne, J. J., Belsham, D. D., & Peever, J. H. (2023) · Current Biology · doi:10.1016/j.cub.2023.03.077 · Cited by 9
Pancreas transplant versus islet transplant versus insulin pump therapy: in which patients and when?
Tamburrini, R., & Odorico, J. S. (2021) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0000000000000857 · Cited by 8
Macrophage activation determines muscle wasting in pancreatic cancer
Chang, C., Huang, P.-H., Chen, S.-Y., Su, P.-C., Ding, L.-Y., Hou, Y., Hung, M., Chen, K.-L., Wu, Y., Wu, S., et al. (2025) · Oncogene · doi:10.1038/s41388-025-03434-9 · Cited by 9
“Elevated CD47-mediated ‘ don ’ t-eat-me ’ signals evade the cell killing of NK [39] and macrophages [40, 41] by suppressing phagocytosis [42], which can be potentiated by metabolic rewiring of macrophages using CpG treatment [43].”
Scaling Insulin-Producing Cells by Multiple Strategies
Choi, J. S., Cayabyab, F., Perez, H., & Yoshihara, E. (2024) · Endocrinology and Metabolism · doi:10.3803/enm.2023.1910 · Cited by 8
Lahimchi, M. R., Maroufi, F., & Maali, A. (2023) · Cellular Reprogramming · doi:10.1089/cell.2023.0041 · Cited by 7
“Their results showed T cell response suppression as well as a significant decrease in NK and macrophage activities (Han et al., 2019).”
Kishino, Y., Tohyama, S., Morita, Y., SOMA, Y., Tani, H., Okada, M., Kanazawa, H., & Fukuda, K. (2023) · Journal of Cardiac Failure · doi:10.1016/j.cardfail.2022.10.433 · Cited by 7
Synthetic Biology Technologies And Genetically Engineering Strategies For Enhanced Cell Therapeutics
Li, S., Tang, H., Li, C., Ma, J., Ali, M., Dong, Q. R., Wu, J., Hui, Y., & Sun, C. (2022) · Stem Cell Reviews and Reports · doi:10.1007/s12015-022-10454-5 · Cited by 9
Direct Reprogramming of Different Cell Lineages into Pancreatic β-Like Cells
Colarusso, J. L., & Zhou, Q. (2022) · Cellular Reprogramming · doi:10.1089/cell.2022.0048 · Cited by 6
“…immune system attack via genetic engineering of their immune system, for instance, by partially or completely disabling the MHCI and II complexes with or without concomitant expression of immune suppressive factors such as PDL1 and CD47 (Deuse et al, 2019; Gornalusse et al, 2017; Han et al, 2019).”
Jiang, L., Liang, J., Huang, W. C., Wu, Z., Paul, C., & Wang, Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207662 · Cited by 7
“Besides the retention of HLA-C, the expression of immunomodulatory factors PD-L1 and HLA-G could promote the immune tolerance of iPSC transplants [67,68].”
BackgroundImmune modulation for β-cell replacement in type 1 diabetes
Yang, Q., Song, Y., Markmann, J. F., & Lei, J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1785523 · Cited by 5
“Overexpression of HLA-E and/or HLA-G provides inhibitory ligands for NK receptors such as NKG2A, KIR2DL4, and LILRB1, suppressing NK activation without restoring classical T-cell recognition (41, 42, 109, 111).”
Wu, X., Jin, S., Pan, Y., Zhen, W., Yu, S., Zhang, Y., Xu, F. Y., Wang, R., Wu, M., Sun, W., et al. (2026) · Stem Cell Research & Therapy · doi:10.1186/s13287-026-04997-4 · Cited by 7
“These strategies have been successfully applied to iPSC-derived therapeutic cell products, resulting in prolonged graft persistence in immunocompetent animal models [113, 114].”
Brown, M. E., Barra, J. M., Pina, M., Proia, J., Brusko, T. M., & Russ, H. A. (2025) · Science Advances · doi:10.1126/sciadv.adx9755 · Cited by 8
Engineering hypoimmune stem cell-derived beta cells
Licht, B. J. M., Duffy, G. P., & Levey, R. E. (2025) · Stem Cell Research & Therapy · doi:10.1186/s13287-025-04745-0 · Cited by 8
“…have been investigated in this regard include B2M −/− pluripotent stem cells (PSC) with co-expression of the minimally polymorphic HLA-E [55], overexpression of the “don’t eat me”-signal-ling ligand CD47 [56], HLA-C retention [57], as well as CIITA −/− with expression of PD-L1, HLA-G and CD47 [58].”
Gilglioni, E. H., Bansal, M., St‐Pierre‐Wijckmans, W., Talamantes, S., Kasarinaite, A., Hay, D. C., & Gurzov, E. N. (2025) · Obesity Reviews · doi:10.1111/obr.13899 · Cited by 4
“152 However, this immune protection carries the risk of generating rogue cells that are resistant to immune clearance, potentially leading to malignancy.”
Metadata
- 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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