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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
Sorted by citations
Items 201–300 of 306
Hypoimmunogenic HLA-E Single Chain Inhibits Alloreactive Immune Responses
Maldini, C. R., Coholan, L. J., & Karaca, C. (2024) · The Journal of Immunology · doi:10.4049/jimmunol.2400491 · Cited by 5
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Dadheech, N., Cuesta‐Gomez, N., Jasra, I. T., Verhoeff, K. K., Marfil‐Garza, B. A., Mouhammed, O., & Shapiro, A. M. J. (2022) · Journal of Immunology and Regenerative Medicine · doi:10.1016/j.regen.2022.100064 · Cited by 6
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“These genetic modi fi cations substantially reduce host immune rejection and prolong graft survival in allogeneic transplantation settings 153,154 .”
Allogeneic Islet Transplantation: Chronicle of a Death Foretold?
Berney, T., Thaunat, O., & Berishvili, E. (2025) · Transplant International · doi:10.3389/ti.2025.14598 · Cited by 4
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“In vitro cytotoxicity assay was performed according to the previous study [20].”
Beaudreault, C. P., Wang, R., Muh, C. R., Rosenberg, A., Funari, A., McGoldrick, P. E., Wolf, S. M., Sacknovitz, A., & Chung, S. (2024) · Brain Sciences · doi:10.3390/brainsci14101027 · Cited by 5
“…as well as the upregulation of immune tolerance-promoting ligands such as programmed death-ligand 1, HLA-G, and CD47 to trigger anergy in T cells, NK cells, and macrophages, respectively, in a human pluripotent stem cell line with the preservation of differentiation capabilities [64].”
BackgroundResultChen, T., Quinn, Z., Mishra, K., O’Connor, E. C., Silver, S. E., Zhang, Y., Valencia, M. J., Mei, Y., Behmoaras, J., Ferreira, L. M. R., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.31.606098 · Cited by 11
“Proteins exceeding 500 amino acids were removed due to GPU constraints.”
Self-citationRole of Cell-Based Therapies in T2D
Ashe, S., & Hebrok, M. (2023) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2023.151432 · Cited by 6
Secreted cytokines provide local immune tolerance for human stem cell-derived isletsPreprint
Gerace, D., Zhou, Q., Kenty, J. H.-R., Sintov, E., Wang, X., Boulanger, K. R., Li, H., & Melton, D. A. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.09.487072 · Cited by 3
Self-citationMisra, P. S., & Nostro, M. C. (2022) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2022.100321 · Cited by 4
Generation of a homozygous CIITA knockout iPS cell line using the CRISPR-Cas9 system
Romano, E., Trionfini, P., Giampietro, R., Benigni, A., & Tomasoni, S. (2021) · Stem Cell Research · doi:10.1016/j.scr.2021.102580 · Cited by 4
Charting the next century of insulin replacement with cell and gene therapies
Lau, H. H., Gan, S. U., Lickert, H., Shapiro, A. M. J., Lee, K., & Teo, A. K. K. (2021) · Med · doi:10.1016/j.medj.2021.09.001 · Cited by 8
Adoptive natural killer cell therapy: a human pluripotent stem cell perspective
Chang, Y., & Bao, X. (2020) · Current Opinion in Chemical Engineering · doi:10.1016/j.coche.2020.08.008 · Cited by 4
Shin, S., Song, E., Kwon, Y., Oh, S., Park, H., Kim, N.-H., & Roh, E. (2020) · Biology of Blood and Marrow Transplantation · doi:10.1016/j.bbmt.2020.05.008 · Cited by 4
Niedźwiedzka-Rystwej, P., Wołącewicz, M., Cywoniuk, P., Klak, M., & Wszoła, M. (2020) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-020-00578-2 · Cited by 4
Navigating challenges in human pluripotent stem cell-derived islet therapy for type 1 diabetes
Usama, M., Deng, Y., Chen, Y., Milland, T., Malleshaiah, M. K., & Aghazadeh, Y. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1625439 · Cited by 4
“Deletion of all HLAs, including HLA-A, B, and C, from iPSCs provided initial protection from acute rejection after transplantation into allogeneic humanized NSG mice, but T cell-mediated rejection led to graft loss within 5 – 6 weeks post-transplantation (113).”
Gantier, M., Ménoret, S., Fourrier, A., Delbos, F., Nguyen, T. H., & Anegón, I. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1507317 · Cited by 3
“CD47 has also been shown to inhibit NK activation by HLA-I-de fi cient iPSC-derivatives (19, 20).”
A new paradigm in transplant immunology: At the crossroad of synthetic biology and biomaterials
Zhang, Z., Ding, L.-Y., Zuo, X.-L., Feng, H., & Xia, Q. (2023) · Med · doi:10.1016/j.medj.2023.05.002 · Cited by 6
Genome Editing of Pluripotent Stem Cells for Adoptive and Regenerative Cell Therapies
Blassberg, R. A. (2022) · GEN Biotechnology · doi:10.1089/genbio.2021.0010 · Cited by 3
“61 However, expression and cell-surface localization of HLA-E were shown to depend on interferon gamma signaling in this system and would thus be limited to conditions of inflammation.”
Knock, E., & Julian, L. M. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.767457 · Cited by 5
“This promising approach is still actively under development but offers substantial potential for long-term sustained impacts (Han et al., 2019).”
BackgroundHeart regeneration: from mouse to human
Weinberger, F., & Eschenhagen, T. (2019) · Current Opinion in Physiology · doi:10.1016/j.cophys.2019.10.010 · Cited by 3
Zhang, L., Tian, L., Dai, X., Yu, H., Wang, J., Lei, A., Zhao, W., Zhu, Y., Sun, Z., Zhang, H., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.03.28.011270 · Cited by 2
“Third, the seed iPSC clone can be expanded in large scale, and when combined with the recently reported techniques in making immune-tolerant universal iPSCs 25-27 , CAR-iMac can be developed into an off-the-shelf product with unlimited sources.”
BackgroundStem cell therapies in diabetes
Kahraman, S., Diegisser, D., & Dirice, E. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-823318-4.00013-5
Exploiting the plasticity of cholangiocytes to repair the biliary tree
Frau, C., & Vallier, L. (2024) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2024.102257 · Cited by 2
“Alternatively, transplanting COs in combination with CRISPR-Cas9 gene editing to knock out major histocompatibility complex class I/II molecules [34] could represent a strategy to develop for preventing the autoimmune reaction against the biliary compartment.”
Exploring CAR cell therapies beyond CAR-T for myeloid malignancies
Li, Y.-R., Chen, Y.-N., & Yang, L.-L. (2026) · Journal of Biomedical Sciences · doi:10.1186/s12929-026-01265-8 · Cited by 2
Plaisse, C., Bézie, S., & Guillonneau, C. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1797186 · Cited by 2
“CD47 overexpression decreases macrophage engulfment of engineered hPSC-derived VSMCs (120).”
InfluentialKaraoglu, I. C., Odabas, A., Onder, T. T., & Kızılel, S. (2025) · bioRxiv · doi:10.3389/fimmu.2026.1759835 · Cited by 2
Pluripotent stem cell-derived cardiomyocyte transplantation: marching from bench to bedside
Yi, H., Liu, J., Wang, W., Li, H., Kong, W., Li, X., Zhang, W., Pahlavan, S., Tang, Y., Wang, X., et al. (2025) · Science China Life Sciences · doi:10.1007/s11427-024-2801-x · Cited by 2
“C and HLA class II, and overexpressing immunomodulatory factors PD-LA, HLA-G, and CD47, are insensitive to T cells, NK cells, and macrophages (Han et al., 2019).”
Combined CLEC2d Expression and CD58 Loss Mitigate Rejection of Allogeneic T Cells
Coholan, L. J., Karaca, C., Musenge, F. M., White, M. L., Camblin, A. J., Leboeuf, D., & Maldini, C. R. (2025) · Journal of Immunotherapy · doi:10.1097/cji.0000000000000552 · Cited by 2
Courot, H., Rigal, É., Adib, N., Criton, M., Cookson, A., Fauvel, B., & Présumey, J. (2025) · Cells · doi:10.3390/cells14040254 · Cited by 4
“Several strategies have been actively investigated to evade the allo-rejection of cell therapy products, including pharmacologic immune suppression, HLA (human leukocyte antigen) matching and gene editing to deplete MHC class I and II molecules [73–75].”
Zhou, M., Brinson, D., Lei, C., & Karoubi, G. (2025) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1155/term/8367426 · Cited by 2
Hiding from allogeneic NK cells and macrophages by a synthetic receptor.
Hotta, A., & Lee, J. (2023) · Cell Stem Cell · doi:10.1016/j.stem.2023.10.005 · Cited by 2
Mercuri, N., & Cox, B. (2021) · bioRxiv · doi:10.1101/2021.11.16.468787 · Cited by 2
“In regenerative medicine research, the immune-modulating genes used by the placenta (Szekeres-Bartho, 2002) are being repurposed to generate universally transplantable stem cells and tissues (Han et al., 2019).”
BackgroundMore Bang for Your Buck: “Off-The-Shelf” Solutions for Cell Replacement Therapy
Meissner, T., & Cowan, C. (2020) · StemJournal · doi:10.3233/stj-200002 · Cited by 2
“SincetheB2Mgeneisstillintact,expressionofthetolerogenicHLAmoleculesHLA-E and-Gisunhamperedwhenusingthisapproach[4]. by natural killer (NK) cells, which patrol the body to eliminate virus-infected or cancerous cells that have lost HLA expression.”
InfluentialSelf-citationGM2 Gangliosidosis: Clinical Features and Current Therapies
Leal, A., Benincore-Flórez, E., Solano-Galarza, D., Jaramillo, R. G. G., Echeverri-Peña, O. Y., Súarez, D. A., Alméciga-Díaz, C., & Espejo-Mojica, A. (2020) · doi:10.20944/preprints202007.0137.v1 · Cited by 2
“In order to overcome these limitations, recent developments using hypoimmunogenic human stem cells have opened a new horizon for the HSCT by avoiding the events of GVHD through evasion of both cellular and humoral immune response [129, 130].”
BackgroundHypoimmune platforms: from rejection to immune evasion and regulatory implications
Campo, F., Bellini, M. I., Scholz, H., Piemonti, L., & Citro, A. (2026) · Transplant International · doi:10.3389/ti.2026.16845 · Cited by 1
“This effect can be amplified through broadly expressed inhibitory receptors such as SIRP α , TIM3, and CD300a [27, 28], or by overexpressing HLA-E [16] and HLA-G [29] to target specific NK subsets.”
Li, Y.-R., Zhu, Y., Shen, X., Chen, Y., & Yang, L. (2026) · Nature Reviews Bioengineering · doi:10.1038/s44222-026-00468-w · Cited by 1
Biomaterials for clinical therapy utilizing cells differentiated from human pluripotent stem cells
Higuchi, A., Wang, T., Kang, X., Tian, Z., Sung, T., & Umezawa, A. (2026) · Materials Today Advances · doi:10.1016/j.mtadv.2026.100860 · Cited by 1
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“B (Xu et al., 2019), or introduction of the non-classical HLA-G in broadly HLA-deficient cells (Han et al., 2019) has been shown to suppress NK cell-mediated cytotoxicity.”
InfluentialRana, M. M., Withers, S. G., Choy, J. C., & Kizhakkedathu, J. N. (2026) · Frontiers in Transplantation · doi:10.3389/frtra.2026.1841203 · Cited by 1
“Most current strategies to mitigate rejection focus on protein-level immunomodulation, including pharmacological inhibition of signaling proteins, costimulatory blockade, human leukocyte antigen (HLA) gene-editing, and engineered expression of immunoregulatory molecules such as programmed death-ligand 1 (PD-L1) or CD4…”
InfluentialAutomated Abnormal Vessel Detection in Re-Endothelialized Mouse Lungs: A Proof of Concept
Paciocco, J., Hasan, A., Chan, J. K. D., Taniguchi, D., Kamata, S., Amon, C., Karoubi, G., & Bazylak, A. (2026) · Tissue Engineering Part C Methods · doi:10.1177/19373384261458003 · Cited by 1
Li, Z., Kang, Y., & Niu, Y. (2026) · Animal Models and Experimental Medicine · doi:10.1002/ame2.70211 · Cited by 1
The therapeutic potential of natural killer (NK) cells to combat aging and age-related diseases
Bari, R., Kang, L., Gosiewska, A., & HARIRI, R. J. (2026) · Discover Immunity. · doi:10.1007/s44368-026-00021-2 · Cited by 1
Cell-based regenerative interventions in Parkinson's disease: Overcoming pharmacological limitations
Padilla, A. L., Lanciego, J. L., Vila, M., de Castro, F., Pozo, D., de Fonseca, F. R., Serrano, A., Sáez‐Valero, J., Núñez, L., Villalobos, C., et al. (2026) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2026.03.031 · Cited by 1
“Residual immunogenicity may arise from aberrant antigen expression or differentiation-induced MHC upregulation 56,57 .”
CRISPR/Cas9-mediated B2m knockout paves the way for allogeneic basal cell transplantation
Chen, H.-J., Luo, W., Ma, N., & Li, S.-Y. (2026) · Respiratory Research · doi:10.1186/s12931-026-03595-5 · Cited by 1
“The application of hypoimmunogenic iPSCs based on B2m KO has also been reported in anti-tumor therapy and cardiovascular tissue regeneration [34–36].”
Deep immune-phenotyping of HLA-homozygous iPS-cardiomyocytes by spectral flow cytometry
Maeding, N., Kundully, D. S., Steinhuber, A., Kriedemann, N., Hernandez-Bautista, C. A., Martins, S., Hochmann, S., Martin, W., Mayr, W. R., Jungbauer, C., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1736994 · Cited by 1
“This separation was again driven, as observed in previous experiments in this study, by signi fi cant upregulation of HLA-ABC (MFI = 478,053 treated vs 1,136 untreated; p < 0.0001), HLA-DR (MFI = 5,530 treated vs -156.8 untreated; p < 0.0001), HLA-E (MFI = 5,225 treated vs -143.7 untreated; p = 0.0023), HLA-F (MFI = 1,…”
InfluentialCardiac regeneration: The present state and future direction of human pluripotent stem cell therapy
Umei, T. C., & Tohyama, S. (2026) · Journal of Cardiology · doi:10.1016/j.jjcc.2026.01.006 · Cited by 1
Mazurek, M., Mlynarski, W. M., & Grzela, D. P. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1720048 · Cited by 1
Integrating synthetic biology to understand and engineer the heart, lung, blood, and sleep systems
Chaikof, E. L., Chen, J., Gillette, M. U., Boyer, L. A., Deans, T. L., Li, P., Hilton, I. B., Daniels, K. G., Goyal, Y., Mei, Y., et al. (2025) · Cell Systems · doi:10.1016/j.cels.2025.101446 · Cited by 2
Computer vision to predict cell seeding coverage in re-endothelialized mouse lungs
Paciocco, J., Hasan, A., Chan, J., Taniguchi, D., Amon, C. H., Karoubi, G., & Bazylak, A. (2025) · Scientific Reports · doi:10.1038/s41598-025-11272-8 · Cited by 2
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Cobos-Figueroa, L., Notario, L., Mir, C., Molpeceres, C., Lauzurica, S., López, D., Lorente, E., & Lauzurica, P. (2025) · ImmunoTargets and Therapy · doi:10.2147/itt.s506352 · Cited by 1
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“15,16 Although in the context of clinical implantation autologous iPS cells would be preferable due to HLA identity, the time and resources required to generate iPS cells from a patient can greatly restrict their utility as a treat-ment strategy.”
Vidman, S. R., Ma, Y. H. E., Fullenkamp, N., & Plant, G. W. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-00901 · Cited by 6
“Although this differentiation was driven toward mesodermal and endodermal lineages, a neuroectodermal differentiation would likely retain the genetic modifications and maintain its pluripotent state (Han et al., 2019).”
Lin, Y., Li, X., Fang, J., Zeng, Q., Cheng, D., Wang, G., Shi, R., Luo, Y., Ma, Y., Li, M., et al. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112070 · Cited by 1
Beta Cells Deficient for Renalase Counteract Autoimmunity by Shaping Natural Killer Cell Activity
Bode, K., Wei, S.-Y., Gruber, I., Kissler, S., & Yi, P. (2024) · bioRxiv · doi:10.1101/2024.02.29.582816 · Cited by 1
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Murata, T., Hama, N., Kamatani, T., Mori, A., Otsuka, R., Wada, H., & Seino, K.-I. (2023) · American Journal of Transplantation · doi:10.1016/j.ajt.2023.05.020 · Cited by 2
Halliez, C., Ibrahim, H., Otonkoski, T., & Mallone, R. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1076683 · Cited by 3
From a Single Cell to a Whole Human Liver: Disease Modeling and Transplantation
Motomura, T., Faccioli, L. A. P., Soto–Gutiérrez, A., Tafaleng, E. N., Díaz‐Aragon, R., Kocas‐Kilicarslan, Z. N., Haep, N., Florentino, R. M., Amirneni, S., Cetin, Z., et al. (2022) · Seminars in Liver Disease · doi:10.1055/a-1934-5404 · Cited by 2
Генерування інсулін-продукуючих клітин зі стовбурових клітин. Перепрограмування соматичних клітин
Tronko, M. D., Pushkarev, V. M., Kovzun, О. I., SOKOLOVA, L. K., & PUSHKAREV, V. V. (2022) · Endokrynologia · doi:10.31793/1680-1466.2022.27-1.43 · Cited by 2
Enabling allogeneic therapies: CIRM‐funded strategies for immune tolerance and immune evasion
Kadyk, L. C., Okamura, R. M., & Talib, S. (2020) · Stem Cells Translational Medicine · doi:10.1002/sctm.20-0079 · Cited by 1
“To prevent cytotoxicity mediated by NKG2A-NK cells, expression of HLA-G, ligand for the inhibitory receptor KIR2DL4, has been proposed.(21)”
BackgroundNK cells prevent the formation of teratomas derived from human induced pluripotent stem cells
Benabdallah, B., Désaulniers-Langevin, C., Colas, C., Li, Y.-Y., Guimont, J. V., Haddad, É., & Beauséjour, C. (2019) · bioRxiv · doi:10.1101/714170 · Cited by 1
“Moreover, it will be essential to demonstrate that hiPSC-based therapies, whether using autologous donors or through the development of universal cell lines, are safe [11; 12; 13].”
BackgroundErmakova, P., Barinova, A. A., Bogomolova, A. Y., Potapov, A. L., Zharova, P. M., Baten'kin, M. A., Zakharina, M. Y., Konev, A. N., Chesnokov, S. A., Karabut, M. M., et al. (2026) · Cells · doi:10.3390/cells15211942
New insights into β‐cell vulnerability in type 1 diabetes—Lessons from nature
Murrall, K., Luckett, T., Lekka, C., Hunter, S. B., Agnello, S., Ferris, P., Haxton, E., Flaxman, C. S., Kannan, A., Dun, X., et al. (2026) · Diabetic Medicine · doi:10.1111/dme.70509
Yamamoto, Y., Ohno, R., Shoda, K., Suzuki, T., Momoi, K., Fujii, S., Kenmochi, Y., Yoshikawa, T., Shimomura, M., Tsukamoto, N., et al. (2026) · iScience · doi:10.1016/j.isci.2026.117933
“36 However, the complicated gene-editing strategy increased off-targeting risks due to the multiple gene modifications, suggesting that a simple gene modification strategy was preferable for safety and quality control in a clinical setting.”
Zhang, L.-H., Cai, B., Li, X.-X., Liu, Y.-X., Lu, P., Liu, Y.-Q., Lei, W., & Mao, G.-H. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.117565
Chen, L., Hu, X., Zheng, C., Huang, Q., Xu, J., You, X., & Wang, C. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1981945
“Reprogramming-associated changes, mixed endocrine identity and the safety of immune-evasion edits must be assessed before clinical use (14, 27, 32).”
InfluentialAntonov, D., Loguinova, M. Y., Fan, H., Sazonova, E. V., Sosnovtseva, A. O., Karpov, D. S., Molchanov, A. D., Nikolenko, V. N., Chekhonin, V. P., & Mokrysheva, N. G. (2026) · Cells · doi:10.3390/cells15201902
Human brain cellular xenografts in neuroimmunology and beyond
Fattorelli, N., Martínez‐Muriana, A., Perry, V. H., & Mancuso, R. (2026) · Immunity · doi:10.1016/j.immuni.2026.09.024
Targeted cell deposition for lung re-endothelialization
Chan, J. K. D., Chadwick, E. A., Taniguchi, D., Ahmadipour, M., Suzuki, T., Romero, D. A., Amon, C. H., Waddell, T., Karoubi, G., & Bazylak, A. (2026) · Biomechanics and Modeling in Mechanobiology · doi:10.1007/s10237-026-02129-8
“…is an emerging approach in lung bioengineering which aims to reduce the immunological complications via repopulation of acellular scaffolds with non-immunogenic universal cell lines or recipient-derived autologous cells (Han et al. 2019; Ott et al. 2010; Petersen et al. 2010; Simpson et al. 2023).”
Engineering an Implantable Bioartificial Pancreas to Balance Transport, Containment, and Retrieval
Shi, H., Li, Y., He, C., & Sun, B. (2026) · Artificial Organs · doi:10.1111/aor.70254
van Wijk, A., den Berg, L. V., Velraeds, I. B. M., Zuluaga, V. O., Peereboom, E., Rabelink, M., Zaldumbide, A., Hoeben, R. C., Goumans, M., Spierings, E., et al. (2026) · Advanced Healthcare Materials · doi:10.1002/adhm.71737
“In tissue donor-PBMC combination 16, where exposure to PBMCs strongly increased IFN γ secretion in control tissues, transduction with LV-US2-Spi9 suppressed this response.”
El‐Sehrawy, A. A. M. A., Khaleel, Z. T., Refatovich, G. R., Koka, N. A., Baig, M. R., Srivastav, S. K., abdullah, S. S., Jabir, M. S., Bainsal, N., & Smerat, A. (2026) · Artificial Organs · doi:10.1111/aor.70242
Kim, D., Choo, S., & Lee, S.-H. S. (2026) · Journal of Cellular Physiology · doi:10.1002/jcp.70226
“Han et al. (2019) engineered iPSCs with multiplex knockout of human leukocyte antigen (HLA)‐”
Induced pluripotent stem cells from discovery to translation
Lee, J., Herron, T. J., Studer, L., Mummery, C. L., & Wu, J. C. (2026) · Nature Medicine · doi:10.1038/s41591-026-04584-3 · Cited by 2
“To move from individualized deployment to population-scale use, immune engineering will be required to treat alloreactivity as a controllable product attribute, reducing reliance on intensive matching or immunosuppression to make off-the-shelf distribution increasingly feasible 53,143,176 .”
Hassanein, A., Cyprian, F., & Akhtar, S. (2026) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2026.2721412
“This is achieved by knocking out immune-stimulating genes/markers involved in antigen presentation within the islet cells, while knocking in certain immune-inhibiting genes/markers [20,25].”
Universal CAR-T cell therapy: mechanisms and evasion strategies of bidirectional immune rejection
Ding, L., Zhao, L., Zhang, M., Chen, T., & Guo, Z. (2026) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2026.189690
Guiding pluripotent stem cell therapies past the immune system
Pizzato, H. A., & Bhattacharya, D. (2026) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szag051
“Most PSC immune evasion strategies employ genetic ablation of HLA molecules directly 21 or factors required for their surface expression 22–25 (Figure 1A). β 2-microglobulin ( β 2M) is a common subunit for HLA-I, and many studies have demonstrated its loss in PSCs is effective in preventing HLA-I…”
Gene-Edited Stem Cells for Ischemic Vascular Disease: Current Advances and Future Perspectives
Han, S., & Kim, S.-W. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48070681
“…pluripotent stem cells lacking key immune recognition molecules exhibited prolonged survival following transplantation, whereas Han et al. further demonstrated that multiplex genome editing could generate universal donor-like human pluripotent stem cells with enhanced graft persistence [21,27].”
Transient culture of adult human hepatocytes as organoids improves engineered liver engraftment
Saxton, S. H., Kang, I., Mitchell, S., Lotto, J., Upadhyay, A., Zou, C.-H., Quirk, C., McCray, T. N., Prado, O., Johansson, F., et al. (2026) · Biomaterials · doi:10.1016/j.biomaterials.2026.124465
From autologous to universal Treg therapies
Plaisse, C., Bézie, S., & Guillonneau, C. (2026) · Trends Open · doi:10.1016/j.treopn.2026.05.005
Generation of therapeutic T cells from human induced pluripotent stem cells
Wang, B., & Kaneko, S. (2026) · Inflammation and Regeneration · doi:10.1186/s41232-026-00425-5
“…translation of iPSC-derived immunotherapies, we established Shinobi Therapeutics, integrating our proprietary differentiation technol-ogy—which reliably regenerates highly potent, cytotoxic CD8αβ T cells—with an advanced hypo-immune strategy developed in collaboration with our U.S. partners [32].”
Induced Pluripotent Stem Cells and Gene Editing: A Transformative Era in Regenerative Medicine
Mathivanan, S., Balaji, A., Syed Mohamed Omar, S., Babu, H., Sujan, S., & Thilan, D. (2026) · International Journal of Drug Delivery Technology · doi:10.25258/ijddt.16.5.136
Boyarskikh, U., Serych, A., Khrapov, E., Shamovskaya, D., & Filipenko, M. (2026) · Bulletin of experimental biology and medicine · doi:10.1007/s10517-026-06739-1
REWRITE Enables Locus-Scale Engineering of Synthetic HLA Haplotypes in Human Pluripotent Stem CellsPreprint
Generoso, S., Levovitz, S., Jaramillo, S., Kim, M., Dara, S., Phen, S. F., Yi, B., Yanagi, T., DesMarais, T. L., Agmon, N., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.16.676382 · Cited by 1
Naumovas, D., Rojas-Araya, B., Polanco, C. M., Andrade, V., Čekauskienė, R., Valatkaite-Rakstiene, B., Laurinaitytė, I., Jakubauskas, A., Stoškus, M., Griškevičius, L., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1626787
Zhang, N., Yang, Y., Chen, M.-Q., Zou, Q., Quan, L.-Q., Huang, J., Zhang, Q.-J., Zhao, Y., Ouyang, Z., Zhang, Z., et al. (2025) · bioRxiv · doi:10.1101/2025.09.03.673895
Maloney, K., Azar, W. S., McKenney, J., Upasani, P., & Gallicano, I. (2025) · Harvard Medical Student Review · doi:10.65539/xdtar040
Stem Cell Therapy in Ischemic Heart Failure
Guo, Q., & Yang, H. (2025) · American Journal of Cardiovascular Drugs · doi:10.1007/s40256-025-00741-0
“Mutations in pseudogenes such as HLA-H may lead to off-target effects, and residual T cell and immune cell responses can interfere with the clinical translation of hypoimmunogenic stem cells [172].”
Heart Regeneration for Clinical Application
Tani, H., & Ieda, M. (2024) · Internal Medicine · doi:10.2169/internalmedicine.4711-24
Dysregulation of immune tolerance to autologous iPSCs and their differentiated derivatives (review)
Bogomiakova, M. E., Bogomazova, A. N., & Lagarkova, M. A. (2024) · Biochemistry (Moscow) · doi:10.31857/s0320972524050036
Dysregulation of Immune Tolerance to Autologous iPSCs and Their Differentiated Derivatives
Bogomiakova, M. E., Bogomazova, A. N., & Lagarkova, M. A. (2024) · Biochemistry (Moscow) · doi:10.1134/s0006297924050031 · Cited by 1
“Differences in cytotoxicity and number of CD107a + , i.e., degranulated NK-cells cocultured with the wild-type SMCs or SMCs not expressing HLA class I, were statistically insignificant [55].”
Vulnerabilität stammzellabgeleiteter β-Zellen gegenüber proinflammatorischen Zytokinen
Naujok, O. (2023) · Diabetologie und Stoffwechsel · doi:10.1055/a-2102-3967
Toward Improving Immunotolerance for Stem Cell-Derived IsletsPreprint
Zhou, Q., Li, H., Gerace, D., Nikolskly, I., Wang, X., Kenty-Ryu, J., Zhang, J.-P., Hinderhofer, M., Robinson, E., & Melton, D. (2022) · bioRxiv · doi:10.1101/2022.09.15.508091
“Projects aimed at preventing allo-rejection include human leukocyte antigen (HLA) haplotype bank or hypoimmunogenic human induced pluripotent stem cells (IPSCs)(6-9).”
BackgroundSelf-citationRetuning hepatocytes improves their functional engraftment
Tchorz, J. S. (2022) · Hepatology · doi:10.1002/hep.32513
“Alternatively, it would be interesting to evaluate the engraftment and regenerative potential of iHEPs generated from hypoimmunogenic human pluripotent stem cells.[10] Therapies enabling rematuration of hepatocytes in vivo would also be exciting and may provide additional benefits to patients because such reprogrammed…”
Background
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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