CoChat
Sign Up
Cited by 32Pluripotent Stem Cells ResearchPancreatic function and diabetesCRISPR and Genetic Engineering

Genetic Engineering of Immune Evasive Stem Cell-Derived Islets

Open access
Sackett, Sara D., Kaplan, Samuel J., Mitchell, Samantha A., Brown, Matthew E., Burrack, Adam L., Grey, Shane, Huangfu, Danwei, Odorico, Jon·2022·Transplant International
DOI 10.3389/ti.2022.10817PMC PMC9762357
Open this paper in CoChat — free accountOpen PDF

Abstract

Genome editing has the potential to revolutionize many investigative and therapeutic strategies in biology and medicine. In the field of regenerative medicine, one of the leading applications of genome engineering technology is the generation of immune evasive pluripotent stem cell-derived somatic cells for transplantation. In particular, as more functional and therapeutically relevant human pluripotent stem cell-derived islets (SCDI) are produced in many labs and studied in clinical trials, there is keen interest in studying the immunogenicity of these cells and modulating allogeneic and autoimmune immune responses for therapeutic benefit. Significant experimental work has already suggested that elimination of Human Leukocytes Antigen (HLA) expression and overexpression of immunomodulatory genes can impact survival of a variety of pluripotent stem cell-derived somatic cell types. Limited work published to date focuses on stem cell-derived islets and work in a number of labs is ongoing. Rapid progress is occurring in the genome editing of human pluripotent stem cells and their progeny focused on evading destruction by the immune system in transplantation models, and while much research is still needed, there is no doubt the combined technologies of genome editing and stem cell therapy will profoundly impact transplantation medicine in the future.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/ti.2022.10817

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Genes targeted include the HLA class I genes either directly or by editing β2-microglobulin, the light chain of the HLA class I dimer.

    “Genes targeted include the HLA class I genes either directly or by editing β2microglobulin, the light chain of the HLA class I dimer.”

    From The future of type 1 diabetes therapy (2025) · cites this paper as [75]

    The genetic-modifications sections (page unavailable) describe both direct knockout of HLA class I genes and B2M editing that disrupts stable MHC class I formation. Our copy does not explicitly identify β2-microglobulin as the light chain of an HLA class I dimer, so that structural detail is not verified by this source. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Additional steps can also be applied, including reduction in major histocompatibility complex class II expression, protection from natural killer cells, and protection from cytokines.

    “Additional steps can also be applied, including reduction in major histocompatibility complex class II expression, protection from natural killer cells, and protection from cytokines.”

    From The future of type 1 diabetes therapy (2025) · cites this paper as [75]

    The genetic-modifications sections (pages unavailable in our copy) describe reducing MHC class II expression and engineering protection from natural killer cells. The Mechanisms of Islet Destruction section proposes ways to reduce responses to cytokine-related inflammation, but says protection of stem cell-derived islets by cytokine inhibitors has not been studied; it does not establish that this protection can be applied. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The second approach is to generate hypoimmune cells by using genome editing tools, such as CRISPR, to delete genes within the transplanted cells that the immune system uses to recognise foreign cells or to overexpress genes that can reduce immune attack.

    “The second approach is to generate hypoimmune cells by using genome editing tools, such as CRISPR, to delete genes within the transplanted cells that the immune system uses to recognise foreign cells or to overexpress genes that can reduce immune attack.75”

    From The future of type 1 diabetes therapy (2025) · cites this paper as [75]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 121 · Cited by 32

Research works printed but not linked: 105

  1. [1]Yuen L Saeedi P Riaz M Karuranga S Divakar H Levitt N Projections of the Prevalence of Hyperglycaemia in Pregnancy in 2019 and beyond: Results from the International Diabetes Federation Diabetes Atlas, 9th Edition. Diabetes Res Clin Pract (2019) 157: 107841. 10.1016/j.diabres.2019.107841 31518656 · DOI
  2. [2]Maahs DM West NA Lawrence JM Mayer-Davis EJ. Epidemiology of Type 1 Diabetes. Endocrinol Metab Clin North Am (2010) 39: 481– 97. 10.1016/j.ecl.2010.05.011 20723815 PMC2925303 · DOI · Paper page
  3. [3]Mayer-Davis EJ Lawrence JM Dabelea D Divers J Isom S Dolan L Incidence Trends of Type 1 and Type 2 Diabetes Among Youths, 2002-2012. N Engl J Med (2017) 376: 1419– 29. 10.1056/NEJMoa1610187 28402773 PMC5592722 · DOI · Paper page
  4. [5]Rother KI Harlan DM. Challenges Facing Islet Transplantation for the Treatment of Type 1 Diabetes Mellitus. J Clin Invest (2004) 114: 877– 83. 10.1172/JCI23235 15467822 PMC518676 · DOI
  5. [6]Agulnick AD Ambruzs DM Moorman MA Bhoumik A Cesario RM Payne JK Insulin-Producing Endocrine Cells Differentiated In Vitro from Human Embryonic Stem Cells Function in Macroencapsulation Devices In Vivo. Stem Cell Transl Med (2015) 4: 1214– 22. 10.5966/sctm.2015-0079 PMC4572906 26304037 · DOI · Paper page
  6. [7]Hogrebe NJ Augsornworawat P Maxwell KG Velazco-Cruz L Millman JR. Targeting the Cytoskeleton to Direct Pancreatic Differentiation of Human Pluripotent Stem Cells. Nat Biotechnol (2020) 38: 460– 70. 10.1038/s41587-020-0430-6 32094658 PMC7274216 · DOI · Paper page
  7. [11]Rezania A Bruin JE Arora P Rubin A Batushansky I Asadi A Reversal of Diabetes with Insulin-Producing Cells Derived In Vitro from Human Pluripotent Stem Cells. Nat Biotechnol (2014) 32: 1121– 33. 10.1038/nbt.3033 25211370 · DOI · Paper page
  8. [12]Shapiro AMJ Thompson D Donner TW Bellin MD Hsueh W Pettus J Insulin Expression and C-Peptide in Type 1 Diabetes Subjects Implanted with Stem Cell-Derived Pancreatic Endoderm Cells in an Encapsulation Device. Cell Rep Med (2021) 2: 100466. 10.1016/j.xcrm.2021.100466 35028608 PMC8714853 · DOI · Paper page
  9. [13]Tremmel DM Mitchell SA Sackett SD Odorico JS. Mimicking Nature-Made Beta Cells: Recent Advances towards Stem Cell-Derived Islets. Curr Opin Organ Transpl (2019) 24: 574– 81. 10.1097/MOT.0000000000000687 PMC6925596 31433306 · DOI
  10. [14]Velazco-Cruz L Goedegebuure MM Millman JR. Advances toward Engineering Functionally Mature Human Pluripotent Stem Cell-Derived Beta Cells. Front Bioeng Biotechnol (2020) 8: 786. 10.3389/fbioe.2020.00786 32733873 PMC7363766 · DOI
  11. [16]Millman JR Xie C Van Dervort A Gurtler M Pagliuca FW Melton DA. Generation of Stem Cell-Derived Beta-Cells from Patients with Type 1 Diabetes. Nat Commun (2016) 7: 11463. 10.1038/ncomms11463 27163171 PMC4866045 · DOI
  12. [17]Siehler J Blochinger AK Meier M Lickert H. Engineering Islets from Stem Cells for Advanced Therapies of Diabetes. Nat Rev Drug Discov (2021) 20: 920– 40. 10.1038/s41573-021-00262-w 34376833 · DOI · Paper page
  13. [19]D'Amour KA Agulnick AD Eliazer S Kelly OG Kroon E Baetge EE. Efficient Differentiation of Human Embryonic Stem Cells to Definitive Endoderm. Nat Biotechnol (2005) 23: 1534– 41. 10.1038/nbt1163 16258519 · DOI · Paper page
  14. [20]D'Amour KA Bang AG Eliazer S Kelly OG Agulnick AD Smart NG Production of Pancreatic Hormone-Expressing Endocrine Cells from Human Embryonic Stem Cells. Nat Biotechnol (2006) 24: 1392– 401. 10.1038/nbt1259 17053790 · DOI
  15. [21]Henry RR Pettus J Wilensky JON Shapiro AJ Senior PA Roep B Initial Clinical Evaluation of VC-01TM Combination Product—A Stem Cell–Derived Islet Replacement for Type 1 Diabetes (T1D). Diabetes (2018) 67: 138– OR. 10.2337/db18-138-or · DOI
  16. [24]Rezania A Bruin JE Riedel MJ Mojibian M Asadi A Xu J Maturation of Human Embryonic Stem Cell-Derived Pancreatic Progenitors into Functional Islets Capable of Treating Pre-existing Diabetes in Mice. Diabetes (2012) 61: 2016– 29. 10.2337/db11-1711 22740171 PMC3402300 · DOI · Paper page
  17. [25]Russ HA Parent AV Ringler JJ Hennings TG Nair GG Shveygert M Controlled Induction of Human Pancreatic Progenitors Produces Functional Beta-like Cells In Vitro. EMBO J (2015) 34: 1759– 72. 10.15252/embj.201591058 25908839 PMC4516429 · DOI · Paper page
  18. [26]Sibley RK Sutherland DE Goetz F Michael AF. Recurrent Diabetes Mellitus in the Pancreas Iso- and Allograft. A Light and Electron Microscopic and Immunohistochemical Analysis of Four Cases. Lab Invest (1985) 53: 132– 44. 3894793
  19. [27]Sutherland DE Goetz FC Sibley RK. Recurrence of Disease in Pancreas Transplants. Diabetes (1989) 38(1): 85– 7. 10.2337/diab.38.1.s85 2642862 · DOI
  20. [28]Burrack AL Martinov T Fife BT. T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes. Front Endocrinol (Lausanne) (2017) 8: 343. 10.3389/fendo.2017.00343 29259578 PMC5723426 · DOI
  21. [29]Marino J Paster J Benichou G. Allorecognition by T Lymphocytes and Allograft Rejection. Front Immunol (2016) 7: 582. 10.3389/fimmu.2016.00582 28018349 PMC5155009 · DOI
  22. [30]Monti P Vignali D Piemonti L. Monitoring Inflammation, Humoral and Cell-Mediated Immunity in Pancreas and Islet Transplants. Curr Diabetes Rev (2015) 11: 135– 43. 10.2174/1573399811666150317125820 25777058 PMC5398085 · DOI
  23. [31]Phillips JM Parish NM Raine T Bland C Sawyer Y De La Pena H Type 1 Diabetes Development Requires Both CD4+ and CD8+ T Cells and Can Be Reversed by Non-depleting Antibodies Targeting Both T Cell Populations. Rev Diabet Stud (2009) 6: 97– 103. 10.1900/RDS.2009.6.97 19806239 PMC2779016 · DOI
  24. [32]Alkemade GM Clemente-Casares X Yu Z Xu BY Wang J Tsai S Local Autoantigen Expression as Essential Gatekeeper of Memory T-Cell Recruitment to Islet Grafts in Diabetic Hosts. Diabetes (2013) 62: 905– 11. 10.2337/db12-0600 23160528 PMC3581210 · DOI
  25. [33]Pietra BA Wiseman A Bolwerk A Rizeq M Gill RG. CD4 T Cell-Mediated Cardiac Allograft Rejection Requires Donor but Not Host MHC Class II. J Clin Invest (2000) 106: 1003– 10. 10.1172/JCI10467 11032860 PMC314344 · DOI
  26. [35]Johansson H Lukinius A Moberg L Lundgren T Berne C Foss A Tissue Factor Produced by the Endocrine Cells of the Islets of Langerhans Is Associated with a Negative Outcome of Clinical Islet Transplantation. Diabetes (2005) 54: 1755– 62. 10.2337/diabetes.54.6.1755 15919797 · DOI
  27. [36]Eldor R Abel R Sever D Sadoun G Peled A Sionov R Inhibition of Nuclear Factor-Κb Activation in Pancreatic β-cells Has a Protective Effect on Allogeneic Pancreatic Islet Graft Survival. PloS one (2013) 8: e56924. 10.1371/journal.pone.0056924 23437272 PMC3578930 · DOI
  28. [37]Shrestha P Batra L Tariq Malik M Tan M Yolcu ES Shirwan H. Immune Checkpoint CD47 Molecule Engineered Islets Mitigate Instant Blood-Mediated Inflammatory Reaction and Show Improved Engraftment Following Intraportal Transplantation. Am J Transpl (2020) 20: 2703– 14. 10.1111/ajt.15958 32342638 · DOI
  29. [38]Gornalusse GG Hirata RK Funk S Riolobos L Lopes VS Manske G HLA-E-expressing Pluripotent Stem Cells Escape Allogeneic Responses and Lysis by NK Cells. Nat Biotechnol (2017) 35: 765– 72. 10.1038/nbt.3860 28504668 PMC5548598 · DOI · Paper page
  30. [40]Smyth LA Hervouet C Hayday T Becker PD Ellis R Lechler RI Acquisition of MHC:peptide Complexes by Dendritic Cells Contributes to the Generation of Antiviral CD8+ T Cell Immunity In Vivo. J Immunol (2012) 189: 2274– 82. 10.4049/jimmunol.1200664 22821960 · DOI
  31. [41]Benichou G Wang M Ahrens K Madsen JC. Extracellular Vesicles in Allograft Rejection and Tolerance. Cell Immunol (2020) 349: 104063. 10.1016/j.cellimm.2020.104063 32087929 PMC7231511 · DOI · Paper page
  32. [42]Bracamonte-Baran W Florentin J Zhou Y Jankowska-Gan E Haynes WJ Zhong W Modification of Host Dendritic Cells by Microchimerism-Derived Extracellular Vesicles Generates Split Tolerance. Proc Natl Acad Sci U S A (2017) 114: 1099– 104. 10.1073/pnas.1618364114 28096390 PMC5293109 · DOI
  33. [43]Marino J Babiker-Mohamed MH Crosby-Bertorini P Paster JT LeGuern C Germana S Donor Exosomes rather Than Passenger Leukocytes Initiate Alloreactive T Cell Responses after Transplantation. Sci Immunol (2016) 1: aaf8759. 10.1126/sciimmunol.aaf8759 27942611 PMC5142759 · DOI
  34. [44]Schwarz C Mahr B Muckenhuber M Wekerle T. Belatacept/CTLA4Ig: an Update and Critical Appraisal of Preclinical and Clinical Results. Expert Rev Clin Immunol (2018) 14: 583– 92. 10.1080/1744666X.2018.1485489 29874474 · DOI
  35. [45]Zammit NW Walters SN Seeberger KL O'Connell PJ Korbutt GS Grey ST. A20 as an Immune Tolerance Factor Can Determine Islet Transplant Outcomes. JCI Insight (2019) 4: 131028. 10.1172/jci.insight.131028 31581152 PMC6948770 · DOI
  36. [46]Zheng D Wang X Zhang Z Li E Yeung C Borkar R Engineering of Human Mesenchymal Stem Cells Resistant to Multiple Natural Killer Subtypes. Int J Biol Sci (2022) 18: 426– 40. 10.7150/ijbs.64640 34975342 PMC8692142 · DOI
  37. [47]Lei J Coronel MM Yolcu ES Deng H Grimany-Nuno O Hunckler MD FasL Microgels Induce Immune Acceptance of Islet Allografts in Nonhuman Primates. Sci Adv (2022) 8: eabm9881. 10.1126/sciadv.abm9881 35559682 PMC9106299 · DOI · Paper page
  38. [49]Alagpulinsa DA Cao JJL Sobell D Poznansky MC. Harnessing CXCL12 Signaling to Protect and Preserve Functional Beta-Cell Mass and for Cell Replacement in Type 1 Diabetes. Pharmacol Ther (2019) 193: 63– 74. 10.1016/j.pharmthera.2018.08.011 30149101 · DOI
  39. [50]Chen T Yuan J Duncanson S Hibert ML Kodish BC MylavaGanam G Alginate Encapsulant Incorporating CXCL12 Supports Long-Term Allo- and Xenoislet Transplantation without Systemic Immune Suppression. Am J Transpl (2015) 15: 618– 27. 10.1111/ajt.13049 25693473 · DOI
  40. [51]Drukker M Benvenisty N. The Immunogenicity of Human Embryonic Stem-Derived Cells. Trends Biotechnol (2004) 22: 136– 41. 10.1016/j.tibtech.2004.01.003 15036864 · DOI
  41. [52]Drukker M Katz G Urbach A Schuldiner M Markel G Itskovitz-Eldor J Characterization of the Expression of MHC Proteins in Human Embryonic Stem Cells. Proc Natl Acad Sci U S A (2002) 99: 9864– 9. 10.1073/pnas.142298299 12114532 PMC125045 · DOI
  42. [53]English K Wood KJ. Immunogenicity of Embryonic Stem Cell-Derived Progenitors after Transplantation. Curr Opin Organ Transpl (2011) 16: 90– 5. 10.1097/MOT.0b013e3283424faa 21150615 · DOI
  43. [54]Medzhitov R Janeway CA Jr.. How Does the Immune System Distinguish Self from Nonself? Semin Immunol (2000) 12: 185– 8. 10.1006/smim.2000.0230 10910738 · DOI
  44. [55]van der Torren CR Zaldumbide A Duinkerken G Brand-Schaaf SH Peakman M Stange G Immunogenicity of Human Embryonic Stem Cell-Derived Beta Cells. Diabetologia (2017) 60: 126– 33. 10.1007/s00125-016-4125-y 27787618 PMC6518073 · DOI
  45. [56]Castro-Gutierrez R Alkanani A Mathews CE Michels A Russ HA. Protecting Stem Cell Derived Pancreatic Beta-like Cells from Diabetogenic T Cell Recognition. Front Endocrinol (Lausanne) (2021) 12: 707881. 10.3389/fendo.2021.707881 34305820 PMC8299417 · DOI
  46. [57]Osum KC Burrack AL Martinov T Sahli NL Mitchell JS Tucker CG Interferon-gamma Drives Programmed Death-Ligand 1 Expression on Islet Beta Cells to Limit T Cell Function during Autoimmune Diabetes. Sci Rep (2018) 8: 8295. 10.1038/s41598-018-26471-9 29844327 PMC5974126 · DOI
  47. [58]Colli ML Hill JLE Marroqui L Chaffey J Dos Santos RS Leete P PDL1 Is Expressed in the Islets of People with Type 1 Diabetes and Is Up-Regulated by Interferons-Alpha And-Gamma via IRF1 Induction. EBioMedicine (2018) 36: 367– 75. 10.1016/j.ebiom.2018.09.040 30269996 PMC6197434 · DOI
  48. [60]Skowera A Ellis RJ Varela-Calvino R Arif S Huang GC Van-Krinks C CTLs Are Targeted to Kill Beta Cells in Patients with Type 1 Diabetes through Recognition of a Glucose-Regulated Preproinsulin Epitope. J Clin Invest (2008) 118: 3390– 402. 10.1172/JCI35449 18802479 PMC2542849 · DOI
  49. [61]Hsu PD Lander ES Zhang F. Development and Applications of CRISPR-Cas9 for Genome Engineering. Cell (2014) 157: 1262– 78. 10.1016/j.cell.2014.05.010 24906146 PMC4343198 · DOI · Paper page
  50. [62]Kishore S De Franco E Cardenas-Diaz FL Letourneau-Freiberg LR Sanyoura M Osorio-Quintero C A Non-coding Disease Modifier of Pancreatic Agenesis Identified by Genetic Correction in a Patient-Derived iPSC Line. Cell Stem Cell (2020) 27: 137– 46. 10.1016/j.stem.2020.05.001 32442395 PMC7335348 · DOI
  51. [63]Shi ZD Lee K Yang D Amin S Verma N Li QV Genome Editing in hPSCs Reveals GATA6 Haploinsufficiency and a Genetic Interaction with GATA4 in Human Pancreatic Development. Cell Stem Cell (2017) 20: 675– 88. 10.1016/j.stem.2017.01.001 28196600 PMC5419850 · DOI
  52. [64]Zhu Z Li QV Lee K Rosen BP Gonzalez F Soh CL Genome Editing of Lineage Determinants in Human Pluripotent Stem Cells Reveals Mechanisms of Pancreatic Development and Diabetes. Cell Stem Cell (2016) 18: 755– 68. 10.1016/j.stem.2016.03.015 27133796 PMC4892994 · DOI
  53. [65]Liu G Lin Q Jin S Gao C. The CRISPR-Cas Toolbox and Gene Editing Technologies. Mol Cel (2022) 82: 333– 47. 10.1016/j.molcel.2021.12.002 34968414 · DOI
  54. [66]Ran FA Hsu PD Lin CY Gootenberg JS Konermann S Trevino AE Double Nicking by RNA-Guided CRISPR Cas9 for Enhanced Genome Editing Specificity. Cell (2013) 154: 1380– 9. 10.1016/j.cell.2013.08.021 23992846 PMC3856256 · DOI · Paper page
  55. [67]Nelson JW Randolph PB Shen SP Everette KA Chen PJ Anzalone AV Engineered pegRNAs Improve Prime Editing Efficiency. Nat Biotechnol (2022) 40: 402– 10. 10.1038/s41587-021-01039-7 34608327 PMC8930418 · DOI · Paper page
  56. [68]Anzalone AV Randolph PB Davis JR Sousa AA Koblan LW Levy JM Search-and-replace Genome Editing without Double-Strand Breaks or Donor DNA. Nature (2019) 576: 149– 57. 10.1038/s41586-019-1711-4 31634902 PMC6907074 · DOI · Paper page
  57. [69]Ma S Viola R Sui L Cherubini V Barbetti F Egli D. β Cell Replacement after Gene Editing of a Neonatal Diabetes-Causing Mutation at the Insulin Locus. Stem Cel Rep (2018) 11: 1407– 15. 10.1016/j.stemcr.2018.11.006 PMC6294262 30503261 · DOI
  58. [70]Petrus-Reurer S Romano M Howlett S Jones JL Lombardi G Saeb-Parsy K. Immunological Considerations and Challenges for Regenerative Cellular Therapies. Commun Biol (2021) 4: 798. 10.1038/s42003-021-02237-4 34172826 PMC8233383 · DOI
  59. [71]Kobold S Guhr A Mah N Bultjer N Seltmann S Seiler Wulczyn AEM A Manually Curated Database on Clinical Studies Involving Cell Products Derived from Human Pluripotent Stem Cells. Stem Cel Rep (2020) 15: 546– 55. 10.1016/j.stemcr.2020.06.014 PMC7419703 32679065 · DOI
  60. [72]Lanza R Russell DW Nagy A. Engineering Universal Cells that Evade Immune Detection. Nat Rev Immunol (2019) 19: 723– 33. 10.1038/s41577-019-0200-1 31417198 · DOI
  61. [73]Latres E Finan DA Greenstein JL Kowalski A Kieffer TJ. Navigating Two Roads to Glucose Normalization in Diabetes: Automated Insulin Delivery Devices and Cell Therapy. Cell Metab (2019) 29: 545– 63. 10.1016/j.cmet.2019.02.007 30840911 · DOI
  62. [74]Kim A Lee KG Kwon Y Yang HM Habib O Off-the-Shelf, Immune-Compatible Human Embryonic Stem Cells Generated via CRISPR-Mediated Genome Editing. Stem Cel Rev Rep (2021) 17: 1053– 67. 10.1007/s12015-020-10113-7 PMC8166669 33423156 · DOI
  63. [75]Pardoll DM. The Blockade of Immune Checkpoints in Cancer Immunotherapy. Nat Rev Cancer (2012) 12: 252– 64. 10.1038/nrc3239 22437870 PMC4856023 · DOI · Paper page
  64. [76]Rong Z Wang M Hu Z Stradner M Zhu S Kong H An Effective Approach to Prevent Immune Rejection of Human ESC-Derived Allografts. Cell Stem Cell (2014) 14: 121– 30. 10.1016/j.stem.2013.11.014 24388175 PMC4023958 · DOI
  65. [77]Bix M Liao NS Zijlstra M Loring J Jaenisch R Raulet D. Rejection of Class I MHC-Deficient Haemopoietic Cells by Irradiated MHC-Matched Mice. Nature (1991) 349: 329– 31. 10.1038/349329a0 1987491 · DOI
  66. [78]Liao NS Bix M Zijlstra M Jaenisch R Raulet D. MHC Class I Deficiency: Susceptibility to Natural Killer (NK) Cells and Impaired NK Activity. Science (1991) 253: 199– 202. 10.1126/science.1853205 1853205 · DOI
  67. [79]Shi L Li W Liu Y Chen Z Hui Y Hao P Generation of Hypoimmunogenic Human Pluripotent Stem Cells via Expression of Membrane-Bound and Secreted β2m-HLA-G Fusion Proteins. Stem cells (2020) 38: 1423– 37. 10.1002/stem.3269 32930470 · DOI
  68. [81]Hoerster K Uhrberg M Wiek C Horn PA Hanenberg H Heinrichs S. HLA Class I Knockout Converts Allogeneic Primary NK Cells into Suitable Effectors for "Off-The-Shelf" Immunotherapy. Front Immunol (2020) 11: 586168. 10.3389/fimmu.2020.586168 33584651 PMC7878547 · DOI
  69. [82]Jaiswal S Jamieson CH Pang WW Park CY Chao MP Majeti R CD47 Is Upregulated on Circulating Hematopoietic Stem Cells and Leukemia Cells to Avoid Phagocytosis. Cell (2009) 138: 271– 85. 10.1016/j.cell.2009.05.046 19632178 PMC2775564 · DOI
  70. [84]Advani R Flinn I Popplewell L Forero A Bartlett NL Ghosh N CD47 Blockade by Hu5F9-G4 and Rituximab in Non-hodgkin's Lymphoma. N Engl J Med (2018) 379: 1711– 21. 10.1056/NEJMoa1807315 30380386 PMC8058634 · DOI
  71. [85]Ferreira LMR Meissner TB Tilburgs T Strominger JL. HLA-G: At the Interface of Maternal-Fetal Tolerance. Trends Immunol (2017) 38: 272– 86. 10.1016/j.it.2017.01.009 28279591 · DOI
  72. [86]Pazmany L Mandelboim O Vales-Gomez M Davis DM Reyburn HT Strominger JL. Protection from Natural Killer Cell-Mediated Lysis by HLA-G Expression on Target Cells. Science (1996) 274: 792– 5. 10.1126/science.274.5288.792 8864122 · DOI
  73. [87]Harding JS Vintersten-Nagy K Shutova MV Induction of Long-Term Allogeneic Cell Acceptance and Formation of Immune Privileged Tissue in Immunocompetent Hosts. bioRxiv (2019).
  74. [88]Misra PS Nostro MC. Designing Next-Generation Islet-like Cells from Human Pluripotent Stem Cells: Advances in Overcoming Allorejection and Recurrent Type 1 Diabetes. Curr Opin Endocr Metab Res (2022) 23: 100321. 10.1016/j.coemr.2022.100321 · DOI
  75. [89]Leite NC Sintov E Meissner TB Brehm MA Greiner DL Harlan DM Modeling Type 1 Diabetes In Vitro Using Human Pluripotent Stem Cells. Cell Rep (2020) 32: 107894. 10.1016/j.celrep.2020.107894 32668238 PMC7359783 · DOI
  76. [91]Chimienti R Baccega T Torchio S Manenti F Pellegrini S Cospito A Engineering of Immune Checkpoints B7-H3 and CD155 Enhances Immune Compatibility of MHC-I(-/-) iPSCs for Beta Cell Replacement. Cel Rep (2022) 40: 111423. 10.1016/j.celrep.2022.111423 PMC9532846 36170817 · DOI
  77. [92]Shultz LD Brehm MA Garcia-Martinez JV Greiner DL. Humanized Mice for Immune System Investigation: Progress, Promise and Challenges. Nat Rev Immunol (2012) 12: 786– 98. 10.1038/nri3311 23059428 PMC3749872 · DOI
  78. [93]Rajesh D Zhou Y Jankowska-Gan E Roenneburg DA Dart ML Torrealba J Th1 and Th17 Immunocompetence in Humanized NOD/SCID/IL2rgammanull Mice. Hum Immunol (2010) 71: 551– 9. 10.1016/j.humimm.2010.02.019 20298731 PMC2875879 · DOI
  79. [94]Kalscheuer H Danzl N Onoe T Faust T Winchester R Goland R A Model for Personalized In Vivo Analysis of Human Immune Responsiveness. Sci Transl Med (2012) 4: 125ra30. 10.1126/scitranslmed.3003481 PMC3697150 22422991 · DOI
  80. [95]Hermsen J Brown ME. Humanized Mouse Models for Evaluation of PSC Immunogenicity. Curr Protoc Stem Cel Biol (2020) 54: e113. 10.1002/cpsc.113 PMC7436941 32588980 · DOI
  81. [96]Shultz LD Keck J Burzenski L Jangalwe S Vaidya S Greiner DL Humanized Mouse Models of Immunological Diseases and Precision Medicine. Mamm Genome (2019) 30: 123– 42. 10.1007/s00335-019-09796-2 30847553 PMC6610695 · DOI
  82. [97]Lan P Tonomura N Shimizu A Wang S Yang YG. Reconstitution of a Functional Human Immune System in Immunodeficient Mice through Combined Human Fetal Thymus/liver and CD34+ Cell Transplantation. Blood (2006) 108: 487– 92. 10.1182/blood-2005-11-4388 16410443 · DOI
  83. [98]Brown ME Zhou Y McIntosh BE Norman IG Lou HE Biermann M A Humanized Mouse Model Generated Using Surplus Neonatal Tissue. Stem Cel Rep (2018) 10: 1175– 83. 10.1016/j.stemcr.2018.02.011 PMC5998340 29576539 · DOI
  84. [99]Kooreman NG de Almeida PE Stack JP Nelakanti RV Diecke S Shao NY Alloimmune Responses of Humanized Mice to Human Pluripotent Stem Cell Therapeutics. Cel Rep (2017) 20: 1978– 90. 10.1016/j.celrep.2017.08.003 PMC5573767 28834758 · DOI
  85. [100]Mold JE Venkatasubrahmanyam S Burt TD Michaelsson J Rivera JM Galkina SA Fetal and Adult Hematopoietic Stem Cells Give Rise to Distinct T Cell Lineages in Humans. Science (2010) 330: 1695– 9. 10.1126/science.1196509 21164017 PMC3276679 · DOI · Paper page
  86. [101]McIntosh BE Brown ME. No Irradiation Required: The Future of Humanized Immune System Modeling in Murine Hosts. Chimerism (2015) 6: 40– 5. 10.1080/19381956.2016.1162360 27171577 PMC5063082 · DOI
  87. [102]Billerbeck E Barry WT Mu K Dorner M Rice CM Ploss A. Development of Human CD4+FoxP3+ Regulatory T Cells in Human Stem Cell Factor-Granulocyte-Macrophage colony-stimulating Factor-And Interleukin-3-Expressing NOD-SCID IL2Rγ(null) Humanized Mice. Blood (2011) 117: 3076– 86. 10.1182/blood-2010-08-301507 21252091 PMC3062310 · DOI
  88. [103]McIntosh BE Brown ME Duffin BM Vereide DT Slukvin II Nonirradiated NOD, B6.SCID Il2rγ-/- Kit(W41/W41) (NBSGW) Mice Support Multilineage Engraftment of Human Hematopoietic Cells. Stem Cel Rep (2015) 4: 171– 80. 10.1016/j.stemcr.2014.12.005 PMC4325197 25601207 · DOI
  89. [104]Ito R Takahashi T Katano I Kawai K Kamisako T Ogura T Establishment of a Human Allergy Model Using Human IL-3/GM-CSF-transgenic NOG Mice. J Immunol (2013) 191: 2890– 9. 10.4049/jimmunol.1203543 23956433 · DOI
  90. [105]Yu H Borsotti C Schickel J-N Zhu S Strowig T Eynon EE A Novel Humanized Mouse Model with Significant Improvement of Class-Switched, Antigen-specific Antibody Production. Blood (2017) 129: 959– 69. 10.1182/blood-2016-04-709584 28077418 PMC5324713 · DOI
  91. [106]Liu Y-W Chen B Yang X Fugate JA Kalucki FA Futakuchi-Tsuchida A Human Embryonic Stem Cell-Derived Cardiomyocytes Restore Function in Infarcted Hearts of Non-human Primates. Nat Biotechnol (2018) 36: 597– 605. 10.1038/nbt.4162 29969440 PMC6329375 · DOI
  92. [107]Tao Y Vermilyea SC Zammit M Lu J Olsen M Metzger JM Autologous Transplant Therapy Alleviates Motor and Depressive Behaviors in Parkinsonian Monkeys. Nat Med (2021) 27: 632– 9. 10.1038/s41591-021-01257-1 33649496 PMC8198752 · DOI
  93. [108]Du Y Liang Z Wang S Sun D Wang X Liew SY Human Pluripotent Stem-Cell-Derived Islets Ameliorate Diabetes in Non-human Primates. Nat Med (2022) 28: 272– 82. 10.1038/s41591-021-01645-7 35115708 · DOI · Paper page
  94. [109]D’Souza SS Kumar A Weinfurter J Park MA Maufort J Tao L Generation of SIV-Resistant T Cells and Macrophages from Nonhuman Primate Induced Pluripotent Stem Cells with Edited CCR5 Locus. Stem Cel Rep (2022) 17: 953– 63. 10.1016/j.stemcr.2022.03.003 PMC9023799 35364011 · DOI
  95. [110]Little CJ Haynes WJ Huang L Daffada CM Wolfe BK Perrin E Robust Engraftment of Fetal Nonhuman Primate CD34-Positive Cells in Immune-Deficient Mice. J Leukoc Biol (2022) 112: 759– 69. n/a. 10.1002/JLB.5TA0921-481RR 35352381 PMC9522924 · DOI
  96. [111]Zhao T Zhang Z-N Rong Z Xu Y. Immunogenicity of Induced Pluripotent Stem Cells. Nature (2011) 474: 212– 5. 10.1038/nature10135 21572395 · DOI
  97. [112]de Almeida PE Meyer EH Kooreman NG Diecke S Dey D Sanchez-Freire V Transplanted Terminally Differentiated Induced Pluripotent Stem Cells Are Accepted by Immune Mechanisms Similar to Self-Tolerance. Nat Commun (2014) 5: 3903. 10.1038/ncomms4903 24875164 PMC4075468 · DOI
  98. [113]Moquin-Beaudry G Benabdallah B Maggiorani D Le O Li Y Colas C Autologous Humanized Mouse Models of iPSC-Derived Tumors Enable Characterization and Modulation of Cancer-Immune Cell Interactions. Cel Rep Methods (2022) 2: 100153. 10.1016/j.crmeth.2021.100153 PMC9017190 35474871 · DOI
  99. [114]Zhao T Zhang Z-n Westenskow PD Todorova D Hu Z Lin T Humanized Mice Reveal Differential Immunogenicity of Cells Derived from Autologous Induced Pluripotent Stem Cells. Cell Stem Cell (2015) 17: 353– 9. 10.1016/j.stem.2015.07.021 26299572 PMC9721102 · DOI
  100. [115]Li QV Dixon G Verma N Rosen BP Gordillo M Luo R Genome-scale Screens Identify JNK-JUN Signaling as a Barrier for Pluripotency Exit and Endoderm Differentiation. Nat Genet (2019) 51: 999– 1010. 10.1038/s41588-019-0408-9 31110351 PMC6545159 · DOI
  101. [116]Naxerova K Di Stefano B Makofske JL Watson EV de Kort MA Martin TD Integrated Loss- and Gain-Of-Function Screens Define a Core Network Governing Human Embryonic Stem Cell Behavior. Genes Dev (2021) 35: 1527– 47. 10.1101/gad.349048.121 34711655 PMC8559676 · DOI
  102. [117]Yang D Cho H Tayyebi Z Shukla A Luo R Dixon G CRISPR Screening Uncovers a central Requirement for HHEX in Pancreatic Lineage Commitment and Plasticity Restriction. Nat Cel Biol (2022) 24: 1064– 76. 10.1038/s41556-022-00946-4 PMC9283336 35787684 · DOI
  103. [118]Yilmaz A Braverman-Gross C Bialer-Tsypin A Peretz M Benvenisty N. Mapping Gene Circuits Essential for Germ Layer Differentiation via Loss-Of-Function Screens in Haploid Human Embryonic Stem Cells. Cell Stem Cell (2020) 27: 679– 91. 10.1016/j.stem.2020.06.023 32735778 · DOI
  104. [119]Cai EP Ishikawa Y Zhang W Leite NC Li J Hou S Genome-scale In Vivo CRISPR Screen Identifies RNLS as a Target for Beta Cell protection in Type 1 Diabetes. Nat Metab (2020) 2: 934– 45. 10.1038/s42255-020-0254-1 32719542 PMC7502486 · DOI
  105. [122]Brehm MA Kenney LL Wiles MV Low BE Tisch RM Burzenski L Lack of Acute Xenogeneic Graft- Versus-Host Disease, but Retention of T-Cell Function Following Engraftment of Human Peripheral Blood Mononuclear Cells in NSG Mice Deficient in MHC Class I and II Expression. FASEB J (2019) 33: 3137– 51. 10.1096/fj.201800636R 30383447 PMC6404556 · DOI

Authors
Sackett, S. D., Kaplan, S. J., Mitchell, S. A., Brown, M. E., Burrack, A. L., Grey, S., Huangfu, D., & Odorico, J.
Affiliations
  • University of Wisconsin–Madison (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • University of Minnesota (US)
  • Garvan Institute of Medical Research (AU)
Corresponding author
Sackett, Sara D.
ORCID
Venue
Transplant International
Publisher
Frontiers Media SA
Published
2022-12-05
Volume
35
Pages
10817-10817
ISSN
  • 0934-0874 (ISSN-L)
  • 1432-2277
DOI
10.3389/ti.2022.10817
PMC
PMC9762357
OpenAlex
W4311624781
Cited by
32
References
121
Citations by year
2026: 8 · 2025: 13 · 2024: 9 · 2023: 2
FWCI
0.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Transplant International (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Defense (W81XWH2010669)
  • Wisconsin Alumni Research Foundation
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (U01HL134764)
  • National Cancer Institute (P30CA008748)
  • National Institute of Allergy and Infectious Diseases (75N93021C00004)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK096239)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
Keywords
genome editing, stem cell-derived islets, immune evasion, immunomodulatory genes, pluripotent stem cells, islet transplantation, allogeneic response, autoimmunity, regenerative medicine
MeSH terms
Gene Editing, Genetic Engineering, Humans, Islets of Langerhans, Stem Cell Transplantation, Pluripotent Stem Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review