Skip to main content

Advertisement

SpringerLink
Log in

Emerging Human Pluripotent Stem Cell-Based Human–Animal Brain Chimeras for Advancing Disease Modeling and Cell Therapy for Neurological Disorders

  • Review
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Human pluripotent stem cell (hPSC) models provide unprecedented opportunities to study human neurological disorders by recapitulating human-specific disease mechanisms. In particular, hPSC-based human–animal brain chimeras enable the study of human cell pathophysiology in vivo. In chimeric brains, human neural and immune cells can maintain human-specific features, undergo maturation, and functionally integrate into host brains, allowing scientists to study how human cells impact neural circuits and animal behaviors. The emerging human–animal brain chimeras hold promise for modeling human brain cells and their interactions in health and disease, elucidating the disease mechanism from molecular and cellular to circuit and behavioral levels, and testing the efficacy of cell therapy interventions. Here, we discuss recent advances in the generation and applications of using human–animal chimeric brain models for the study of neurological disorders, including disease modeling and cell therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4 

Similar content being viewed by others

References

  1. Okano H, Morimoto S. iPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders. Cell Stem Cell 2022, 29: 189–208.

    Article  CAS  PubMed  Google Scholar 

  2. Eichmüller OL, Knoblich JA. Human cerebral organoids—a new tool for clinical neurology research. Nat Rev Neurol 2022, 18: 661–680.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Corsini NS, Knoblich JA. Human organoids: New strategies and methods for analyzing human development and disease. Cell 2022, 185: 2756–2769.

    Article  CAS  PubMed  Google Scholar 

  4. Seto Y, Eiraku M. Human brain development and its in vitro recapitulation. Neurosci Res 2019, 138: 33–42.

    Article  PubMed  Google Scholar 

  5. Iwata R, Casimir P, Erkol E, Boubakar L, Planque M, Gallego López IM. Mitochondria metabolism sets the species-specific tempo of neuronal development. Science 2023, 379: eabn4705.

    Article  CAS  PubMed  Google Scholar 

  6. Beaulieu-Laroche L, Brown NJ, Hansen M, Toloza EHS, Sharma J, Williams ZM, et al. Allometric rules for mammalian cortical layer 5 neuron biophysics. Nature 2021, 600: 274–278.

    Article  CAS  PubMed  ADS  Google Scholar 

  7. Linaro D, Vermaercke B, Iwata R, Ramaswamy A, Libé-Philippot B, Boubakar L, et al. Xenotransplanted human cortical neurons reveal species-specific development and functional integration into mouse visual circuits. Neuron 2019, 104: 972-986.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Geirsdottir L, David E, Keren-Shaul H, Weiner A, Bohlen SC, Neuber J, et al. Cross-species single-cell analysis reveals divergence of the primate microglia program. Cell 2020, 181: 746.

    Article  CAS  PubMed  Google Scholar 

  9. Gosselin D, Skola D, Coufal NG, Holtman IR, Schlachetzki JCM, Sajti E, et al. An environment-dependent transcriptional network specifies human microglia identity. Science 2017, 356: eaal3222.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Galatro TF, Holtman IR, Lerario AM, Vainchtein ID, Brouwer N, Sola PR, et al. Transcriptomic analysis of purified human cortical microglia reveals age-associated changes. Nat Neurosci 2017, 20: 1162–1171.

    Article  CAS  PubMed  Google Scholar 

  11. Falcone C, Martínez-Cerdeño V. Astrocyte evolution and human specificity. Neural Regen Res 2023, 18: 131–132.

    Article  PubMed  Google Scholar 

  12. Han X, Chen M, Wang F, Windrem M, Wang S, Shanz S, et al. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 2013, 12: 342–353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Oberheim NA, Takano T, Han X, He W, Lin JHC, Wang F, et al. Uniquely hominid features of adult human astrocytes. J Neurosci 2009, 29: 3276–3287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gargareta VI, Reuschenbach J, Siems SB, Sun T, Piepkorn L, Mangana C, et al. Conservation and divergence of myelin proteome and oligodendrocyte transcriptome profiles between humans and mice. eLife 2022, 11: e77019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. de Rus Jacquet A, Denis HL, Cicchetti F, Alpaugh M. Current and future applications of induced pluripotent stem cell-based models to study pathological proteins in neurodegenerative disorders. Mol Psychiatry 2021, 26: 2685–2706.

    Article  Google Scholar 

  16. Zhao X, Bhattacharyya A. Human models are needed for studying human neurodevelopmental disorders. Am J Hum Genet 2018, 103: 829–857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Espuny-Camacho I, Arranz AM, Fiers M, Snellinx A, Ando K, Munck S, et al. Hallmarks of Alzheimer’s disease in stem-cell-derived human neurons transplanted into mouse brain. Neuron 2017, 93: 1066-1081.e8.

    Article  CAS  PubMed  Google Scholar 

  18. Balusu S, Horré K, Thrupp N, Craessaerts K, Snellinx A, Serneels L, et al. MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer’s disease. Science 2023, 381: 1176–1182.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  19. Chang AN, Liang Z, Dai HQ, Chapdelaine-Williams AM, Andrews N, Bronson RT, et al. Neural blastocyst complementation enables mouse forebrain organogenesis. Nature 2018, 563: 126–130.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  20. Wu J, Platero-Luengo A, Sakurai M, Sugawara A, Gil MA, Yamauchi T, et al. Interspecies chimerism with mammalian pluripotent stem cells. Cell 2017, 168: 473-486.e15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Muotri AR, Nakashima K, Toni N, Sandler VM, Gage FH. Development of functional human embryonic stem cell-derived neurons in mouse brain. Proc Natl Acad Sci U S A 2005, 102: 18644–18648.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  22. Ourednik V, Ourednik J, Flax JD, Zawada WM, Hutt C, Yang C, et al. Segregation of human neural stem cells in the developing primate forebrain. Science 2001, 293: 1820–1824.

    Article  CAS  PubMed  ADS  Google Scholar 

  23. Brüstle O, Choudhary K, Karram K, Hüttner A, Murray K, Dubois-Dalcq M, et al. Chimeric brains generated by intraventricular transplantation of fetal human brain cells into embryonic rats. Nat Biotechnol 1998, 16: 1040–1044.

    Article  PubMed  Google Scholar 

  24. Revah O, Gore F, Kelley KW, Andersen J, Sakai N, Chen X, et al. Maturation and circuit integration of transplanted human cortical organoids. Nature 2022, 610: 319–326.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  25. Xu R, Li X, Boreland AJ, Posyton A, Kwan K, Hart RP, et al. Human iPSC-derived mature microglia retain their identity and functionally integrate in the chimeric mouse brain. Nat Commun 2020, 11: 1577.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  26. Espuny-Camacho I, Michelsen KA, Gall D, Linaro D, Hasche A, Bonnefont J, et al. Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo. Neuron 2013, 77: 440–456.

    Article  CAS  PubMed  Google Scholar 

  27. Windrem MS, Schanz SJ, Guo M, Tian GF, Washco V, Stanwood N, et al. Neonatal chimerization with human glial progenitor cells can both remyelinate and rescue the otherwise lethally hypomyelinated shiverer mouse. Cell Stem Cell 2008, 2: 553–565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Flax JD, Aurora S, Yang C, Simonin C, Wills AM, Billinghurst LL, et al. Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes. Nat Biotechnol 1998, 16: 1033–1039.

    Article  CAS  PubMed  Google Scholar 

  29. Schafer ST, Mansour AA, Schlachetzki JCM, Pena M, Ghassemzadeh S, Mitchell L, et al. An in vivo neuroimmune organoid model to study human microglia phenotypes. Cell 2023, 186: 2111-2126.e20.

    Article  CAS  PubMed  Google Scholar 

  30. Lu P, Woodruff G, Wang Y, Graham L, Hunt M, Wu D, et al. Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron 2014, 83: 789–796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sabaté O, Horellou P, Vigne E, Colin P, Perricaudet M, Buc-Caron MH, et al. Transplantation to the rat brain of human neural progenitors that were genetically modified using adenoviruses. Nat Genet 1995, 9: 256–260.

    Article  PubMed  Google Scholar 

  32. Lamptey RNL, Chaulagain B, Trivedi R, Gothwal A, Layek B, Singh J. A review of the common neurodegenerative disorders: Current therapeutic approaches and the potential role of nanotherapeutics. Int J Mol Sci 1851, 2022: 23.

    Google Scholar 

  33. Zoghbi HY, Bear MF. Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb Perspect Biol 2012, 4: a009886.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Calsolaro V, Edison P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimers Dement 2016, 12: 719–732.

    Article  PubMed  Google Scholar 

  35. Maroof AM, Keros S, Tyson JA, Ying SW, Ganat YM, Merkle FT, et al. Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell 2013, 12: 559–572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature 2011, 480: 547–551.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  37. Roy NS, Cleren C, Singh SK, Yang L, Beal MF, Goldman SA. Functional engraftment of human ES cell–derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med 2006, 12: 1259–1268.

    Article  CAS  PubMed  Google Scholar 

  38. Chen C, Kim WY, Jiang P. Humanized neuronal chimeric mouse brain generated by neonatally engrafted human iPSC-derived primitive neural progenitor cells. JCI Insight 2016, 1: e88632.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Krzyspiak J, Yan J, Ghosh HS, Galinski B, Lituma PJ, Alvina K, et al. Donor-derived vasculature is required to support neocortical cell grafts after stroke. Stem Cell Res 2022, 59: 102642.

    Article  CAS  PubMed  Google Scholar 

  40. Xu R, Brawner AT, Li S, Liu JJ, Kim H, Xue H, et al. OLIG2 drives abnormal neurodevelopmental phenotypes in human iPSC-based organoid and chimeric mouse models of down syndrome. Cell Stem Cell 2019, 24: 908-926.e8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Huo HQ, Qu ZY, Yuan F, Ma L, Yao L, Xu M, et al. Modeling down syndrome with patient iPSCs reveals cellular and migration deficits of GABAergic neurons. Stem Cell Reports 2018, 10: 1251–1266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang L, Mirabella VR, Dai R, Su X, Xu R, Jadali A, et al. Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a gain-of-function synaptic mechanism. Mol Psychiatry 2022, https://doi.org/10.1038/s41022-01834-x.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Reidling JC, Relaño-Ginés A, Holley SM, Ochaba J, Moore C, Fury B, et al. Human neural stem cell transplantation rescues functional deficits in R6/2 and Q140 Huntington’s disease mice. Stem Cell Rep 2018, 10: 58–72.

    Article  CAS  Google Scholar 

  44. Park HJ, Jeon J, Choi J, Kim JY, Kim HS, Huh JY, et al. Human iPSC-derived neural precursor cells differentiate into multiple cell types to delay disease progression following transplantation into YAC128 Huntington’s disease mouse model. Cell Prolif 2021, 54: e13082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Xiong M, Tao Y, Gao Q, Feng B, Yan W, Zhou Y, et al. Human stem cell-derived neurons repair circuits and restore neural function. Cell Stem Cell 2021, 28: 112-126.e6.

    Article  CAS  PubMed  Google Scholar 

  46. Sofroniew MV. Astrocyte reactivity: Subtypes, states, and functions in CNS innate immunity. Trends Immunol 2020, 41: 758–770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sofroniew MV, Vinters HV. Astrocytes: Biology and pathology. Acta Neuropathol 2010, 119: 7–35.

    Article  PubMed  Google Scholar 

  48. Clarke LE, Barres BA. Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci 2013, 14: 311–321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Brandebura AN, Paumier A, Onur TS, Allen NJ. Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders. Nat Rev Neurosci 2023, 24: 23–39.

    Article  CAS  PubMed  Google Scholar 

  50. Khakh BS, Goldman SA. Astrocytic contributions to Huntington’s disease pathophysiology. Ann N Y Acad Sci 2023, 1522: 42–59.

    Article  CAS  PubMed  ADS  Google Scholar 

  51. Udovin L, Quarracino C, Herrera MI, Capani F, Otero-Losada M, Perez-Lloret S. Role of astrocytic dysfunction in the pathogenesis of Parkinson’s disease animal models from a molecular signaling perspective. Neural Plast 2020, 2020: 1859431.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Seifert G, Schilling K, Steinhäuser C. Astrocyte dysfunction in neurological disorders: A molecular perspective. Nat Rev Neurosci 2006, 7: 194–206.

    Article  CAS  PubMed  Google Scholar 

  53. Benraiss A, Wang S, Herrlinger S, Li X, Chandler-Militello D, Mauceri J, et al. Human glia can both induce and rescue aspects of disease phenotype in Huntington disease. Nat Commun 2016, 7: 11758.

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  54. Vieira R, Mariani JN, Huynh NPT, Stephensen HJT, Solly R, Tate A, et al. Young glial progenitor cells competitively replace aged and diseased human glia in the adult chimeric mouse brain. Nat Biotechnol 2023, https://doi.org/10.1038/s41587-023-01798-5.

    Article  PubMed  Google Scholar 

  55. Chen C, Jiang P, Xue H, Peterson SE, Tran HT, McCann AE, et al. Role of astroglia in Down’s syndrome revealed by patient-derived human-induced pluripotent stem cells. Nat Commun 2014, 5: 4430.

    Article  CAS  PubMed  ADS  Google Scholar 

  56. Preman P, Tcw J, Calafate S, Snellinx A, Alfonso-Triguero M, Corthout N, et al. Human iPSC-derived astrocytes transplanted into the mouse brain undergo morphological changes in response to amyloid-β plaques. Mol Neurodegener 2021, 16: 68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Padmashri R, Ren B, Oldham B, Jung Y, Gough R, Dunaevsky A. Modeling human-specific interlaminar astrocytes in the mouse cerebral cortex. J Comp Neurol 2021, 529: 802–810.

    Article  PubMed  Google Scholar 

  58. Kondo Y, Windrem MS, Zou L, Chandler-Militello D, Schanz SJ, Auvergne RM, et al. Human glial chimeric mice reveal astrocytic dependence of JC virus infection. J Clin Invest 2014, 124: 5323–5336.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Nave KA, Trapp BD. Axon-glial signaling and the glial support of axon function. Annu Rev Neurosci 2008, 31: 535–561.

    Article  CAS  PubMed  Google Scholar 

  60. Dulamea AO. Role of oligodendrocyte dysfunction in demyelination, remyelination and neurodegeneration in multiple sclerosis. Adv Exp Med Biol 2017, 958: 91–127.

    Article  CAS  PubMed  Google Scholar 

  61. Windrem MS, Nunes MC, Rashbaum WK, Schwartz TH, Goodman RA, McKhann G 2nd, et al. Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain. Nat Med 2004, 10: 93–97.

    Article  CAS  PubMed  Google Scholar 

  62. Wang S, Bates J, Li X, Schanz S, Chandler-Militello D, Levine C, et al. Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 2013, 12: 252–264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Windrem MS, Schanz SJ, Zou L, Chandler-Militello D, Kuypers NJ, Nedergaard M, et al. Human glial progenitor cells effectively remyelinate the demyelinated adult brain. Cell Rep 2020, 31: 107658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kawabata S, Takano M, Numasawa-Kuroiwa Y, Itakura G, Kobayashi Y, Nishiyama Y, et al. Grafted human iPS cell-derived oligodendrocyte precursor cells contribute to robust remyelination of demyelinated axons after spinal cord injury. Stem Cell Reports 2016, 6: 1–8.

    Article  CAS  PubMed  Google Scholar 

  65. Ehrlich M, Mozafari S, Glatza M, Starost L, Velychko S, Hallmann AL, et al. Rapid and efficient generation of oligodendrocytes from human induced pluripotent stem cells using transcription factors. Proc Natl Acad Sci U S A 2017, 114: E2243–E2252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Windrem MS, Osipovitch M, Liu Z, Bates J, Chandler-Militello D, Zou L, et al. Human iPSC glial mouse chimeras reveal glial contributions to schizophrenia. Cell Stem Cell 2017, 21: 195-208.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Augusto-Oliveira M, Arrifano GP, Lopes-Araújo A, Santos-Sacramento L, Takeda PY, Anthony DC, et al. What do microglia really do in healthy adult brain? Cells 2019, 8: 1293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Askew K, Li K, Olmos-Alonso A, Garcia-Moreno F, Liang Y, Richardson P, et al. Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep 2017, 18: 391–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Uddin MS, Kabir MT, Jalouli M, Rahman MA, Jeandet P, Behl T, et al. Neuroinflammatory signaling in the pathogenesis of Alzheimer’s disease. Curr Neuropharmacol 2022, 20: 126–146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Streit WJ, Graeber MB, Kreutzberg GW. Functional plasticity of microglia: A review. Glia 1988, 1: 301–307.

    Article  CAS  PubMed  Google Scholar 

  71. Paolicelli RC, Sierra A, Stevens B, Tremblay ME, Aguzzi A, Ajami B, et al. Microglia states and nomenclature: A field at its crossroads. Neuron 2022, 110: 3458–3483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol 2017, 35: 441–468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Muzio L, Viotti A, Martino G. Microglia in neuroinflammation and neurodegeneration: From understanding to therapy. Front Neurosci 2021, 15: 742065.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, et al. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 2015, 138: 1738–1755.

    Article  PubMed  PubMed Central  Google Scholar 

  75. George S, Rey NL, Tyson T, Esquibel C, Meyerdirk L, Schulz E, et al. Microglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease. Mol Neurodegener 2019, 14: 34.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Bellenguez C, Küçükali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet 2022, 54: 412–436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rexach JE, Polioudakis D, Yin A, Swarup V, Chang TS, Nguyen T, et al. Tau pathology drives dementia risk-associated gene networks toward chronic inflammatory states and immunosuppression. Cell Rep 2020, 33: 108398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Deming Y, Filipello F, Cignarella F, Cantoni C, Hsu S, Mikesell R, et al. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk. Sci Transl Med 2019, 11: eaau2291.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Jin SC, Benitez BA, Karch CM, Cooper B, Skorupa T, Carrell D, et al. Coding variants in TREM2 increase risk for Alzheimer’s disease. Hum Mol Genet 2014, 23: 5838–5846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sharma K, Bisht K, Eyo UB. A comparative biology of microglia across species. Front Cell Dev Biol 2021, 9: 652748.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Tcw J, Qian L, Pipalia NH, Chao MJ, Liang SA, Shi Y, et al. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Cell 2022, 185: 2213-2233.e25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ferrer I. The primary microglial leukodystrophies: A review. Int J Mol Sci 2022, 23: 6341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch N, Soto-Ortolaza A, et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet 2011, 44: 200–205.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Mancuso R, Van Den Daele J, Fattorelli N, Wolfs L, Balusu S, Burton O, et al. Stem-cell-derived human microglia transplanted in mouse brain to study human disease. Nat Neurosci 2019, 22: 2111–2116.

    Article  CAS  PubMed  Google Scholar 

  85. Hasselmann J, Coburn MA, England W, Figueroa Velez DX, Kiani Shabestari S, Tu CH, et al. Development of a chimeric model to study and manipulate human microglia in vivo. Neuron 2019, 103: 1016-1033.e10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Jin M, Xu R, Wang L, Alam MM, Ma Z, Zhu S, et al. Type-I-interferon signaling drives microglial dysfunction and senescence in human iPSC models of Down syndrome and Alzheimer’s disease. Cell Stem Cell 2022, 29: 1135-1153.e8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Shibuya Y, Kumar KK, Mader MMD, Yoo Y, Ayala LA, Zhou M, et al. Treatment of a genetic brain disease by CNS-wide microglia replacement. Sci Transl Med 2022, 14: eabl9945.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Chadarevian JP, Lombroso SI, Peet GC, Hasselmann J, Tu C, Marzan DE, et al. Engineering an inhibitor-resistant human CSF1R variant for microglia replacement. J Exp Med 2023, 220: e20220857.

    Article  CAS  PubMed  Google Scholar 

  89. Abud EM, Ramirez RN, Martinez ES, Healy LM, Nguyen CHH, Newman SA, et al. iPSC-derived human microglia-like cells to study neurological diseases. Neuron 2017, 94: 278-293.e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Spiteri AG, Ni D, Ling ZL, Macia L, Campbell IL, Hofer MJ, et al. PLX5622 reduces disease severity in lethal CNS infection by off-target inhibition of peripheral inflammatory monocyte production. Front Immunol 2022, 13: 851556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Merry TL, Brooks AES, Masson SW, Adams SE, Jaiswal JK, Jamieson SMF, et al. The CSF1 receptor inhibitor pexidartinib (PLX3397) reduces tissue macrophage levels without affecting glucose homeostasis in mice. Int J Obes (Lond) 2020, 44: 245–253.

    Article  PubMed  Google Scholar 

  92. Xu Z, Rao Y, Huang Y, Zhou T, Feng R, Xiong S, et al. Efficient strategies for microglia replacement in the central nervous system. Cell Rep 2020, 33: 108443.

    Article  CAS  PubMed  Google Scholar 

  93. Vandana JJ, Manrique C, Lacko LA, Chen S. Human pluripotent-stem-cell-derived organoids for drug discovery and evaluation. Cell Stem Cell 2023, 30: 571–591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chen HI, Wolf JA, Blue R, Song MM, Moreno JD, Ming GL, et al. Transplantation of human brain organoids: Revisiting the science and ethics of brain chimeras. Cell Stem Cell 2019, 25: 462–472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wilson MN, Thunemann M, Liu X, Lu Y, Puppo F, Adams JW, et al. Multimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex. Nat Commun 2022, 13: 7945.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  96. Fisher EMC, Bannerman DM. Mouse models of neurodegeneration: Know your question, know your mouse. Sci Transl Med 1818, 2019: eaaq1818.

    Google Scholar 

  97. Marsee A, Roos FJM, Verstegen MMA, Organoid Consortium HPB, Gehart H, de Koning E, et al. Building consensus on definition and nomenclature of hepatic, pancreatic, and biliary organoids. Cell Stem Cell 2021, 28: 816–832.

    Article  CAS  PubMed  Google Scholar 

  98. Fan P, Wang Y, Xu M, Han X, Liu Y. The application of brain organoids in assessing neural toxicity. Front Mol Neurosci 2022, 15: 799397.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Xu R, Boreland AJ, Li X, Erickson C, Jin M, Atkins C, et al. Developing human pluripotent stem cell-based cerebral organoids with a controllable microglia ratio for modeling brain development and pathology. Stem Cell Reports 2021, 16: 1923–1937.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Tong G, Izquierdo P, Raashid RA. Human induced pluripotent stem cells and the modelling of Alzheimer’s disease: The human brain outside the dish. Open Neurol J 2017, 11: 27–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Goldman SA, Nedergaard M, Windrem MS. Modeling cognition and disease using human glial chimeric mice. Glia 2015, 63: 1483–1493.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Goldman SA, Nedergaard M, Windrem MS. Glial progenitor cell-based treatment and modeling of neurological disease. Science 2012, 338: 491–495.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  103. Behringer RR. Human-animal chimeras in biomedical research. Cell Stem Cell 2007, 1: 259–262.

    Article  CAS  PubMed  Google Scholar 

  104. Nair RR, Corrochano S, Gasco S, Tibbit C, Thompson D, Maduro C, et al. Uses for humanised mouse models in precision medicine for neurodegenerative disease. Mamm Genome 2019, 30: 173–191.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Crane AT, Voth JP, Shen FX, Low WC. Concise review: Human-animal neurological chimeras: Humanized animals or human cells in an animal? Stem Cells 2019, 37: 444–452.

    Article  PubMed  Google Scholar 

  106. Schweitzer JS, Song B, Herrington TM, Park TY, Lee N, Ko S, et al. Personalized iPSC-derived dopamine progenitor cells for Parkinson’s disease. N Engl J Med 2020, 382: 1926–1932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. da Cruz L, Fynes K, Georgiadis O, Kerby J, Luo YH, Ahmado A, et al. Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration. Nat Biotechnol 2018, 36: 328–337.

    Article  PubMed  Google Scholar 

  108. Sugai K, Sumida M, Shofuda T, Yamaguchi R, Tamura T, Kohzuki T, et al. First-in-human clinical trial of transplantation of iPSC-derived NS/PCs in subacute complete spinal cord injury: Study protocol. Regen Ther 2021, 18: 321–333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Svoboda DS, Barrasa MI, Shu J, Rietjens R, Zhang S, Mitalipova M, et al. Human iPSC-derived microglia assume a primary microglia-like state after transplantation into the neonatal mouse brain. Proc Natl Acad Sci U S A 2019, 116: 25293–25303.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  110. Xu R, Boreland AJ, Li X, Posyton A, Kwan K, Hart RP, et al. Functional mature human microglia developed in human iPSC microglial chimeric mouse brain. bioRxiv 2019, https://doi.org/10.1101/594721.

    Article  Google Scholar 

  111. Osipovitch M, Asenjo Martinez A, Mariani JN, Cornwell A, Dhaliwal S, Zou L, et al. Human ESC-derived chimeric mouse models of Huntington’s disease reveal cell-intrinsic defects in glial progenitor cell differentiation. Cell Stem Cell 2019, 24: 107-122.e7.

    Article  CAS  PubMed  Google Scholar 

  112. Capano LS, Sato C, Ficulle E, Yu A, Horie K, Kwon JS, et al. Recapitulation of endogenous 4R tau expression and formation of insoluble tau in directly reprogrammed human neurons. Cell Stem Cell 2022, 29: 918-932.e8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Vermaercke B, Bonin V, Vanderhaeghen P. Studying human neural function in vivo at the cellular level: Chasing chimeras? Cell 2022, 185: 4869–4872.

    Article  CAS  PubMed  Google Scholar 

  114. Rossi F, Cattaneo E. Opinion: Neural stem cell therapy for neurological diseases: Dreams and reality. Nat Rev Neurosci 2002, 3: 401–409.

    Article  CAS  PubMed  Google Scholar 

  115. Prinz M, Priller J. The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci 2017, 20: 136–144.

    Article  CAS  PubMed  Google Scholar 

  116. Filiano AJ, Gadani SP, Kipnis J. Interactions of innate and adaptive immunity in brain development and function. Brain Res 2015, 1617: 18–27.

    Article  CAS  PubMed  Google Scholar 

  117. Park TY, Jeon J, Lee N, Kim J, Song B, Kim JH, et al. Co-transplantation of autologous Treg cells in a cell therapy for Parkinson’s disease. Nature 2023, 619: 606–615.

    Article  CAS  PubMed  ADS  Google Scholar 

  118. Sugimura R, Jha DK, Han A, Soria-Valles C, da Rocha EL, Lu YF, et al. Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature 2017, 545: 432–438.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  119. French A, Yang CT, Taylor S, Watt SM, Carpenter L. Human induced pluripotent stem cell-derived B lymphocytes express sIgM and can be generated via a hemogenic endothelium intermediate. Stem Cells Dev 2015, 24: 1082–1095.

    Article  CAS  PubMed  Google Scholar 

  120. Vizcardo R, Masuda K, Yamada D, Ikawa T, Shimizu K, Fujii SI, et al. Regeneration of human tumor antigen-specific T cells from iPSCs derived from mature CD8+ T cells. Cell Stem Cell 2013, 12: 31–36.

    Article  CAS  PubMed  Google Scholar 

  121. Themeli M, Kloss CC, Ciriello G, Fedorov VD, Perna F, Gonen M, et al. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat Biotechnol 2013, 31: 928–933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Nishimura T, Kaneko S, Kawana-Tachikawa A, Tajima Y, Goto H, Zhu D, et al. Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation. Cell Stem Cell 2013, 12: 114–126.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank members of the Xu lab for the discussions and feedback on this manuscript. This review was supported by a Showalter grant to X.R. and a Purdue Institute for Integrative Neuroscience Research grant (iPSC/Organoid Technologies) to X.R.

Author information

Authors and Affiliations

  1. Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, 47907, USA

    Yanru Ji, Jenna Lillie McLean & Ranjie Xu

Authors
  1. Yanru Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jenna Lillie McLean
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ranjie Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ranjie Xu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ji, Y., McLean, J.L. & Xu, R. Emerging Human Pluripotent Stem Cell-Based Human–Animal Brain Chimeras for Advancing Disease Modeling and Cell Therapy for Neurological Disorders. Neurosci. Bull. (2024). https://doi.org/10.1007/s12264-024-01189-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12264-024-01189-z

Keywords

Search

Navigation