Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Progress
  • Published:

Modelling microglial function with induced pluripotent stem cells: an update

Abstract

It is becoming increasingly apparent that microglia, the immune cells of the CNS, and their peripheral counterparts, macrophages, have a major role in normal physiology and pathology. Recent technological advances in the production of particular cell types from induced pluripotent stem cells have led to an interest in applying this methodology to the production of microglia. Here, we discuss recent advances in this area and describe how they will aid our future understanding of microglia.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The physiological and pathological functions of microglia.
Fig. 2: Induced pluripotent stem cell-derived microglia phenotype characterization: basic and comprehensive.

Similar content being viewed by others

References

  1. Wolf, S. A. Boddeke, H. W. & Kettenmann, H. Microglia in physiology and disease. Annu. Rev. Physiol. 10, 619–643 (2017).

    Article  CAS  Google Scholar 

  2. Amor, S. et al. Inflammation in neurodegenerative diseases – an update. Immunology 142, 151–166 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Brazelton, T. R. Rossi, F. M. Keshet, G. I. & Blau, H. M. From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290, 1775–1779 (2000).

    Article  PubMed  CAS  Google Scholar 

  4. Waisman, A. Ginhoux, F. Greter, M. Bruttger, J. Homeostasis of microglia in the adult brain: review of novel microglia depletion systems. Trends Immunol. 36, 625–636 (2015).

    Article  PubMed  CAS  Google Scholar 

  5. Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013).

    Article  PubMed  CAS  Google Scholar 

  6. Karch, C. M. & Goate, A. M. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol. Psychiatry 77, 43–51 (2015).

    Article  PubMed  CAS  Google Scholar 

  7. Villegas-Llerena, C. et al. Microglial genes regulating neuroinflammation in the progression of Alzheimer’s disease. Curr. Opin. Neurobiol. 36, 74–81 (2016).

    Article  PubMed  CAS  Google Scholar 

  8. Gonsette, R. E. Neurodegeneration in multiple sclerosis: the role of oxidative stress and excitotoxicity. J. Neurol. Sci. 274, 48–53 (2008).

    Article  PubMed  CAS  Google Scholar 

  9. Tansey, M. G. & Goldberg, M. S. Neuroinflammation in Parkinson’s disease; its role in neuronal death and implications for therapeutic intervention. Neurobiol. Dis. 37, 510–518 (2010).

    Article  PubMed  CAS  Google Scholar 

  10. Crotti, A. & Glass, C. K. The choreography of neuroinflammation in Huntington’s disease. Trends Immunol. 36, 364–373 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Morello, G. Spampinato, A. G. Cavallaro, S. Neuroinflammation and ALS: transcriptomic insights into molecular disease mechanisms and therapeutic targets. Mediators Inflamm. https://doi.org/10.1155/2017/7070469 (2017).

  12. Sha nks, N. Greek, R. Greek, J. Are animal models predictive for humans? Philos. Ethics Humanit. Med. 4, 2 (2009).

    Article  Google Scholar 

  13. Keene, C. D. et al. Neuropathological assessment and validation of mouse models for Alzheimer’s disease: applying NIA-AA guidelines. Pathobiol. Aging Age Relat. Dis. 6, 32397 (2016).

    Article  PubMed  Google Scholar 

  14. Swami, V., Furnham, A. & Christopher, A. N. Free the animals? Investigating attitudes toward animal testing in Britain and the United States. Scand. J. Psychol. 49, 269–276 (2008).

    Article  PubMed  Google Scholar 

  15. Ohgidani, M. et al. Direct induction of ramified microglia-like cells from human monocytes: dynamic microglial dysfunction in Nasu-Hakola disease. Sci. Rep. 4, 4957 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Ryan, K. J. et al. A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants. Sci. Trans. Med. 20, 421 (2017).

    Google Scholar 

  17. Sturgeon, C. M. et al. Wnt signaling controls the specification of definitive and primitive hematopoiesis from human pluripotent stem cells. Nat. Biotechnol. 32, 554–561 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Arber, C. Lovejoy, C. Wray, S. Stem cell models of Alzheimer’s disease: progress and challenges. Alzheimers Res. Ther. 9, 42–59 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Kierdorf, K. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013).

    Article  PubMed  CAS  Google Scholar 

  21. Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).

    Article  PubMed  CAS  Google Scholar 

  22. Davies, L. C. & Taylor, P. R. Tissue-resident macrophages: then and now. Immunology 144, 541–548 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Butovsky, O. et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).

    Article  PubMed  CAS  Google Scholar 

  24. Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).

    Article  PubMed  CAS  Google Scholar 

  25. Hoeffel, G. et al. C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Buchrieser, J. James, W. Moore, M. D. Human induced pluripotent stem cell-derived macrophages share ontogeny with MYB-independent tissue-resident macrophages. Stem Cell Rep. 8, 334–345 (2017).

    Article  CAS  Google Scholar 

  27. Muffat, J. et al. Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat. Med. 22, 1358–1367 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Douvaras, P. et al. Directed Differentiation of Human Pluripotent Stem Cells to Microglia. Stem Cell Rep. 8, 1516–1524 (2017).

    Article  CAS  Google Scholar 

  29. Pandya, H. et al. Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. Nat. Neurosci. 20, 753–759 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Abud, E. et al. iPSC-derived human microglia-like cells to study neurological diseases. Neuron 94, 278–293 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Haenseler, W. et al. A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response. Stem Cell Rep. 8, 1727–1742 (2017).

    Article  CAS  Google Scholar 

  32. Takata, K. et al. Induced-pluripotent-stem-cell-derived primitive macrophages provide a platform for modeling tissue-resident macrophage differentiation and function. Immunity 47, 183–198 (2017).

    Article  PubMed  CAS  Google Scholar 

  33. Karlsson, K. R. Homogeneous monocytes and macrophages from human embryonic stem cells following coculture-free differentiation in M-CSF and IL-3. Exp. Hematol. 36, 1167–1175 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Lachmann, N. et al. Large-scale haematopoietic differentiation of human induced pluripotent stem cells provides granulocytes or macrophages for cell replacement therapies. Stem Cell Rep. 4, 282–296 (2015).

    Article  CAS  Google Scholar 

  35. Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Moore, C. S. et al. P2Y12 expression and function in alternatively activated human microglia. Neurol. Neuroimmunol. Neuroinflamm. 2, e80 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Pocock, J. M. & Kettenmann, H. Neurotransmitter receptors on microglia. Trends Neurosci. 30, 527–535 (2007).

    Article  PubMed  CAS  Google Scholar 

  38. Domercq, M. Vázquez-Villoldo, N. Matute, C. Neurotransmitter signaling in the pathophysiology of microglia. Front. Cell Neurosci. 7, 49 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  39. Greter, M. Stroma-derived interleukin-34 controls the development and maintenance of langerhans cells and the maintenance of microglia. Immunity 37, 1050–1060 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Gosselin, D. An environment-dependent transcriptional network specifies human microglia identity. Science 356, eaal3222 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007).

    Article  PubMed  CAS  Google Scholar 

  42. Sousa, C. Biber, K. & Michelucci, A. Cellular and molecular characterization of microglia: a unique immune cell population. Front. Immunol. 8, 198 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  43. Bennett, M. L. et al. New tools for studying microglia in the mouse and human CNS. Proc. Natl Acad. Sci. USA 113, E1738–E1746 (2016).

    Article  PubMed  CAS  Google Scholar 

  44. Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Perry, V. H. Cunningham, C. Holmes, C. Systemic infections and inflammation affect chronic neurodegeneration. Nat. Rev. Immunol. 7, 161–167 (2007).

    Article  PubMed  CAS  Google Scholar 

  46. Morris, J. K. et al. Is Alzheimer’s disease a systemic disease? Biochim. Biophys. Acta. 1842, 1340–1349 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Yamasaki, R. et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J. Exp. Med. 211, 1533–1549 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Hooper, C. et al. Differential effects of albumin on microglia and macrophages: implications for neurodegeneration following blood-brain barrier damage. J. Neurochem. 109, 694–705 (2009).

    Article  PubMed  CAS  Google Scholar 

  49. Nimmerjahn, A. Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).

    Article  PubMed  CAS  Google Scholar 

  50. Vogel, D. Y. et al. Human macrophage polarization in vitro: maturation and activation methods compared. Immunobiology 219, 695–703 (2014).

    Article  PubMed  CAS  Google Scholar 

  51. Suzuki, H. et al. Glycolytic pathway affects differentiation of human monocytes to regulatory macrophages. Immunol. Lett. 176, 18–27 (2016).

    Article  PubMed  CAS  Google Scholar 

  52. Bershteyn, M. et al. Human iPSC-derived cerebral organoids model cellular features of lissencephaly and reveal prolonged mitosis of outer radial glia. Cell Stem Cell 20, 435–449 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Mucci, A. et al. Murine iPSC-derived macrophages as a tool for disease modelling of hereditary pulmonary alveolar proteinosis due to Csf2rb deficiency. Stem Cell Rep. 7, 292–305 (2016).

    Article  CAS  Google Scholar 

  54. Biber, K. Möller, T. Boddeke, E. Prinz, M. Central nervous system myeloid cells as drug targets: current status and translational challenges. Nat. Rev. Drug Discov. 15, 110–124 (2016).

    Article  PubMed  CAS  Google Scholar 

  55. Chen, S. K. et al. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141, 775–785 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Biju, K. C. et al. Bone-marrow-derived microglia-based neurturin delivery protects against dopaminergic neurodegeneration in a mouse model of Parkinson’s disease. Neurosci. Lett. 535, 24–29 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Conde, J. R. & Streit, W. J. Microglia in the aging brain. J. Neuropathol. Exp. Neurol. 65, 199–203 (2006).

    Article  PubMed  Google Scholar 

  58. Angelov, D. N. et al. Temporospatial relationships between macroglia and microglia during in vitro differentiation of murine stem cells. Dev. Neurosci 20, 42–51 (1998).

    Article  PubMed  CAS  Google Scholar 

  59. Tsuchiya, T. et al. Characterization of microglia induced from mouse embryonic stem cells and their migration into the brain parenchyma. J. Neuroimmunol. 160, 210–218 (2005).

    Article  PubMed  CAS  Google Scholar 

  60. Napoli, I. Kierdorf, K. Neumann, H. Microglial precursors derived from mouse embryonic stem cells. Glia 57, 1660–1671 (2009).

    Article  PubMed  Google Scholar 

  61. Beutner, C. Roy, K. Linnartz, B. Napoli, I. Neumann, H. Generation of microglial cells from mouse embryonic stem cells. Nat. Protoc. 5, 1481–1494 (2010).

    Article  PubMed  CAS  Google Scholar 

  62. van Wilgenburg, B. Browne, C. Vowles, J. Cowley, S. A. Efficient, long term production of monocyte-derived macrophages from human pluripotent stem cells under partly-defined and fully-defined conditions. PLoS ONE 8, e71098 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

J.M.P. made a substantial contribution to discussions of the content of the article. J.M.P. and T.M.P. researched data for the article, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Jennifer M. Pocock or Thomas M. Piers.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pocock, J.M., Piers, T.M. Modelling microglial function with induced pluripotent stem cells: an update. Nat Rev Neurosci 19, 445–452 (2018). https://doi.org/10.1038/s41583-018-0030-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41583-018-0030-3

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing