Hasselmann J, Coburn MA, England W, Figueroa Velez DX, Kiani Shabestari S, Tu CH, McQuade A, Kolahdouzan M, Echeverria K, Claes C, Nakayama T, Azevedo R, Coufal NG, Han CZ, Cummings BJ, Davtyan H, Glass CK, Healy LM, Gandhi SP, Spitale RC, Blurton-Jones M. Development of a Chimeric Model to Study and Manipulate Human Microglia In Vivo. Neuron. 2019 Sep 25;103(6):1016-1033.e10. Epub 2019 Jul 30 PubMed.

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  1. Some research groups were recently able to generate a surrogate of human microglia using induced-pluripotent stem cells (iPSC) derived from human fibroblasts (Muffat et al., 2016; Abud et al., 2017; Pandya et al., 2017; Takata et al., 2017). These studies were mostly carried out with in vitro co-culture systems, organtypic cultures, or brain organoids, which only partially recapitulate the complexity of the brain’s physiology in vivo. Indeed, modelling human microglia in an in vivo-like setting still represents a technical challenge.

    Here, Hasselmann and colleagues transplanted human iPSC-derived hematopoietic progenitor cells (HPCs) into the brains of newborn immunodeficient mice. After transplantation, human HPCs spread throughout the mouse brain and successfully differentiate into microglia-like cells. Importantly, these cells exhibit a gene-expression profile resembling human microglia from surgical brain specimens. Moreover, IPSC-derived human microglia become readily activated upon acute inflammatory challenges, such as laser-induced cortical lesion or systemic LPS injection. In a mouse model of amyloid pathology, iPSC-derived human microglia efficiently migrate toward amyloid plaques and exhibit increased expression of immune-related genes (especially APOE, HLA-DR, MAFB, LGALS3, MS4A7, ITGAX, and TREM2).

    Interestingly, iPSC-derived human microglia harboring the R47H TREM2 mutation (a well-known risk allele for Alzheimer’s disease in humans) show reduced clustering around the amyloid plaques, as compared to their wild-type counterpart. These findings suggest that microglia in subjects with R47H polymorphism might be hyporesponsive to Aβ, thus conveying a greater risk of developing Alzheimer’s disease during senility. Lastly, some genes that were previously reported to be upregulated in mouse microglia during amyloid pathology (such as Tyrobp, Cst7, Clec7a, and Csf1) were not significantly changed in iPSC-derived human microglia. These data suggest that mouse and human microglia mount different immunological responses against amyloid pathology in vivo. To conclude, the work by Hasselmann et al. offers a powerful tool to better investigate human microglia during brain disease.

    References:

    Muffat J, Li Y, Yuan B, Mitalipova M, Omer A, Corcoran S, Bakiasi G, Tsai LH, Aubourg P, Ransohoff RM, Jaenisch R. Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med. 2016 Nov;22(11):1358-1367. Epub 2016 Sep 26 PubMed.

    Abud EM, Ramirez RN, Martinez ES, Healy LM, Nguyen CH, Newman SA, Yeromin AV, Scarfone VM, Marsh SE, Fimbres C, Caraway CA, Fote GM, Madany AM, Agrawal A, Kayed R, Gylys KH, Cahalan MD, Cummings BJ, Antel JP, Mortazavi A, Carson MJ, Poon WW, Blurton-Jones M. iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases. Neuron. 2017 Apr 19;94(2):278-293.e9. PubMed.

    Pandya H, Shen MJ, Ichikawa DM, Sedlock AB, Choi Y, Johnson KR, Kim G, Brown MA, Elkahloun AG, Maric D, Sweeney CL, Gossa S, Malech HL, McGavern DB, Park JK. Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. Nat Neurosci. 2017 May;20(5):753-759. Epub 2017 Mar 2 PubMed.

    Takata K, Kozaki T, Lee CZ, Thion MS, Otsuka M, Lim S, Utami KH, Fidan K, Park DS, Malleret B, Chakarov S, See P, Low D, Low G, Garcia-Miralles M, Zeng R, Zhang J, Goh CC, Gul A, Hubert S, Lee B, Chen J, Low I, Shadan NB, Lum J, Wei TS, Mok E, Kawanishi S, Kitamura Y, Larbi A, Poidinger M, Renia L, Ng LG, Wolf Y, Jung S, Önder T, Newell E, Huber T, Ashihara E, Garel S, Pouladi MA, Ginhoux F. Induced-Pluripotent-Stem-Cell-Derived Primitive Macrophages Provide a Platform for Modeling Tissue-Resident Macrophage Differentiation and Function. Immunity. 2017 Jul 18;47(1):183-198.e6. PubMed.

    View all comments by Marco Colonna

  2. To further dissect the response to AD pathology, Hasselmann and collaborators used single-cell transcriptomic profiling and compared xenotransplanted microglia (xMG) isolated from aged control versus xMG from 5X-MITRG mice. Interestingly, xMG from both control and disease model mice showed similar cellular heterogeneity, presenting clusters of MHC class II cells, type I interferon responding cells, seemingly homeostatic cells, and a cell group resembling the previously reported murine-disease-associated microglia (DAM) (Keren-Shaul et al., 2017). The latter population, marked by CD9, TREM2, LPL, and ITGAX; seemed increased in relative cell number in 5X-MITRG mice. However, when comparing the expression profiles of DAM versus homeostatic cells in the 5X-MITRG animals, the authors found a substantial number of differentially expressed genes not previously found in the murine DAM, suggesting a gene signature unique to human xMGs.

    The lack of global agreement with murine DAM is consistent with our recent findings upon analyzing the single-cell heterogeneity of postmortem cortical samples (Mathys et al., 2019). Although partially overlapping with mouse disease-associated (Keren-Shaul et al., 2017) and mouse late-response (Mathys et al., 2017) microglia, a human AD-pathology-associated microglial subpopulation identified in our study also showed distinctive signatures not observed in mouse models. Future direct comparisons of global single-cell transcriptomic profiles, beyond marker-gene-set overlap and aided by larger samples, will likely help clarify the particularities of AD-responsive human microglia, their complete repertoire of cell states, and their similarity with the heterogeneity produced in previous mouse and “xenocultured” mouse models.

    References:

    Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 PubMed.

    Mathys H, Adaikkan C, Gao F, Young JZ, Manet E, Hemberg M, De Jager PL, Ransohoff RM, Regev A, Tsai LH. Temporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution. Cell Rep. 2017 Oct 10;21(2):366-380. PubMed.

    Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, Menon M, He L, Abdurrob F, Jiang X, Martorell AJ, Ransohoff RM, Hafler BP, Bennett DA, Kellis M, Tsai LH. Single-cell transcriptomic analysis of Alzheimer's disease. Nature. 2019 Jun;570(7761):332-337. Epub 2019 May 1 PubMed.

    View all comments by Li-Huei Tsai

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