Schafer ST, Mansour AA, Schlachetzki JC, Pena M, Ghassemzadeh S, Mitchell L, Mar A, Quang D, Stumpf S, Ortiz IS, Lana AJ, Baek C, Zaghal R, Glass CK, Nimmerjahn A, Gage FH. An in vivo neuroimmune organoid model to study human microglia phenotypes. Cell. 2023 May 11;186(10):2111-2126.e20. PubMed.

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  1. Humanized systems are becoming increasingly popular due to their translational potential. However, current in vitro models do not fully recapitulate important features, such as acquisition of mature cell states, three-dimensional structure, or cell-to-cell communication.

    The article by Schaefer and colleagues establishes a new paradigm to study human neuron-glia communication by integrating human-derived microglia progenitors into a human brain organoid (HBOs). This is the first time that such a model is described in vivo, and it would help to elucidate the complex interplay between the innate immune system and neurons in neurological disorders, such as Autism or Alzheimer’s disease.

    As described previously (Gosselin et al., 2017; Mancuso et al., 2019; Hasselmann et al., 2019; Xu et al., 2020), human-derived microglia produced in vitro lack key environmental cues to fully transition to a mature state, locking them in an artificial activation phenotype. This article also demonstrates that the integration of human microglia into HBOs in vitro is not enough to rescue this phenotype, suggesting that human-derived microglia need multiple brain-derived factors to reach maturation. In vivo, the HBO appears to secrete key human microglia factors—CSF-1 and IL-34—that influence the maturation of human microglia.

    This is an improvement compared to current microglia xenotransplantation systems (Mancuso et al., 2019; Hasselmann et al., 2019; Xu et al., 2020), where, to achieve a successful engraftment there is the need to express humanized cytokines, such as CSF1 (Mancuso et al., 2019; Xu et al., 2020) or CSF1/GM-CSF/IL3 (Hasselmann et al., 201). This model also goes one step further to decipher not only the individual contribution from each cell type, but the complex cross talk between them. The presence of human neurons in this experimental model is a very valuable addition, since we have demonstrated that xenotransplantation of human neurons recapitulates key pathological hallmarks of AD when exposed to amyloid pathology (Balusu et al., 2022). However, an in-depth exploration of the reciprocal cross talk between microglia and the organoid is still needed.

    In conclusion, this is a really exciting model to study neuron-microglia communication in vivo and it opens the possibility to perform genetic perturbations at multiple levels to better model human diseases.

    References:

    Gosselin D, Skola D, Coufal NG, Holtman IR, Schlachetzki JC, Sajti E, Jaeger BN, O'Connor C, Fitzpatrick C, Pasillas MP, Pena M, Adair A, Gonda DD, Levy ML, Ransohoff RM, Gage FH, Glass CK. An environment-dependent transcriptional network specifies human microglia identity. Science. 2017 Jun 23;356(6344) Epub 2017 May 25 PubMed.

    Mancuso R, Van Den Daele J, Fattorelli N, Wolfs L, Balusu S, Burton O, Liston A, Sierksma A, Fourne Y, Poovathingal S, Arranz-Mendiguren A, Sala Frigerio C, Claes C, Serneels L, Theys T, Perry VH, Verfaillie C, Fiers M, De Strooper B. Stem-cell-derived human microglia transplanted in mouse brain to study human disease. Nat Neurosci. 2019 Dec;22(12):2111-2116. Epub 2019 Oct 28 PubMed.

    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.

    Xu R, Li X, Boreland AJ, Posyton A, Kwan K, Hart RP, Jiang P. Human iPSC-derived mature microglia retain their identity and functionally integrate in the chimeric mouse brain. Nat Commun. 2020 Mar 27;11(1):1577. PubMed.

    Balusu S, Horre K, Thrupp N, Snellinx A, Serneels L, Chrysidou I, Arranz AM, Sierksma A, Simren J, Karikari T, Zetterberg H, Chen W-T, Thal DR, Salta E, Fiers M, DeStrooper B. Long noncoding RNA MEG3 activates neuronal necroptosis in Alzheimer's disease. 2022 Feb 20 10.1101/2022.02.18.480849 (version 1) bioRxiv.

    View all comments by Nicola Fattorelli

  2. This organoid system described by Gage and colleagues is a big step forward in attempts to model AD with human cells. It will now be critical to determine whether these microglia, matured in transplanted human brain organoids, would more closely mimic disease-associated microglia signatures following exposure to Aβ. Previously, the Blurton-Jones lab reported that human iPSC-derived microglia, matured in 5XFAD mouse brains, display human-specific Aβ-responsive genes, and are differentiated from mouse microglia Aβ-responsive genes (Hasselmann et al., 2019) studies, it will be important to know how these new human organoid-matured microglia respond to Aβ accumulation, and how that response compares to microglia found in human AD brains.

    References:

    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.

    View all comments by Rudy Tanzi

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