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An in vivo neuroimmune organoid model to study human microglia phenotypes. ​

Literature Information ​

DOI10.1016/j.cell.2023.04.022
PMID37172564
JournalCell
Impact Factor42.5
JCR QuartileQ1
Publication Year2023
Times Cited101
KeywordsHuman microglia, autism spectrum disorders, brain organoids, iPSCs, microglia in vivo identity
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN0092-8674
Pages2111-2126.e20
Issue186(10)
AuthorsSimon T Schafer, Abed AlFatah Mansour, Johannes C M Schlachetzki, Monique Pena, Saeed Ghassemzadeh, Lisa Mitchell, Amanda Mar, Daphne Quang, Sarah Stumpf, Irene Santisteban Ortiz, Addison J Lana, Clara Baek, Raghad Zaghal, Christopher K Glass, Axel Nimmerjahn, Fred H Gage

TL;DR ​

This study introduces an innovative in vivo xenotransplantation approach to model human microglia (hMGs) within a vascularized immunocompetent human brain organoid (iHBO), revealing that hMGs adopt human-specific transcriptomic profiles and actively monitor and respond to their environment. The findings provide significant insights into the functional roles of hMGs in health and disease, particularly highlighting their involvement in immune responses related to conditions such as autism with macrocephaly.

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Human microglia · autism spectrum disorders · brain organoids · iPSCs · microglia in vivo identity

Abstract ​

Microglia are specialized brain-resident macrophages that play crucial roles in brain development, homeostasis, and disease. However, until now, the ability to model interactions between the human brain environment and microglia has been severely limited. To overcome these limitations, we developed an in vivo xenotransplantation approach that allows us to study functionally mature human microglia (hMGs) that operate within a physiologically relevant, vascularized immunocompetent human brain organoid (iHBO) model. Our data show that organoid-resident hMGs gain human-specific transcriptomic signatures that closely resemble their in vivo counterparts. In vivo two-photon imaging reveals that hMGs actively engage in surveilling the human brain environment, react to local injuries, and respond to systemic inflammatory cues. Finally, we demonstrate that the transplanted iHBOs developed here offer the unprecedented opportunity to study functional human microglia phenotypes in health and disease and provide experimental evidence for a brain-environment-induced immune response in a patient-specific model of autism with macrocephaly.

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Primary Questions Addressed ​

  1. How do different microglial phenotypes respond to various types of neurological injuries within the in vivo organoid model?
  2. What are the implications of human-specific transcriptomic signatures of microglia in understanding neurodegenerative diseases?
  3. How can the in vivo neuroimmune organoid model be utilized to study the role of microglia in other neurodevelopmental disorders beyond autism?
  4. What are the potential therapeutic applications of manipulating microglial responses in the context of the organoid model?
  5. How does the vascularization of the immunocompetent human brain organoid influence microglial behavior compared to traditional models?

Key Findings ​

Research Background and Objectives ​

Microglia are specialized macrophages in the brain that are essential for brain development, homeostasis, and response to disease. Previous research has faced challenges in modeling the interactions between human brain environments and microglia. This study aims to develop a novel in vivo xenotransplantation approach to investigate functionally mature human microglia within a vascularized immunocompetent human brain organoid model.

Main Methods/Materials/Experimental Design ​

The study employed a xenotransplantation technique to create human brain organoids (iHBOs) that support the integration of human microglia. The methodology involved the following key steps:

Mermaid diagram
  1. Development of Human Brain Organoids (iHBO): Human brain organoids were cultured to mimic the vascularized and immunocompetent environment of the human brain.
  2. Transplantation of Human Microglia (hMGs): Functionally mature human microglia were transplanted into the organoids.
  3. In vivo Two-Photon Imaging: This imaging technique was used to visualize the behavior of hMGs within the organoids in real-time.
  4. Assessment of Microglia Activity: The activity of hMGs in response to local injuries and systemic inflammation was monitored.
  5. Transcriptomic Analysis of hMGs: Gene expression profiles of hMGs were compared to their in vivo counterparts to assess maturation and functionality.
  6. Study of Immune Responses in Disease Models: The model was utilized to explore immune responses in specific conditions, including a patient-specific model of autism with macrocephaly.

Key Results and Findings ​

  • The transplanted hMGs exhibited human-specific transcriptomic signatures, closely mirroring those found in vivo.
  • In vivo imaging demonstrated that hMGs actively surveil the brain environment, responding to injuries and systemic inflammatory signals.
  • The study provided experimental evidence of a brain-environment-induced immune response, particularly in the context of autism with macrocephaly.

Main Conclusions/Significance/Innovation ​

The development of the iHBO model represents a significant advancement in the study of human microglia, allowing for the exploration of their roles in health and disease. This model offers a unique platform to investigate microglial function and immune responses in a controlled, patient-specific context, enhancing our understanding of neurodevelopmental disorders and other brain diseases.

Research Limitations and Future Directions ​

  • Limitations: The study's findings are based on a specific patient model, which may not generalize to all neurodevelopmental disorders. Additionally, the long-term viability and functionality of hMGs within the organoid environment need further investigation.
  • Future Directions: Future research should aim to expand the range of patient models studied, investigate the therapeutic potential of modulating microglial activity, and explore the implications of these findings for other neurological diseases.
AspectDetails
Research FocusHuman microglia interactions in brain organoids
MethodologyIn vivo xenotransplantation, two-photon imaging
Key FindingsHuman-specific transcriptomic signatures, immune responses
SignificanceNew model for studying human microglia in health/disease
LimitationsSpecificity to one patient model, need for long-term studies
Future DirectionsBroaden patient models, therapeutic implications

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Literatures Citing This Work ​

  1. CRISPRi-based screens in iAssembloids to elucidate neuron-glia interactions. - Emmy Li;Camila Benitez;Steven C Boggess;Mark Koontz;Indigo V L Rose;Delsy Martinez;Nina Draeger;Olivia M Teter;Avi J Samelson;Na'im Pierce;Erik M Ullian;Martin Kampmann - bioRxiv : the preprint server for biology (2024)
  2. Context matters: hPSC-derived microglia thrive in a humanized brain environment in vivo. - Jonas Cerneckis;Yanhong Shi - Cell stem cell (2023)
  3. Genetics of human brain development. - Yi Zhou;Hongjun Song;Guo-Li Ming - Nature reviews. Genetics (2024)
  4. Replacing microglia to treat Alzheimer's disease. - Peng Jiang;Mengmeng Jin - Cell stem cell (2023)
  5. Microglial contribution to the pathology of neurodevelopmental disorders in humans. - Rugile Matuleviciute;Elizabeth T Akinluyi;Tim A O Muntslag;Jennifer M Dewing;Katherine R Long;Anthony C Vernon;Marie-Eve Tremblay;David A Menassa - Acta neuropathologica (2023)
  6. Noteworthy perspectives on microglia in neuropsychiatric disorders. - Hongrui Zhu;Ao Guan;Jiayuan Liu;Li Peng;Zhi Zhang;Sheng Wang - Journal of neuroinflammation (2023)
  7. Brain organoids for hypoxic-ischemic studies: from bench to bedside. - Romane Gaston-Breton;Auriane Maïza Letrou;Rifat Hamoudi;Barbara S Stonestreet;Aloïse Mabondzo - Cellular and molecular life sciences : CMLS (2023)
  8. [Nature and immune mechanisms of mental illnesses]. - Josef Priller;Simon Schäfer;Shima Safaiyan - Der Nervenarzt (2023)
  9. Human iPSC-derived glia models for the study of neuroinflammation. - Nina Stöberl;Emily Maguire;Elisa Salis;Bethany Shaw;Hazel Hall-Roberts - Journal of neuroinflammation (2023)
  10. iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer. - Dong Shin Park;Tatsuya Kozaki;Satish Kumar Tiwari;Marco Moreira;Ahad Khalilnezhad;Federico Torta;Nicolas Olivié;Chung Hwee Thiam;Oniko Liani;Aymeric Silvin;Wint Wint Phoo;Liang Gao;Alexander Triebl;Wai Kin Tham;Leticia Gonçalves;Wan Ting Kong;Sethi Raman;Xiao Meng Zhang;Garett Dunsmore;Charles Antoine Dutertre;Salanne Lee;Jia Min Ong;Akhila Balachander;Shabnam Khalilnezhad;Josephine Lum;Kaibo Duan;Ze Ming Lim;Leonard Tan;Ivy Low;Kagistia Hana Utami;Xin Yi Yeo;Sylvaine Di Tommaso;Jean-William Dupuy;Balazs Varga;Ragnhildur Thora Karadottir;Mufeeda Changaramvally Madathummal;Isabelle Bonne;Benoit Malleret;Zainab Yasin Binte;Ngan Wei Da;Yingrou Tan;Wei Jie Wong;Jinqiu Zhang;Jinmiao Chen;Radoslaw M Sobota;Shanshan W Howland;Lai Guan Ng;Frédéric Saltel;David Castel;Jacques Grill;Veronique Minard;Salvatore Albani;Jerry K Y Chan;Morgane Sonia Thion;Sang Yong Jung;Markus R Wenk;Mahmoud A Pouladi;Claudia Pasqualini;Veronique Angeli;Olivier N F Cexus;Florent Ginhoux - Nature (2023)

... (91 more literatures)

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