Modeling Hereditary Diffuse Leukoencephalopathy with Axonal Spheroids using microglia-sufficient brain organoids

Wong, W. J.; Zhu, Y.; Wang, H.; Qian, J. W.; Li, Z.; Song, L.; Liu, Z.; Wei, G.; Zhang, S. Y.; Su, B.; Ping, H. F.; Wang, K.; Ginhoux, F.

doi:10.1101/2024.02.12.579869

bioRxiv · 10.1101/2024.02.12.579869

Modeling Hereditary Diffuse Leukoencephalopathy with Axonal Spheroids using microglia-sufficient brain organoids

Wong, W. J.·Zhu, Y.·Wang, H.·Qian, J. W.·Li, Z.·Song, L.·Liu, Z.·Wei, G.·Zhang, S. Y.·Su, B.·Ping, H. F.·Wang, K.·Ginhoux, F.

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Abstract

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare, fatal, adult-onset neurodegenerative disease that is most often caused by mutations affecting the Colony Stimulating factor-1 Receptor (CSF-1R). To understand how CSF-1R-mutation affects human microglia - the specialized brain-resident macrophages of the central nervous system - and the downstream consequences for neuronal cells, we used a macrophage and forebrain organoid co-culture system based on induced pluripotent stem cells generated from two patients with HDLS, with CSF-1R gene-corrected isogenic organoids as controls. Macrophages derived from iPSC (iMacs) of patients exhibited a metabolic shift towards the glycolytic pathway and reduced CSF-1 sensitivity, which was associated with higher levels of IL-1{beta} production and an activated inflammatory phenotype. Single-cell RNA sequencing revealed that iMacs adopt a reactive state that leads to impaired regulation of neuronal cell populations in organoid cultures, thereby identifying microglial dysregulation and specifically IL-1{beta} production as key contributors to the degenerative neuro-environment in HDLS.

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Wong, W. J., Zhu, Y., Wang, H., Qian, J. W., Li, Z., Song, L., Liu, Z., Wei, G., Zhang, S. Y., Su, B., Ping, H. F., Wang, K., Ginhoux, F.. 2024-02-12. Modeling Hereditary Diffuse Leukoencephalopathy with Axonal Spheroids using microglia-sufficient brain organoids. https://doi.org/10.1101/2024.02.12.579869

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