FG Kronenberg-Versteeg

Given the crucial role of microglia in development, brain homeostasis, aging and disease, there is a growing need for human(ized) screening tools and disease models to aid in the search for new treatment options. However, the identity of microglia is shaped by ontogeny and microenvironment, making this a challenging task. We recently developed a chimeric brain slice culture model that merges murine organotypic brain slice cultures with human iPSC-derived microglia, efficaciously combining ontogeny and microenvironment. We achieve a nearly complete exchange of murine to human microglia in the brain tissue slice and could show that the iPSC-derived microglia in the chimeric slices develop age- and disease-related transcriptional profiles upon prolonged time in culture or in the presence of α-synuclein proteopathy, reminiscent of in vivo human microglia. In addition, we found that maturation of the iPSC-derived microglia in the tissue is due to previously underappreciated cross-species human colony stimulating factor 1 receptor (hCSF1R) binding of murine interleukin 34 (IL34) (Erlebach et al., submitted). We are currently investigating how microglial genetic risk factors may alter microglial phenotypes, proteopathic disease pathology and neurodegeneration in those slices, as well as testing therapeutics that target human microglial responses.

In addition to chimeric murine brain slice cultures, we are working closely with Drs Henner Koch and Thomas Wuttke (Dept. of Epileptology, Hertie Institute for Clinical Brain Research) to validate important experiments in human brain slice cultures derived from tissue from surgical resections (see also Schwarz et al., eLife, 2019). We recently demonstrated the successful induction of α-synuclein proteopathic lesions in such cultures (Barth et al., Mol Neurodegener, 2021) and were able to engraft human iPSC-derived microglia in these as well in order to investigate the dichotomous responses of endogenous human versus iPSC-derived microglia.

Furthermore, in addition to the aforementioned chimeric brain slice cultures we also co-cultured human organoids with murine brain slice cultures and observed enhanced maturation of the human organoids. Upon co-culturing human brain organoids with chimeric brain slice cultures we found that the iPSC-derived microglia migrated from the brain slice cultures to the human organoid and displayed a ramified morphology (Panagiotakopoulou et al, submitted), therefore creating an even further humanized culture system that allows us to gain further mechanistic insights into the role of microglia in physiological and pathophysiological conditions.