Epigenomic states of microglia driving central nervous system repair in humans

• Applicant: Dr. Leif Ludwig, since 12/2022
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 500300783

Cellular regeneration of the central nervous system requires precise spatial and temporal control of proliferation and differentiation of neural stem- and progenitor cells to regulate the generation of new cells and ensure correct integration of newly generated cells into the local microenvironment. Damage to the human central nervous system often results in chronic disability, accompanied by high personal and economic burden. Hopes to relieve this burden lie in the development of regenerative therapies, which aim to enhance the brain’s endogenous capacity for repair.Microglia constitute the tissue-resident macrophages in the CNS, and are an integral part of the regenerative niches, including the subventricular zone. Their activation states range from a rather degenerative phenotype, associated with cytotoxicity, to a potentially beneficial regenerative phenotype, that may support CNS repair. Despite the thus far unmet clinical relevance, the contexts that control diversification of microglia states and function in the human CNS are still widely unknown.In previous work, we have investigated the versatile effects of diverse microglia phenotypes on the balance of endogenous CNS regeneration vs. degeneration. We have shown that microglia from the subventricular zone may adopt a regenerative phenotype that controls endogenous repair of oligodendrocytes and remyelination during neuroinflammation. We have further identified galectin-1 as a crucial factor to transform microglia from a degenerative towards a regenerative phenotype. Yet, their susceptibility to such transformation depends on differential microglial surface glycosylation signatures, which control their interaction with the local microenvironment, including the extracellular matrix. However, the contextual determinants and molecular regulation of microglia states in the human brain are still widely unknown. Extensive efforts in transcriptomic and proteomic measurements of microglia have provided invaluable insight into the heterogeneity of microglia. However, these measurements cannot capture the epigenetic or glycomic heterogeneity that may drive microglia into distinct activation states and functions.To overcome this knowledge gap, we propose to characterize the open chromatin landscapes of microglia on a single cell level in a region-and context-aware manner, focusing on subventricular zone and frontal cortex from individuals with ALS, MS and non-demented controls. Mechanistically, we will investigate how distinct extracellular matrix-glycome interaction shapes microglial epigenomic states and function, by generating patient-derived brain scaffolds for the culture of iPSC-microglia, followed by high-resolution microscopy and machine-learning driven data analysis.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2395: Local and peripheral drivers of microglial diversity and function
• Co-Investigators: Professor Dr. Dieter Beule; Dr. Helena Radbruch
• Ehemalige Antragstellerin: Dr. Sarah C Staroßom, until 12/2022