Identification of factors regulating fate and function of microglia and macrophages in the CNS.
Final Report Abstract
In this project, we uncovered the ontogenetic trajectory, distribution, kinetics, gene expression profiles, as well as crucial intercellular communications and molecular machineries for defined subsets of CAN-associated macrophages (CAMs). Using scRNA-seq, we identified a distinct Mrc1 (CD206)+ subset within the A2 pre-macrophage population. A recent study described a similar CD206+ YS population and suggested that these cells were committed progenitors of CAMs, distinct from the microglia ancestry. However, our fate mapping analysis with the newly generated Mrc1CreERT2 mouse line revealed instead that CD206+ YS progenitors represent an intermediate state of cells during embryogenesis that can give rise to all types of CNS macrophages, confirming their ontogenetic resemblance. Furthermore, our present data indicate that the definitive specification of CNS macrophage populations is accomplished by a stepwise program at perinatal stages within their anatomical CNS niche and is seemingly imprinted by local cues. The establishment of pvMΦ requires the presence of arterial VSMCs and integrin signaling. Importantly, single-cell profiling of vessel-associated cells in mice lacking Notch3 revealed that CAMs and microglia were basically unaltered, whereas arterial VSMCs exhibited a changed transcriptomic pattern with arterial-to-venous-shift, as observed previously. Therefore, the reduced number of pvMΦ in Notch3-deficient mice might also be related to the loss of arterial identity rather than due to the loss of arterial VSMC, which should be explored experimentally in the future. Taken together, our analysis sheds new light on the ontogeny and specification of CNS macrophages within their specific tissue niches. Since behavior and functions of CAMs during normal CNS development, steady state and disease are still ill-defined, our novel Mrc1-based mouse tool to specifically target CAMs will help to elucidate CAM biology. This may open new avenues for a better understanding of CNS development and disease.
Publications
- Origin, fate and dynamics of macrophages at CNS interfaces. Nat Immunol, 17(7):797-805
Goldmann T, Wieghofer P, Jordão MJC, Prutek F, Hagemeyer N, Frenzel K, Amann L, Staszewski O, Kierdorf K, Krueger M, Locatelli G, Hochgerner H, Zeiser R, Epelman S, Geissmann F, Priller J, Rossi FMV, Bechmann I, Kerschensteiner M, Linnarson S, Jung S, Prinz M
(See online at https://doi.org/10.1038/ni.3423) - A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat Neurosci, 20(6):793-803
Tay TL, Mai D, Dautzenberg J, Fernandez-Klett F, Li G, Sagar, Datta M, Stempfl T, Ardura-Fabergat A, Staszewski O, Margineau A, Sporbert A, Jung S, Priller J, Grün D, Ronneberger O, Prinz M
(See online at https://doi.org/10.1038/nn.4547) - Novel Hexb-based tools for studying microglia in the CNS. Nat Immunol, 21(7):802-815
Masuda T, Amann L, Sankowski R, Staszewski O, Lenz M, d`Errico P, Snaidero N, Jordao MJC, Böttcher C, Kierdorf K, Jung S, Priller J, Misgeld T, Vlachos A, Meyer-Luehmann, Knobeloch KP, Prinz M
(See online at https://doi.org/10.1038/s41590-020-0707-4)
