Cellular and molecular mechanisms of block of dendritic cell development in growth factor receptor mutant mice
Zusammenfassung der Projektergebnisse
It remains unknown how the dendritic cell pool size is regulated in vivo. The data generated in the context of the project provides evidence for an unprecedented mechanism of dendritic cell pool size control by cells of an ontogenetically different origin. Work published over the last decade suggested that CSF1R-mediated signals play no role for the differentiation of spleen dendritic cells in vivo and significant efforts were made to characterize dendritic cell identity based on the isolation of lineage-restricted or committed precursor cells, lineage tracing, and transcription- and growth factor-requirements important for differentiation. Despite these efforts definite information on the differentiation path and/or growth factor requirements for dendritic cell generation in vivo remains incomplete. Dendritic cells are continuously replenished from hematopoietic stem cells and FLK2-mediated signals cell-intrinsically regulate the homeostatic expansion of dendritic cells in the spleen. In this report we present experiments showing that CSF1R-mediated signals control the spleen dendritic cell pool size in FLK2-deficient animals by a cell-extrinsic and non-hematopoietic mechanism providing a novel layer of complexity for the regulation of the differentiation of mature blood cells from adult hematopoietic stem cells. The dendritic cell pool in the spleen of constitutive Flk2 and Csf1r double null mice is severely reduced compared to either growth factor receptor mutant alone, defining the growth factor receptors necessary and sufficient for the generation of dendritic cells in vivo. FLK2 is important for homeostatic expansion by regulating cell division of dendritic cells in the spleen. In contrast, using novel genetic tools, we show in the provided result part that CSF1R is important for the regulation of the dendritic cell pool size by an indirect mechanism engaging embryo-derived tissue-resident macrophages during development and in adulthood in vivo. With these experiments we assign a novel and unprecedented function to spleen tissue resident macrophages of embryonic origin in supporting the establishment and maintenance of a sizable dendritic cell pool in Flk2 null mice. Taken together our results link blood cell differentiation of adult hematopoietic stem cells to a cell type of a different ontogeny, providing a novel regulatory principle for innate immune cell differentiation. The interdependency between cells of different ontogenies may be just an example and the differentiation of other cells of the mononuclear phagocyte system and maybe also of adaptive immune cells may depend on similar principles. When we applied for funding we hypothesized that CSF1R-mediated signals are cell-intrinsically required for the generation of dendritic cells in vivo. However, extensive transplantation and Cre/LoxP-mediated depletion of CSF1R on adult hematopoietic stem cells and their cellular progeny strongly suggested the existence of a cell-extrinsic mechanism. To test this exciting novel hypothesis we generated a lineage-specific reporter mouse strain instead of performing the next generation sequencing experiments that we had originally outlined in the application. Using our novel mouse tool we spatiotemporally controlled the expression of CSF1R during development and could verify our data-driven hypothesis and generate solid data on the novel regulatory circuit on the regulation of continuous hematopoiesis from definitive hematopoietic stem cells in adult mice.
Projektbezogene Publikationen (Auswahl)
- (2016) The bulk of the hematopoietic stem cell population is dispensable for murine steady-state and stress hematopoiesis. Blood 128 (19) 2285–2296
Schoedel, Kristina B.; Morcos, Mina N. F.; Zerjatke, Thomas; Roeder, Ingo; Grinenko, Tatyana; Voehringer, David; Göthert, Joachim R.; Waskow, Claudia; Roers, Axel; Gerbaulet, Alexander
(Siehe online unter https://doi.org/10.1182/blood-2016-03-706010) - 2014. Kit Regulates HSC Engraftment across the Human-Mouse Species Barrier. Cell Stem Cell, 15:227-238
Cosgun KN, Rahmig S, Mende N, Reinke S, Hauber I, Schäfer C, Petzold A, Weisbach H, Heidkamp G, Purbojo A, Cesnjevar R, Platz A, Bornhäuser M, Schmitz M, Dudziak D, Hauber J, Kirberg J, Waskow C
(Siehe online unter https://doi.org/10.1016/j.stem.2014.06.001) - 2015. Ccnd1/Cdk4-mediated cell cycle progression provides a competitive advantage for human hemantopoietic stem cells in vivo. J Exp Med; 212(8):1171-1183
Mende N, Kuchen E, Lesche M, Grinenko T, Kokkaliaris Kd, Hanenberg H, Lindemann D, Dahl A, Platz A, Hoefer T, Calegari F, Waskow C
(Siehe online unter https://doi.org/10.1084/jem.20150308) - 2015. Humanized mouse models for type 1 diabetes including pancreatic islet transplantation. Horm. Metab. Res 47:43- 47
Rahmig, S, Bornstein SR, Chavakis T, Jaeckel E, and Waskow C
(Siehe online unter https://doi.org/10.1055/s-0034-1390446) - 2015. Space constraints govern fate of hematopoietic stem and progenitor cells in vitro. Biomaterials 53:709-715
Muller, E, Grinenko T, Pompe T, Waskow C, and Werner C
(Siehe online unter https://doi.org/10.1016/j.biomaterials.2015.02.095) - 2016. Improved human erythropoiesis and platelet formation in humanized NSGW41 mice. Stem Cell Reports, 11:7(4):591-601
Rahmig S, Kronstein-Wiedemann R, Fohgrub J, Kronstein N, Nevmerzhitskaya A, Bornhäuser M, Gassmann M, Platz A, Ordemann R, Tonn T, and Waskow C
(Siehe online unter https://doi.org/10.1016/j.stemcr.2016.08.005)
