Cellular reprogramming of human monocytes is regulated by time-dependent IL4 signalling and NCOR2
| Autor: | Andreas Schlitzer, Anna-Lena Hardt, Anna C. Aschenbrenner, Florent Ginhoux, Lauterbach Mar, Kathrin Klee, Evan W. Newell, Wolfgang Krebs, Kraut M, Nicholas A. Melosh, Waldemar Kolanus, B. Martin, Marc Beyer, Bin Sumatoh Hr, Jia Xue, Patrick Günther, Sven Burgdorf, Lan Do Th, Lisa Schmidleithner, Bettina Wiegmann, Jonas Schulte-Schrepping, Kevin Baßler, Stefanie Herresthal, Kristian Händler, Branko Cirovic, Naomi McGovern, Joachim L. Schultze, Thomas Ulas, Christoph Kreer, Eicke Latz, Quast K, Christine S. Falk, Susanne V. Schmidt, Olympia Papantonopoulou, Heidi Theis, Alexander M. Xu, Jil Sander |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0303 health sciences
education.field_of_study CD14 medicine.medical_treatment Population Dendritic cell Biology Cell biology Transcriptome 03 medical and health sciences 0302 clinical medicine Cytokine Transcriptional regulation medicine education Reprogramming Ex vivo 030304 developmental biology 030215 immunology |
| DOI: | 10.1101/204180 |
| Popis: | The clinical and therapeutic value of humanin vitrogenerated monocyte-derived dendritic cell (moDC) and macrophages is well established. However, in line with recent findings regarding myeloid cell ontogeny and due to our limited understanding of their physiological counterparts, transcriptional regulation and heterogeneity, the full potential of these important cellular systems is still underestimated.In this study, we use cutting edge high-dimensional analysis methods to better understand the transcriptional organization, phenotypic heterogeneity and functional differences between humanex vivoisolated andin vitrogenerated mononuclear phagocytes with the aim to better realize their full potential in the clinic.We demonstrate that human monocytes activated by MCSF or GMCSF most closely resemble inflammatory macrophages identifiedin vivo, while IL4 signalling in the presence of GMCSF generates moDCs resembling inflammatory DCsin vivo, but not steady state cDC1 or cDC2. Moreover, these reprogramming regimes lead to activated monocytes that present with profoundly different transcriptomic, metabolic, phenotypic and functional profiles. Furthermore, we demonstrate that CD14+monocytes are integrating multiple exogenous activation signals such as GMCSF and IL4 in a combinatorial and temporal fashion, resulting in a high-dimensional cellular continuum of reprogrammed monocytes dependent on the mode and timing of cytokine exposure. Utilizing nanostraw-based knockdown technology, we demonstrate that the IL4-dependent generation of moDCs relies on the induction, nuclear localization and function of the transcriptional regulator NCOR2.Finally, we unravel unappreciated heterogeneity within the clinically moDCs population and propose a novel high-dimensional phenotyping strategy to better tailor clinical quality control strategies for patient need and culture conditions to enhance therapeutic outcome. |
| Databáze: | OpenAIRE |
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