RT Journal Article
SR Electronic
T1 Cellular reprogramming of human monocytes is regulated by time-dependent IL4 signalling and NCOR2
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 204180
DO 10.1101/204180
A1 Jil Sander
A1 Susanne V. Schmidt
A1 Branko Cirovic
A1 Naomi McGovern
A1 Olympia Papantonopoulou
A1 Anna-Lena Hardt
A1 Anna C. Aschenbrenner
A1 Christoph Kreer
A1 Kreer Quast
A1 Alexander M. Xu
A1 Lisa M. Schmidleithner
A1 Heidi Theis
A1 Thi Huong Lan Do
A1 Hermi Rizal Bin Sumatoh
A1 Mario A. R. Lauterbach
A1 Jonas Schulte-Schrepping
A1 Patrick Gunther
A1 Jia Xue
A1 Kevin Baßler
A1 Thomas Ulas
A1 Kathrin Klee
A1 Stefanie Herresthal
A1 Wolfgang Krebs
A1 Bianca Martin
A1 Eicke Latz
A1 Kristian Händler
A1 Michael Kraut
A1 Waldemar Kolanus
A1 Marc Beyer
A1 Christine S. Falk
A1 Bettina Wiegmann
A1 Sven Burgdorf
A1 Nicholas A. Melosh
A1 Evan W. Newell
A1 Florent Ginhoux
A1 Andreas Schlitzer
A1 Joachim L. Schultze
YR 2017
UL http://biorxiv.org/content/early/2017/10/16/204180.abstract
AB The clinical and therapeutic value of human in vitro generated 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 human ex vivo isolated and in vitro generated 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 identified in vivo, while IL4 signalling in the presence of GMCSF generates moDCs resembling inflammatory DCs in 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.