Journal
MOLECULAR CELL
Volume 75, Issue 3, Pages 644-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2019.07.028
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Funding
- NIH [DK102456, DK079862, DK084771, GM114160, GM122932]
- Michigan Diabetes Research Center [DK020572]
- Welch Foundation [I-1800]
- UCLA Clinical and Intramural Award [UL1TR001881]
- NIH NRSA fellowship [F30 DK117615]
- MSTP training grant [T32GM007863]
- Patten Predoctoral Fellowship by the University of Michigan
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Cell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers. Secretome gene analysis revealed a highly connected network of intrahepatic signaling and disruption of vascular signaling in NASH. We uncovered the emergence of NASH-associated macrophages (NAMs), which are marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions. Finally, hepatic stellate cells (HSCs) serve as a hub of intrahepatic signaling via HSC-derived stellakines and their responsiveness to vasoactive hormones. These results provide unprecedented insights into the landscape of intercellular crosstalk and reprogramming of liver cells in health and disease.
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