BMP9 and BMP10 coordinate liver cellular crosstalk to maintain liver health

The liver is a largest solid organ in the body and is majorly composed of HCs, ECs, KCs, and HSCs, which spatially interact and cooperate each other to maintain liver homeostasis. However, the complexity and molecular mechanisms underlying the crosstalk between these different cell types remain to be revealed. Here, we generated mice with conditional deletion of Bmp9/10 in different liver cell types and demonstrated that HSCs was the major source of BMP9 and BMP10 in the liver. Using transgenic ALK1 (receptor for BMP9/10) reporter mice, we found that ALK1 is expressed on KCs and ECs other than HCs and HSCs. KCs from Bmp9/10HSC-KO (conditional deletion of Bmp9/10 from HSCs) mice lost their signature genes expression, such as ID1/3, CLEC4F, VSIG4 and CLEC2, and were replaced by monocyte-derived macrophages. ECs from Bmp9/10HSC-KO mice also lost their identity and were transdifferentiated to continuous ECs, ultimately leading to collagen IV deposition and liver fibrosis. Hepatic ECs expressed several angiocrine factors, such as BMP2, BMP6, Wnt2 and Rspo3, to regulate liver iron metabolism and metabolic zonation. We found that these angiocrine factors were significantly decreased in ECs from Bmp9/10HSC-KO mice, which further resulted in liver iron overload and disruption of HCs zonation. In addition, focal fatty liver spontaneously occurred in Bmp9/10HSC-KO mice at the age of 28W. In summary, we demonstrated that HSCs play a central role in mediating liver cell-cell crosstalk via production of BMP9/10 to maintain liver health. To investigate how BMP9/10 affected liver macrophages and endothelial cells, we performed bulk RNA-seq analysis of sorted liver macrophages and endothelial cell from Bmp9/10HSC-KO and their control mice. To investigate how Smad4 affected liver macrophages, we performed bulk RNA-seq analysis of sorted liver macrophages from Smad4 cKO mice and their control mice. To investigate how livers were affected in Bmp9/10HSC-KO mice, we performed bulk RNA-seq analysis of liver tissues from Bmp9/10HSC-KO and their control mice.