BMP9 and BMP10 coordinate liver cellular crosstalk to maintain liver health

Abstract

The liver is the largest solid organ in the body and is primarily composed of HCs, ECs, KCs, and HSCs, which spatially interact and cooperate with 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 were 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 Bmp9/10 HSC-KO (conditional deletion of Bmp9/10 from HSCs) mice lost their signature gene expression, such as ID1/3, CLEC4F, VSIG4 and CLEC2, and were replaced by monocyte-derived macrophages. ECs from Bmp9/10 HSC-KO mice also lost their identity and were transdifferentiated into continuous ECs, ultimately leading to collagen IV deposition and liver fibrosis. Hepatic ECs express 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 Bmp9/10 HSC-KO mice, which further resulted in liver iron overload and disruption of HC zonation. In summary, we demonstrated that HSCs play a central role in mediating liver cell‒cell crosstalk via the production of BMP9/10 to maintain liver health.