GDF2 and BMP10 coordinate liver cellular crosstalk to maintain liver health
Dianyuan Zhao,
Ziwei Huang,
Xiaoyu Li,
Huan Wang,
Qingwei Hou,
Yuyao Wang,
Fang Yan,
Wenting Yang,
Di Liu,
Shaoqiong Yi,
Chunguang Han,
Yanan Hao,
Li Tang
Affiliations
Dianyuan Zhao
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
Ziwei Huang
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China; Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
Xiaoyu Li
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China; Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
Huan Wang
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
Qingwei Hou
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China; School of Basic Medicine, Qingdao University, Qingdao, China
Yuyao Wang
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China; School of Basic Medicine, Qingdao University, Qingdao, China
Fang Yan
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
Wenting Yang
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
Di Liu
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
Shaoqiong Yi
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
Chunguang Han
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
Yanan Hao
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China; Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China; School of Basic Medicine, Qingdao University, Qingdao, China
The liver is the largest solid organ in the body and is primarily composed of hepatocytes (HCs), endothelial cells (ECs), Kupffer cells (KCs), and hepatic stellate cells (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 Gdf2 (also known as Bmp9) and Bmp10 in different liver cell types and demonstrated that HSCs were the major source of GDF2 and BMP10 in the liver. Using transgenic ALK1 (receptor for GDF2 and BMP10) reporter mice, we found that ALK1 is expressed on KCs and ECs other than HCs and HSCs, and GDF2 and BMP10 secreted by HSCs promote the differentiation of KCs and ECs and maintain their identity. Pdgfb expression was significantly upregulated in KCs and ECs after Gdf2 and Bmp10 deletion, ultimately leading to HSCs activation and liver fibrosis. ECs express several angiocrine factors, such as BMP2, BMP6, Wnt2, and Rspo3, to regulate HC iron metabolism and metabolic zonation. We found that these angiocrine factors were significantly decreased in ECs from Gdf2/Bmp10HSC-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 GDF2 and BMP10, highlighting the important role of intercellular interaction in organ development and homeostasis.
