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.
Elife. 2024 Oct 25;13:RP95811. doi: 10.7554/eLife.95811.
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 (also known as ) and 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. expression was significantly upregulated in KCs and ECs after and 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 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.
肝脏是人体最大的实质性器官，主要由肝细胞（HCs）、内皮细胞（ECs）、枯否细胞（KCs）和肝星状细胞（HSCs）组成，它们在空间上相互作用并协同工作，以维持肝脏的稳态。然而，这些不同细胞类型之间相互作用的复杂性和分子机制仍有待揭示。在这里，我们生成了在不同的肝实质细胞中条件性缺失 和 的小鼠，并证明了 HSCs 是肝脏中 GDF2 和 BMP10 的主要来源。利用转基因 ALK1（GDF2 和 BMP10 的受体）报告小鼠，我们发现 ALK1 在 KCs 和 ECs 上表达，而不在 HCs 和 HSCs 上表达，并且 HSCs 分泌的 GDF2 和 BMP10 促进了 KCs 和 ECs 的分化，并维持了它们的特性。在 和 缺失后， KCs 和 ECs 中 的表达显著上调，最终导致 HSCs 激活和肝纤维化。ECs 表达几种血管生成因子，如 BMP2、BMP6、Wnt2 和 Rspo3，以调节 HC 的铁代谢和代谢分区。我们发现，这些血管生成因子在 小鼠的 ECs 中表达显著降低，这进一步导致肝脏铁过载和 HC 分区紊乱。总之，我们证明了 HSCs 通过产生 GDF2 和 BMP10 在介导肝细胞间相互作用中起核心作用，强调了细胞间相互作用在器官发育和稳态中的重要作用。
