The liver vascular network is patterned by sinusoidal and hepatocyte co-zonation. How intra-liver vessels acquire their hierarchical specialized functions is unknown. We study heterogeneity of hepatic vascular cells during mouse development through functional and single-cell RNA-sequencing. The acquisition of sinusoidal endothelial cell identity is initiated during early development and completed postnatally, originating from a pool of undifferentiated vascular progenitors at E12. The peri-natal induction of the transcription factor c-Maf is a critical switch for the sinusoidal identity determination. Endothelium-restricted deletion of c-Maf disrupts liver sinusoidal development, aberrantly expands postnatal liver hematopoiesis, promotes excessive postnatal sinusoidal proliferation, and aggravates liver pro-fibrotic sensitivity to chemical insult. Enforced c-Maf overexpression in generic human endothelial cells switches on a liver sinusoidal transcriptional program that maintains hepatocyte function. c-Maf represents an inducible intra-organotypic and niche-responsive molecular determinant of hepatic sinusoidal cell identity and lays the foundation for the strategies for vasculature-driven liver repair.

肝血管网络由正弦曲线和肝细胞共带构成。肝内血管如何获得其分层的专门功能尚不清楚。我们通过功能和单细胞 RNA 测序研究小鼠发育过程中肝血管细胞的异质性。正弦内皮细胞特性的获得在早期发育过程中开始，并在出生后完成，起源于 E12 的未分化血管祖细胞池。转录因子 c-Maf 的围产期诱导是正弦曲线身份确定的关键开关。内皮限制性 c-Maf 缺失会破坏肝窦发育，异常扩大出生后肝造血，促进出生后肝窦过度增殖，并加重肝脏对化学损伤的促纤维化敏感性。普通人内皮细胞中强制的 c-Maf 过表达会启动维持肝细胞功能的肝窦转录程序。c-Maf 代表肝窦细胞特性的诱导型器官内和生态位响应分子决定因素，并为脉管系统驱动的肝修复策略奠定了基础。