Wang Man, Rahmawati Fitriana Nur, Li Wenting, Bal Zeynep, Sitompul Faya Nuralda, Muramatsu Fumitaka, Jia Weizhen, Takakura Nobuyuki
Department of Signal Transduction, Research Institute for Microbial Diseases, The University of Osaka, 3-1 Yamada-Oka, Suita, Osaka, 565-0871, Japan.
World Premier Institute Immunology Frontier Research Center, The University of Osaka, 3-1 Yamada-Oka, Suita, Osaka, 565-0871, Japan.
Inflamm Regen. 2025 Aug 4;45(1):25. doi: 10.1186/s41232-025-00389-y.
CD157 marks a population of tissue-resident vascular endothelial stem cells (VESCs) in mice known for their critical role in homeostatic endothelial cell (EC) turnover and the rapid response to vascular damage in the liver by regeneration. Nevertheless, the mechanism underlying the maintenance and differentiation of postnatal VESCs under both physiological and pathological conditions remains unclear.
APJ knockout (KO) mice were utilized to explore the role of apelin/APJ signaling in VESC functionality. Flow cytometry, colony-forming unit assays, and in vitro differentiation experiments were conducted to characterize VESC populations. Partial hepatectomy (PHx) was performed to assess vascular regeneration.
APJ deficiency led to an accumulation of VESCs in the liver of adult mice, which displayed enhanced colony-forming capacity but delayed differentiation into mature ECs. APJ KO mice exhibited impaired vascular regeneration following PHx, linked to compromised VESC differentiation. Transcriptomic analysis revealed upregulation of transcription factors EGR1 and EGR2 and downregulation of Ccnd1 in APJ KO VESCs, implicating disrupted cell cycle regulation. Additionally, APJ deletion reduced collagen IV levels, weakening the basement membrane and contributing to the maintenance of VESCs in an undifferentiated state.
APJ signaling is critical for balancing VESC self-renewal and differentiation. APJ deficiency disrupts this balance, leading to impaired vascular regeneration in the liver due to delayed VESC differentiation. This defect is associated with altered transcriptional regulation, favoring a proliferative, undifferentiated state and extracellular matrix changes that weaken structural integrity. These findings highlight the apelin/APJ pathway as a potential therapeutic target to enhance vascular regeneration in regenerative medicine.
CD157标记小鼠体内一群组织驻留血管内皮干细胞（VESCs），这些细胞在稳态内皮细胞（EC）更新以及肝脏对血管损伤的再生快速反应中发挥关键作用。然而，出生后VESCs在生理和病理条件下维持和分化的潜在机制仍不清楚。
利用APJ基因敲除（KO）小鼠探究apelin/APJ信号通路在VESCs功能中的作用。进行流式细胞术、集落形成单位分析和体外分化实验以表征VESCs群体。实施部分肝切除术（PHx）以评估血管再生。
APJ缺陷导致成年小鼠肝脏中VESCs积累，这些VESCs表现出增强的集落形成能力，但向成熟ECs的分化延迟。APJ KO小鼠在PHx后表现出血管再生受损，这与VESCs分化受损有关。转录组分析显示，APJ KO VESCs中转录因子EGR1和EGR2上调，Ccnd1下调，这意味着细胞周期调控受到破坏。此外，APJ缺失降低了IV型胶原水平，削弱了基底膜，并有助于将VESCs维持在未分化状态。
APJ信号通路对于平衡VESCs自我更新和分化至关重要。APJ缺陷破坏了这种平衡，由于VESCs分化延迟导致肝脏血管再生受损。这种缺陷与转录调控改变有关，有利于增殖、未分化状态以及削弱结构完整性的细胞外基质变化。这些发现突出了apelin/APJ通路作为再生医学中增强血管再生的潜在治疗靶点。
