Li Chenxiao, Zhang Mengtian, Du Yushan, Liu Shuang, Li Da, Zhang Shukui, Ji Fen, Zhang Jingjing, Jiao Jianwei
Affiliated Hospital of Guangdong Medical University & Key Laboratory of Zebrafish Model for Development and Disease of Guangdong Medical University, Zhanjiang, China.
Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of Science, Beijing, China.
Cell Prolif. 2024 Dec;57(12):e13710. doi: 10.1111/cpr.13710. Epub 2024 Jul 15.
Blood vessels play a crucial role in maintaining the stem cell niche in both tumours and developing organs. Cell competition is critical for tumour progression. We hypothesise that blood vessels may act as a regulator of this process. As a pioneer, the secretions of blood vessels regulate the intensity of cell competition, which is essential for tumour invasion and developmental organ extension. Brd4 expresses highly in endothelial cells within various tumours and is positively correlated with numerous invasive genes, making it an ideal focal point for further research on the relationship between blood vessels and cell competition. Our results indicated that the absence of endothelial Brd4 led to a reduction in neural stem cell mortality and compromised cell competition. Endothelial Brd4 regulated cell competition was dependent on Testican2. Testican2 was capable of depositing Sparc and acted as a suppressor of Sparc. Compromised cell competition resulted in the depletion of neural stem cells and accelerated brain ageing. Testican2 could rescue the run-off of neural stem cells and accelerate the turnover rate of neurons. AD patients show compromised cell competition. Through the cloning of a point mutant of Brd4 identified in a subset of AD patients, it was demonstrated that the mutant lacked the ability to promote cell competition. This study suggests a novel approach for treating age-related diseases by enhancing the intensity of cell competition.
血管在维持肿瘤和发育中的器官中的干细胞生态位方面发挥着关键作用。细胞竞争对肿瘤进展至关重要。我们假设血管可能是这一过程的调节因子。作为先驱，血管的分泌物调节细胞竞争的强度，这对肿瘤侵袭和发育器官的扩展至关重要。Brd4在各种肿瘤的内皮细胞中高表达，并且与许多侵袭性基因呈正相关，使其成为进一步研究血管与细胞竞争之间关系的理想焦点。我们的结果表明，内皮Brd4的缺失导致神经干细胞死亡率降低和细胞竞争受损。内皮Brd4调节的细胞竞争依赖于Testican2。Testican2能够沉积Sparc并作为Sparc的抑制剂。受损的细胞竞争导致神经干细胞耗竭并加速脑老化。Testican2可以挽救神经干细胞的流失并加速神经元的周转率。阿尔茨海默病（AD）患者表现出细胞竞争受损。通过克隆在一部分AD患者中鉴定出的Brd4点突变体，证明该突变体缺乏促进细胞竞争的能力。这项研究提出了一种通过增强细胞竞争强度来治疗与年龄相关疾病的新方法。
