Nonbone Marrow CD34+ Cells Are Crucial for Endothelial Repair of Injured Artery
Nonbone Marrow CD34+ Cells Are Crucial for Endothelial Repair of Injured Artery
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非骨髓 CD34( ) 细胞对于受损动脉内皮修复至关重要
DOI：
10.1161/circresaha.121.319494
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发表时间：
2021-10-01
影响因子：
20.1
通讯作者：
Zhang, Li
中科院分区：
文献类型：
--
作者：
Jiang, Liujun;Chen, Ting;Zhang, Li
理论基础：血管内皮细胞在多种心血管疾病中起着关键作用。循环CD34(+)细胞被认为是内皮祖细胞，已被用于治疗心血管疾病。然而，CD34(+)细胞在血管再生中的确切身份和作用仍不清楚。目的：探讨CD34(+)细胞在血管再生中的确切身份和作用。方法和结果：与正常动脉相比，患者股动脉病变组织中CD34的表达百分率显著增加。利用钢丝诱导的内皮剥离模型，我们报道了3万多个细胞的单细胞RNA测序分析，并提供了正常和受损小鼠动脉的细胞图谱，其中显示了CD34(+)细胞的异质性群体。结合诱导谱系示踪CD34-Creer(T2)；R26-td番茄小鼠模型和骨髓移植实验，我们发现非骨髓CD34(+)间充质细胞在血管损伤后获得内皮细胞命运而不是前内皮细胞，而骨髓来源的CD34(+)细胞在血管损伤后局部分化为免疫细胞。使用白喉毒素诱导的细胞消融模型去除非骨髓CD34(+)细胞会加剧受损血管的新生内膜病变。此外，分离的血管外膜CD34(+)细胞存在内皮细胞分化，其中microRNA-21-Smad7-pSmad2/3通路调控内皮细胞分化过程中内皮基因的表达和功能。结论：我们的研究提供了内皮剥离后血管的转录和细胞图像。我们的发现表明，异质CD34(+)细胞不仅对内皮再生有贡献，而且是一种炎症反应，可能为血管疾病的治疗提供见解。
Rationale: Endothelial cells play a critical role in multiple cardiovascular diseases. Circulating CD34(+) cells are believed to be endothelial progenitors that have been used to treat cardiovascular diseases. However, the exact identity and the role of CD34(+) cells in vascular regeneration remains unclear. Objective: We aimed to investigate the exact identity and the role of CD34(+) cells in vascular regeneration. Methods and Results: Compared with healthy arteries, CD34 expression percentage was significantly increased in diseased femoral arteries from patients. Using a guidewire-induced endothelial denudation model, we reported the transcriptional profiling of over 30 000 cells by single-cell RNA sequencing analysis and provided a cell atlas of normal and lesioned arteries in mouse, in which a heterogeneous population of CD34(+) cells was revealed. Combining the inducible lineage tracing Cd34-CreER(T2);R26-tdTomato mouse model and bone marrow transplantation experiments, we showed that nonbone marrow CD34(+) mesenchymal cells acquired endothelial cell fate in the injured femoral artery rather than preexiting endothelial cells, while bone marrow-derived CD34(+) cells differentiated into immune cells locally after vessel injury. Depletion of nonbone marrow CD34(+) cells using diphtheria toxin-induced cell ablation models exacerbate neointimal lesions of the injured vessel. Furthermore, isolated vascular adventitia CD34(+) cells displayed endothelial differentiation, in which microRNA-21-Smad7-pSmad2/3 pathway regulated endothelial gene expression and function during differentiation. Conclusions: Our study provides a transcriptional and cellular landscape of vessels after endothelial denudation. Our findings suggest heterogeneous CD34(+) cells serve as a contributor not only to endothelial regeneration but also an inflammatory response that may provide therapeutic insights into vascular diseases.