Nonbone Marrow CD34 ⁺ Cells Are Crucial for Endothelial Repair of Injured Artery

Abstract

Rationale: Endothelial cells (EC) 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 to healthy arteries, CD34 expression percentage was significantly increased in diseased femoral arteries from patients. Using a guide-wire 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 were revealed. Combining the inducible lineage tracing Cd34-CreERT2;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 pre-exiting ECs, 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.

Next-Generation and Single-Cell Sequencing Approaches to Study Atherosclerosis and Vascular Inflammation Pathophysiology: A Systematic Review

“…Five articles ( 18 , 23 , 25 , 30 , 42 ) specifically address the role of stem/progenitor cells in atherosclerosis and vascular inflammation. Four ( 18 , 23 , 25 , 42 ) of these articles utilize single-cell sequencing explicitly, whilst the remaining article ( 30 ) utilized next-generation RNA sequencing.…”

“…Jiang et al ( 42 ) utilized single-cell sequencing to investigate the exact identity and role of CD34 + cells using femoral artery tissue from WT C57BL/6J mice. This data was compared to lineage-traced Cd34-CreER T2 ; R26-tdTomato mice which underwent guide-wire injury, and the analysis revealed a heterogenous perivascular tissue population of CD34 + cells predominantly attributed to mesenchymal and EC origin.…”

“…From the SYRCLE assessment, no information was provided regarding random outcome assessment in any of the included articles. Four articles provided unclear information about random housing, with the remaining articles providing no information ( 22 , 26 , 42 , 43 ). Six articles had low risk of bias for sequence generation, with the remaining providing no information ( 19 , 22 , 26 , 29 , 42 , 48 ).…”

Vascular Stem/Progenitor Cells in Vessel Injury and Repair

“…The CD34 + cells differentiated into CD31 + cells and αSMA + cells after scaffold implantation, which may contribute to the formation of stenosis. Recently, a study found that the elimination of non-bone marrow CD34 + cells could reduce the vascular lumen area and increase intima thickness ( 23 ). The non-bone marrow CD34 + cells could differentiate into ECs after femoral artery injury, maintaining vascular integrity, and preventing the formation of neointima.…”

Recent Advances in Polyurethane/POSS Hybrids for Biomedical Applications

“…The second approach to functionalization are biomimetic surfaces that are getting more and more attention in the new compositions for stent coating. A remarkable advance was the composites’ ability to capture anti-CD34, the epithelial progenitor cells (EPC) antibodies, crucial for endothelialization [ 175 ]. Authors used at first a blend of amino-functionalized silica with POSS-PCU copolymer [ 176 ].…”