Cardiovascular research · 2026
CD34+ myofibroblasts promote neointima formation in vein grafts by activating ferroptosis-induced smooth muscle cell phenotype switch.
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Xu Simon S, Wang Han, Zhu Pengwei, Qiao Li, Xu Xiaodong, Chen Kai, Patel Ashish, Yang Xiaoping, Bai Yunpeng, Hu Xiaoshen, Xu Qingbo, Smith Alberto, Xiao Qingzhong, Modarai Bijan
Аннотация
AIM: Vein graft (VG) failure due to adverse remodeling and aggressive neointimal hyperplasia is a major complication and key limiting factor for maintaining long-term VG patency. CD34+ cells have been implicated in multiple cardiovascular diseases, but their functional involvements and contributions to VG failure remain elusive. In this study, we aimed to investigate the functional role of CD34+ cells in VG pathogenesis.
METHODS AND RESULT: Single cell RNA sequencing (scRNA-seq) analysis was conducted to uncover cellular heterogeneity of normal healthy and grafted veins as well as CD34+ cells in VGs. Genetic lineage tracing and depletion strategies were applied to delineate the functional involvements and potential contributions of CD34+ cells to VG remodeling. Multiple functional and biochemistry assays were conducted to identify and elucidate the key signal pathways underpinning smooth muscle cell (SMC) ferroptosis and phenotype switching.A total of 22,213 cells from normal healthy and grafted veins were included in scRNA-seq analysis, which showed a heterogeneous population of CD34+ cells as well as activated ferroptosis pathways and SMC phenotypic alterations in VGs. Using the inducible lineage tracing Cd34-CreERT2;R26-tdTomato mouse model, we showed that CD34+ cells were mainly differentiated into fibroblasts in VGs. Depletion of CD34+/Postn+ myofibroblasts in a triple transgenic (Cd34-Dre;Postn-CreERT2;Dou-tdT-DTR) mouse model significantly decreased VG-induced neointimal hyperplasia. Cellular communication analysis identified Jagged 1/Notch3 (neurogenic locus notch homolog protein 3) as the most upregulated signaling axis between CD34+ cell-derived fibroblasts and SMCs. Notch3 activation in SMCs by CD34+ cell-derived fibroblasts promoted SMC ferroptosis and switching to a synthetic/secretory phenotype in VGs. Blocking Jagged1 and Notch3 signalling as well as inhibition of ferroptosis attenuated vascular adverse remodeling and neointimal hyperplasia in VGs.
CONCLUSIONS: This study provides a transcriptional and cellular landscape in normal healthy and grafted veins and shows that heterogeneous CD34+ cells serve as a key contributor to vascular remodeling and neointimal hyperplasia in VGs. We also demonstrate that CD34+ cell-derived myofibroblasts promote neointimal hyperplasia through Jagged1/Notch3 signal axis, suggesting that blocking Jagged1/Notch3 activation or inhibiting ferroptosis may provide a novel approach to prevent VG failure.
METHODS AND RESULT: Single cell RNA sequencing (scRNA-seq) analysis was conducted to uncover cellular heterogeneity of normal healthy and grafted veins as well as CD34+ cells in VGs. Genetic lineage tracing and depletion strategies were applied to delineate the functional involvements and potential contributions of CD34+ cells to VG remodeling. Multiple functional and biochemistry assays were conducted to identify and elucidate the key signal pathways underpinning smooth muscle cell (SMC) ferroptosis and phenotype switching.A total of 22,213 cells from normal healthy and grafted veins were included in scRNA-seq analysis, which showed a heterogeneous population of CD34+ cells as well as activated ferroptosis pathways and SMC phenotypic alterations in VGs. Using the inducible lineage tracing Cd34-CreERT2;R26-tdTomato mouse model, we showed that CD34+ cells were mainly differentiated into fibroblasts in VGs. Depletion of CD34+/Postn+ myofibroblasts in a triple transgenic (Cd34-Dre;Postn-CreERT2;Dou-tdT-DTR) mouse model significantly decreased VG-induced neointimal hyperplasia. Cellular communication analysis identified Jagged 1/Notch3 (neurogenic locus notch homolog protein 3) as the most upregulated signaling axis between CD34+ cell-derived fibroblasts and SMCs. Notch3 activation in SMCs by CD34+ cell-derived fibroblasts promoted SMC ferroptosis and switching to a synthetic/secretory phenotype in VGs. Blocking Jagged1 and Notch3 signalling as well as inhibition of ferroptosis attenuated vascular adverse remodeling and neointimal hyperplasia in VGs.
CONCLUSIONS: This study provides a transcriptional and cellular landscape in normal healthy and grafted veins and shows that heterogeneous CD34+ cells serve as a key contributor to vascular remodeling and neointimal hyperplasia in VGs. We also demonstrate that CD34+ cell-derived myofibroblasts promote neointimal hyperplasia through Jagged1/Notch3 signal axis, suggesting that blocking Jagged1/Notch3 activation or inhibiting ferroptosis may provide a novel approach to prevent VG failure.