Single-cell analysis reveals urothelial cell heterogeneity and regenerative cues following cyclophosphamide-induced bladder injury

• Published in: Cell death & disease Vol. 12; no. 5; p. 446
• Main Authors: Cheng, Xiaomu, Lai, Huadong, Luo, Wenqin, Zhang, Man, Miao, Juju, Song, Weichen, Xing, Shunpeng, Wang, Jia, Gao, Wei-Qiang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-05-2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/51; 14/19; 38/39; 38/91; 631/136/2091; 631/80; 64/60; Antibodies; Biochemistry; Biomedical and Life Sciences; Bladder; CD34 antigen; Cell Biology; Cell Culture; Cyclophosphamide; Cystitis; Fibroblast growth factor receptor 7; Fibroblast growth factor receptors; Fibroblasts; Hemorrhage; Hemorrhagic cystitis; Immunology; Life Sciences; Mesenchyme; Progenitor cells; Stem cells
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03740-6

Cyclophosphamide is a commonly used chemotherapeutic drug to treat cancer with side effects that trigger bladder injury and hemorrhagic cystitis. Although previous studies have demonstrated that certain cell subsets and communications are activated to drive the repair and regeneration of bladder, it is not well understood how distinct bladder cell subsets function synergistically in this process. Here, we used droplet-based single-cell RNA sequencing (scRNA-seq) to profile the cell types within the murine bladder mucous layer under normal and injured conditions. Our analysis showed that superficial cells are directly repaired by cycling intermediate cells. We further identified two resident mesenchymal lineages (
Acta2
+
myofibroblasts and
Cd34
+
fibroblasts). The delineation of cell-cell communications revealed that
Acta2
+
myofibroblasts upregulated
Fgf7
expression during acute injury, which activated Fgfr signaling in progenitor cells within the basal/intermediate layers to promote urothelial cell growth and repair. Overall, our study contributes to a more comprehensive understanding of the cellular dynamics during cyclophosphamide-induced bladder injury and may help identify important niche factors contributing to the regeneration of injured bladders.