Single-cell dissection of cellular and molecular features underlying mesenchymal stem cell therapy in ischemic acute kidney injury

Wenjuan Wang; Min Zhang; Xuejing Ren; Yanqi Song; Yue Xu; Kaiting Zhuang; Tuo Xiao; Xinru Guo; Siyang Wang; Quan Hong; Zhe Feng; Xiangmei Chen; Guangyan Cai

doi:10.1016/j.ymthe.2023.07.024

Single-cell dissection of cellular and molecular features underlying mesenchymal stem cell therapy in ischemic acute kidney injury

Mol Ther. 2023 Oct 4;31(10):3067-3083. doi: 10.1016/j.ymthe.2023.07.024. Epub 2023 Aug 2.

Authors

Wenjuan Wang¹, Min Zhang², Xuejing Ren³, Yanqi Song², Yue Xu², Kaiting Zhuang², Tuo Xiao², Xinru Guo¹, Siyang Wang², Quan Hong², Zhe Feng², Xiangmei Chen⁴, Guangyan Cai⁵

Affiliations

¹ School of Medicine, Nankai University, Tianjin 300071, China; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China.
² Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China.
³ Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan Key Laboratory of Kidney Disease and Immunology, Academy of Medical Sciences, Zhengzhou, Henan 450001, China.
⁴ Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China. Electronic address: xmchen301@126.com.
⁵ School of Medicine, Nankai University, Tianjin 300071, China; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China. Electronic address: caiguangyan@sina.com.

PMID: 37533253
PMCID: PMC10556187 (available on 2024-10-04)
DOI: 10.1016/j.ymthe.2023.07.024

Abstract

Mesenchymal stem cells (MSCs) exert beneficial therapeutic effects in acute kidney injury (AKI), while the detailed repair mechanism remains unclear. Herein, we probed the underlying mechanisms of MSC therapy in AKI by performing unbiased single-cell RNA sequencing in IRI model with/without MSC treatment. Our analyses uncovered the tubular epithelial cells (TECs) and immune cells transcriptomic diversity and highlighted a repair trajectory involving renal stem/progenitor cell differentiation. Our findings also suggested that profibrotic TECs expressing pro-fibrotic factors such as Zeb2 and Pdgfb promoted the recruitment of inflammatory monocytes and Th17 cells to injured kidney tissue, inducing TGF-β1 secretion and renal fibrosis. Finally, in addition to activating the repair properties of renal progenitor/stem cells, we uncovered a role for MSC-derived miR-26a-5p in mediating the therapeutic effects of MSCs by inhibiting Zeb2 expression and suppressing pro-fibrotic TECs and its subsequent recruitment of immune cell subpopulations. These findings may help to optimize future AKI treatment strategies.

Keywords: acute kidney injury; intercellular crosstalk; mesenchymal stem cells; single-cell sequencing; trajectory analysis.