CCR2-overexpressing mesenchymal stem cells targeting damaged liver enhance recovery of acute liver failure

Stem Cell Research & Therapy

Huizhu Lin¹  Jiarou Shan²  Ruixuan Xu²  Lijie Pan²  Yizhan He²  Beibei Ni²  Qi Zhang³  Wenjie Chen³  Li Wang⁴  Guo Lv⁴ 

[1] Biotherapy Centre, The Third Affiliated Hospital, Sun Yat-Sen University, 600# Tianhe Road, 510630, Guangzhou, China;Biotherapy Centre, The Third Affiliated Hospital, Sun Yat-Sen University, 600# Tianhe Road, 510630, Guangzhou, China;Cell-Gene Therapy Translational Medicine Research Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China;Biotherapy Centre, The Third Affiliated Hospital, Sun Yat-Sen University, 600# Tianhe Road, 510630, Guangzhou, China;Cell-Gene Therapy Translational Medicine Research Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China;Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China;Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China;

关键词: Acute liver failure;    Mesenchymal stem cells;    CCL2;    CCR2;    Homing;   

DOI  :  10.1186/s13287-022-02729-y

来源: Springer

【 摘 要 】

BackgroundMesenchymal stem cell (MSC) transplantation is emerging as a promising cell therapeutic strategy in acute liver failure (ALF) clinical research. The potency of MSCs to migrate and engraft into targeted lesions could largely determine their clinical efficacy, in which chemokine/receptor axes play a crucial role. Unfortunately, the downregulation of chemokine receptors expression after in vitro expansion results in a poor homing capacity of MSCs.MethodsBy evaluating the chemokine expression profile in the liver of ALF patients and ALF mice, we found that CCL2 expression was highly upregulated in damaged livers, while the corresponding receptor, CCR2, was lacking in cultured MSCs. Thus, we genetically modified MSCs to overexpress CCR2 and investigated the targeted homing capacity and treatment efficacy of MSCCCR2 compared to those of the MSCvector control.ResultsIn vivo and ex vivo near-infrared fluorescence imaging showed that MSCCCR2 rapidly migrated and localized to injured livers in remarkably greater numbers following systemic infusion, and these cells were retained in liver lesions for a longer time than MSCvector. Furthermore, MSCCCR2 exhibited significantly enhanced efficacy in the treatment of ALF in mice, which was indicated by a dramatically improved survival rate, the alleviation of liver injury with reduced inflammatory infiltration and hepatic apoptosis, and the promotion of liver regeneration.ConclusionsAltogether, these results indicate that CCR2 overexpression enhances the targeted migration of MSCs to damaged livers, improves their treatment effect, and may provide a novel strategy for improving the efficacy of cell therapy for ALF.

【 授权许可】

CC BY