DLL4 restores damaged liver by enhancing hBMSC differentiation into cholangiocytes

Stem Cell Research

Tong Cheng¹  Dongyan Shi¹  Sihan Ruan²  Keke Ren²  Suwan Sun²  Qian Zhou²  Jiaojiao Xin²  Jiaxian Chen²  Xiaojun Jin²  Xingping Zhou²  Jing Jiang²  Beibei Guo²  Zhanglu An²  Jun Li³  Lunzhi Yuan³  Ningshao Xia⁴ 

[1] Graduate School, Hebei North University, Zhangjiakou, Hebei 075000, China;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China;State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences and School of Public Health, Xiamen University, Xiamen 361102, China;Taizhou Central Hospital, Taizhou University Hospital, 999 Donghai Rd., Taizhou 318000, China;

关键词: Biliary restoration;    hBMSC;    DLL4;    Cholangiocyte differentiation;   

DOI  :  

来源: DOAJ

【 摘 要 】

Background & aims: Biliary injury is one of the main pathological mechanisms of fulminant hepatic failure (FHF). Delta-like ligand 4 (DLL4)-mediated Notch activation contributes to reversing biliary injury; however, the specific role of DLL4 in biliary restoration is still unclear. This study aimed to determine whether human bone marrow mesenchymal stem cells (hBMSCs) can differentiate into biliary epithelial cells (cholangiocytes) in vitro and in vivo and to clarify the role of DLL4 in restoring damaged liver by enhancing cholangiocyte differentiation. Methods: hBMSCs were transplanted into immunodeficient mice (FRGS) with FHF induced by the hamster-anti-mouse CD95 antibody JO2. The appearance of human cholangiocytes was evaluated in the generated hBMSC-FRGS mice by q-PCR expression, flow cytometry and immunohistochemistry. The potency of DLL4 in inducing cholangiocyte differentiation from hBMSCs was assessed by observing the cell morphology and measuring the expression of cholangiocyte-specific genes and proteins. Results: Human KRT19- and KRT7-double-positive cholangiocyte-like cells appeared in hBMSC-FRGS mice at 12 weeks after transplantation. After these cells were separated and collected by fluorescent-activated cell sorting (FACS), there were high levels of expression of eight typical human cholangiocyte-specific genes and proteins (e.g., KRT19 and KRT7). Furthermore, hBMSC-derived cholangiocytes induced by DLL4 had a better shape with higher nucleus/cytoplasm ratios and showed a specific increase in the expression of cholangiocyte-specific genes and proteins (e.g., KRT19, KRT7, SOX9 and CFTR). Conclusions: Cholangiocytes can be efficiently differentiated from hBMSCs in vivo and in vitro. DLL4 restores damaged liver by enhancing cholangiocyte differentiation from hBMSCs and has the potential to be used in future clinical therapeutic applications.

【 授权许可】

Unknown