Hepatocyte growth factor enhances the ability of dental pulp stem cells to ameliorate atherosclerosis in apolipoprotein E-knockout mice

Han Duan; Ning Tao; Lin Lv; Kai-Xin Yan; Yong-Gang You; Zhuang Mao; Chang-Yao Wang; Xue Li; Jia-Yan Jin; Chu-Tse Wu; Hua Wang

doi:10.4252/wjsc.v16.i5.575

Hepatocyte growth factor enhances the ability of dental pulp stem cells to ameliorate atherosclerosis in apolipoprotein E-knockout mice

World J Stem Cells. 2024 May 26;16(5):575-590. doi: 10.4252/wjsc.v16.i5.575.

Authors

Han Duan¹, Ning Tao², Lin Lv², Kai-Xin Yan³, Yong-Gang You⁴, Zhuang Mao², Chang-Yao Wang¹, Xue Li², Jia-Yan Jin⁵, Chu-Tse Wu², Hua Wang^{1

6}

Affiliations

¹ School of Life Sciences, Hebei University, Baoding 071002, Hebei Province, China.
² Beijing Institute of Radiation Medicine, Beijing 100850, China.
³ Department of Cardiology, The Sixth Medical Centre, Chinese People's Liberation Army General Hospital, Beijing 100037, China.
⁴ Department of Orthopaedics, The Fourth Medical Centre, Chinese People's Liberation Army General Hospital, Beijing 100853, China.
⁵ Third Cadet Regiment, School of Basic Medical Science, Air Force Medical University, Xi'an 710032, Shaanxi Province, China.
⁶ Beijing Institute of Radiation Medicine, Beijing 100850, China. 18511712135@163.com.

Abstract

Background: Atherosclerosis (AS), a chronic inflammatory disease of blood vessels, is a major contributor to cardiovascular disease. Dental pulp stem cells (DPSCs) are capable of exerting immunomodulatory and anti-inflammatory effects by secreting cytokines and exosomes and are widely used to treat autoimmune and inflammation-related diseases. Hepatocyte growth factor (HGF) is a pleiotropic cytokine that plays a key role in many inflammatory and autoimmune diseases.

Aim: To modify DPSCs with HGF (DPSC-HGF) and evaluate the therapeutic effect of DPSC-HGF on AS using an apolipoprotein E-knockout (ApoE^-/-) mouse model and an in vitro cellular model.

Methods: ApoE^-/- mice were fed with a high-fat diet (HFD) for 12 wk and injected with DPSC-HGF or Ad-Null modified DPSCs (DPSC-Null) through tail vein at weeks 4, 7, and 11, respectively, and the therapeutic efficacy and mechanisms were analyzed by histopathology, flow cytometry, lipid and glucose measurements, real-time reverse transcription polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay at the different time points of the experiment. An in vitro inflammatory cell model was established by using RAW264.7 cells and human aortic endothelial cells (HAOECs), and indirect co-cultured with supernatant of DPSC-Null (DPSC-Null-CM) or DPSC-HGF-CM, and the effect and mechanisms were analyzed by flow cytometry, RT-PCR and western blot. Nuclear factor-κB (NF-κB) activators and inhibitors were also used to validate the related signaling pathways.

Results: DPSC-Null and DPSC-HGF treatments decreased the area of atherosclerotic plaques and reduced the expression of inflammatory factors, and the percentage of macrophages in the aorta, and DPSC-HGF treatment had more pronounced effects. DPSCs treatment had no effect on serum lipoprotein levels. The FACS results showed that DPSCs treatment reduced the percentages of monocytes, neutrophils, and M1 macrophages in the peripheral blood and spleen. DPSC-Null-CM and DPSC-HGF-CM reduced adhesion molecule expression in tumor necrosis factor-α stimulated HAOECs and regulated M1 polarization and inflammatory factor expression in lipopolysaccharide-induced RAW264.7 cells by inhibiting the NF-κB signaling pathway.

Conclusion: This study suggested that DPSC-HGF could more effectively ameliorate AS in ApoE^-/- mice on a HFD, and could be of greater value in stem cell-based treatments for AS.

Keywords: Apolipoprotein E-knockout mice; Atherosclerosis; Cell therapy; Dental pulp stem cells; Hepatocyte growth factor.