A combination of ultrasound-targeted microbubble destruction with transplantation of bone marrow mesenchymal stem cells promotes recovery of acute liver injury

Abstract

BackgroundBone marrow mesenchymal stem cells (BMSCs) can provide an additional source of therapeutic stem cells for regeneration of liver cells during acute liver injury (ALI). However, the insufficient hepatic homing by the transplanted BMSCs limits their applications. Ultrasound-targeted microbubble destruction (UTMD) has been reported to promote the homing of transplanted stem cells into the ischemic myocardium. In this study, we investigated whether UTMD promotes the hepatic homing of BMSCs in ALI rats and evaluated the therapeutic effect.MethodsBMSCs were isolated from the femurs and tibias of Sprague-Dawley (SD) rats. The isolated BMSCs were stably transfected with a lentivirus expressing enhanced green fluorescent protein (EGFP) that can be visualized and quantified in vivo after transplantation. Both tumor necrosis factor α (TNF-α) and stromal cell-derived factor 1 (SDF-1) were used to verify the appropriate ultrasound parameters. The ALI rats were divided into four groups: control, BMSCs, UTMD, and UTMD + BMSCs. The protein and mRNA expression levels of SDF-1, intercellular cell adhesion molecule (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), hepatocyte growth factor (HGF), and monocyte chemotactic protein 1 (MCP-1) in the exposed livers were analyzed at 48 h after treatment. ALI recovery was determined by serum biochemical parameters and histology.ResultsThe isolated rat BMSCs demonstrated a good proliferation potential that was both osteogenic and adipogenic in differentiation and expressed cluster of differentiation (CD) 29 and CD90, but not CD45 or CD11b/c. After BMSC and/or UTMD treatment, the number of GFP-labeled BMSCs in the UTMD + BMSCs group was significantly higher than that of the BMSCs group (9.8 ± 2.3 vs. 5.2 ± 1.1/per high-power field). Furthermore, the expression of GFP mRNA was performed for evaluation of the homing rate of BMSCs in injury sites as well. In addition, the expression levels of SDF-1, ICAM-1, VCAM-1, HGF, and MCP-1 were higher (p < 0.01) in UTMD+BMSCs group. The serum levels of biomarkers were significantly lower in the UTMD + BMSCs group, and the apoptotic rate of hepatocytes in the UTMD + BMSCs group was markedly lower than that of the BMSCs group (all p < 0.05). The hepatic pathology was significantly alleviated in the UTMD + BMSCs group.ConclusionsUTMD treatment efficiently induced a favorable microenvironment for cell engraftment, resulting in improvement of hepatic homing of BMSCs, which was probably mediated through upregulation of the expression of adhesion molecules and cytokines. UTMD treatment appeared to be an effective and noninvasive approach to achieve better efficacy of BMSC-based therapy for repairing a severely injured liver.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1098-4) contains supplementary material, which is available to authorized users.

RETRACTED: Hepatoma Cell-Derived Extracellular Vesicles Promote Liver Cancer Metastasis by Inducing the Differentiation of Bone Marrow Stem Cells Through microRNA-181d-5p and the FAK/Src Pathway

“…Despite the improvement in liver cancer in the last decades, the efficacy on this aggressive disease remains disappointing (Ding, 2016). Stem cells are a source of hepatocyte regeneration to repair the damaged liver, among which BMSCs have potential therapeutic value for liver diseases (Li, 2018). TDEs transfer the key factors from tumor cells to facilitate tumorigenesis, immune evasion and metastasis during HCC (Ba, 2020).…”

Ultrasound‑targeted microbubble destruction‑mediated Galectin‑7‑siRNA promotes the homing of bone marrow mesenchymal stem cells to alleviate acute myocardial infarction in rats

“…Some articles have elucidated that SDF-1 and VCAM-1 expression is implicated in the liver homing of BMSCs ( 48 - 50 ). Recently, it has been revealed that increased VCAM-1 expression indicates that UTMD may induce BMSC migration by enhancing interstitial and intercellular capillary permeability ( 51 ). Furthermore, when the UTMD procedure is performed following a pre-injection of BMSCs, or when UTMD is combined with BMSC transplantation, there is a beneficial effect on the engraftment of cells ( 52 , 53 ).…”

“…Furthermore, when the UTMD procedure is performed following a pre-injection of BMSCs, or when UTMD is combined with BMSC transplantation, there is a beneficial effect on the engraftment of cells ( 52 , 53 ). Ultrasound microbubbles can enhance the therapeutic effect of BMSCs in diseases and promote BMSC homing ( 51 , 54 , 55 ). In the present study, the BUTMD + siRNA NC group had an intermediate therapeutic effect.…”

Mesenchymal stem cell homing to improve therapeutic efficacy in liver disease

“…This preliminary liver irradiation significantly promoted the homing and re-proliferation of BM-MSCs and significantly improved liver fibrosis in rat models [ 134 ]. Ultrasound-targeted microbubble destruction therapy effectively induces a favorable microenvironment for cell implantation, thus improving liver homing of BM-MSCs, which may be mediated by upregulation of adhesion molecules and cytokine expression [ 135 ]. Sun et al confirmed that combined application of BM-MSCs-HGF and ultrasound-targeted microbubble destruction technologies further promoted the homing of BM-MSCs and, more importantly, further improved their response to liver fibrosis [ 136 ].…”