Therapeutic potential of transplanted placental mesenchymal stem cells in treating Chinese miniature pigs with acute liver failure

Recent studies have described beneficial effects of an infusion of mesenchymal stem cells (MSCs) derived from Wharton’s jelly tissue, for the treatment of acute liver failure (ALF). However, data on the therapeutic potential of culture-expanded MSCs are lacking. We examined the therapeutic potential of passage five (P5) and ten (P10) human umbilical cord- (hUC-) MSCs via their transplantation into Sprague-Dawley (SD) rats with D-galactosamine (D-GalN) and LPS-induced acute liver failure (ALF). SD rats were randomly divided into three groups: control group, P5 hUC-MSCs group, and P10 hUC-MSCs group. After transplantation, P5 hUC-MSCs provided a significant survival benefit. The analysis of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) levels showed that transplantation with P5 hUC-MSCs was more effective than treatment with P10 hUC-MSCs. P5 hUC-MSCs also successfully downregulated the hepatic activity index (HAI) scores. Compared to P10 hUC-MSCs in vivo, P5 hUC-MSCs significantly enhanced the regeneration and inhibited the apoptosis of hepatocytes. CM-Dil-labeled hUC-MSCs were found to engraft within the recipient liver, whereas the homing of cells to the recipient liver in the P10 hUC-MSCs group was less effective compared to the P5 hUC-MSCs group. Previous studies have shown that the concentration of hepatocyte growth factor (HGF) in the injured liver was significantly increased. HGF is commonly known as the ligand of c-Met. The level of c-Met in hUC-MSCs as detected by Western blotting indicated that at a higher passage number, there is a decrease in c-Met. These data suggest that direct transplantation of P5 hUC-MSCs can more efficiently home to an injured liver. Subsequently, the P5 hUC-MSCs can rescue ALF and repopulate the livers of rats through the stimulation of endogenous liver regeneration and inhibition of hepatocellular apoptosis for compensated liver function, which is dependent on the higher level of c-Met than P10 hUC-MSCs.

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The Effects of Conditioned Medium Derived from Mesenchymal Stem Cells Cocultured with Hepatocytes on Damaged Hepatocytes and Acute Liver Failure in Rats

Stem Cells International ◽

10.1155/2018/9156560 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Li Chen ◽

Jiexin Zhang ◽

Lu Yang ◽

Guoying Zhang ◽

Yingjie Wang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Liver Failure ◽

Acute Liver Failure ◽

Conditioned Medium ◽

Therapeutic Potential ◽

L02 Cells ◽

Cells Cultured

Mesenchymal stem cells (MSCs) and hepatocytes are two attractive sources of cell-based therapies for acute liver failure (ALF). The cotransplantation of hepatocytes with MSCs can improve the therapeutic performance for the treatment of ALF. However, the therapeutic potential of conditioned medium (CM) derived from MSCs cocultured with hepatocytes (MSC-H-CM) remains unclear. The purpose of this study was to investigate the effects of MSC-H-CM on damaged hepatocytes in vitro and on D-galactosamine-induced ALF in vivo. D-Galactosamine-treated L02 cells cultured in MSC-H-CM exhibited higher of cell viability and total protein synthesis than L02 cells cultured in MSC-CM, CM derived from hepatocytes (H-CM), MSC-CM + H-CM, or with nonconditioned medium (NCM). Lactate dehydrogenase and aspartate aminotransferase levels were lower in the supernatant of damaged L02 cells cultured in MSC-H-CM than in that of L02 cells cultured in other types of CM. The lowest percentage of apoptotic cells was observed after the MSC-H-CM treatment. When CM was injected into the tail vein of rats with ALF, MSC-H-CM was the most successful at preventing the release of liver injury biomarkers and in promoting the recovery of liver structure. The greatest survival rate 7 days after the first treatment was observed in the MSC-H-CM-treated rats. Our results reveal that the delivery of MSC-H-CM could be a novel strategy for integrating the therapeutic potentials of hepatocytes and MSCs for the treatment of ALF.

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Concise Review: Therapeutic Potential of Mesenchymal Stem Cells for the Treatment of Acute Liver Failure and Cirrhosis

Stem Cells ◽

10.1002/stem.1818 ◽

2014 ◽

Vol 32 (11) ◽

pp. 2818-2823 ◽

Cited By ~ 103

Author(s):

Vladislav Volarevic ◽

Jasmin Nurkovic ◽

Nebojsa Arsenijevic ◽

Miodrag Stojkovic

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Liver Failure ◽

Acute Liver Failure ◽

Therapeutic Potential ◽

Concise Review

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Therapeutic Potential of HGF-Expressing Human Umbilical Cord Mesenchymal Stem Cells in Mice with Acute Liver Failure

International Journal of Hepatology ◽

10.1155/2016/5452487 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 12

Author(s):

Yunxia Tang ◽

Qiongshu Li ◽

Fanwei Meng ◽

Xingyu Huang ◽

Chan Li ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cell Therapy ◽

Liver Failure ◽

Acute Liver Failure ◽

Umbilical Cord ◽

Therapeutic Potential ◽

Redox Homeostasis ◽

Ectopic Expression ◽

Human Umbilical Cord

Human umbilical cord-derived mesenchymal stem cells (UCMSCs) are particularly attractive cells for cellular and gene therapy in acute liver failure (ALF). However, the efficacy of this cell therapy in animal studies needs to be significantly improved before it can be translated into clinics. In this study, we investigated the therapeutic potential of UCMSCs that overexpress hepatocyte growth factor (HGF) in an acetaminophen-induced acute liver failure mouse model. We found that the HGF-UCMSC cell therapy protected animals from acute liver failure by reducing liver damage and prolonging animal survival. The therapeutic effect of HGF-UCMSCs was associated with the increment in serum glutathione (GSH) and hepatic enzymes that maintain redox homeostasis, includingγ-glutamylcysteine synthetase (γ-GCS), superoxide dismutase (SOD), and catalase (CAT). Immunohistochemical staining confirmed that HGF-UCMSCs were mobilized to the injured areas of the liver. Additionally, HGF-UCMSCs modulated apoptosis by upregulating the antiapoptotic Bcl2 and downregulating proapoptotic genes, including Bax and TNFα. Taken together, these data suggest that ectopic expression of HGF in UCMSCs protects animals from acetaminophen-induced acute liver failure through antiapoptosis and antioxidation mechanisms.

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Extracellular vesicles from three dimensional culture of human placental mesenchymal stem cells ameliorated renal ischemia/reperfusion injury

The International Journal of Artificial Organs ◽

10.1177/0391398820986809 ◽

2021 ◽

pp. 039139882098680

Author(s):

Xuefeng Zhang ◽

Nan Wang ◽

Yuhua Huang ◽

Yan Li ◽

Gang Li ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Extracellular Vesicles ◽

Therapeutic Potential ◽

Expression Profiles ◽

Ischemia Reperfusion ◽

Three Dimensional ◽

3D Culture ◽

Placental Mesenchymal Stem Cells ◽

2D And 3D

Background: Three-dimensional (3D) culture has been reported to increase the therapeutic potential of mesenchymal stem cells (MSCs). The present study assessed the therapeutic efficacy of extracellular vesicles (EVs) from 3D cultures of human placental MSCs (hPMSCs) for acute kidney injury (AKI). Methods: The supernatants from monolayer culture (2D) and 3D culture of hPMSCs were ultra-centrifuged for EVs isolation. C57BL/6 male mice were submitted to 45 min bilateral ischemia of kidney, followed by renal intra-capsular administration of EVs within a 72 h reperfusion period. Histological, immunohistochemical, and ELISA analyses of kidney samples were performed to evaluate cell death and inflammation. Kidney function was evaluated by measuring serum creatinine and urea nitrogen. The miRNA expression profiles of EVs from 2D and 3D culture of hPMSCs were evaluated using miRNA microarray analysis. Results: The 3D culture of hPMSCs formed spheroids with different diameters depending on the cell density seeded. The hPMSCs produced significantly more EVs in 3D culture than in 2D culture. More importantly, injection of EVs from 3D culture of hPMSCs into mouse kidney with ischemia-reperfusion (I/R)-AKI was more beneficial in protecting from progression of I/R than those from 2D culture. The EVs from 3D culture of hPMSCs were more efficient against apoptosis and inflammation than those from 2D culture, which resulted in a reduction in tissue damage and amelioration of renal function. MicroRNA profiling analysis revealed that a set of microRNAs were significantly changed in EVs from 3D culture of hPMSCs, especially miR-93-5p. Conclusion: The EVs from 3D culture of hPMSCs have therapeutic potential for I/R-AKI.

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