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Spheroid-cultured human umbilical cord-derived mesenchymal stem cells attenuate hepatic ischemia-reperfusion injury in rats.

ABSTRACT: Mesenchymal stem cell (MSC) transplantation is a promising treatment for ischemia-reperfusion injury (IRI). However, its effects on hepatic IRI were not consistent in the previous studies. 3D spheroid-cultured MSCs enhance their production of trophic and anti-inflammatory properties, but their effects on hepatic IRI remain unclear. In this study, we compared the 3D spheroid-cultured human umbilical derived MSCs (3D UC-MSCs) with 2D-cultured UC-MSCs (2D UC-MSCs) on treating hepatic IRI. The RNA sequencing data showed that suppression of cell mitosis, response to hypoxia, inflammation, and angiogenesis were the top genetic changes in 3D UC-MSCs compared with 2D UC-MSCs. Although both pro-inflammatory and anti-inflammatory genes were upregulated in the 3D UC-MSCs, the mRNA and protein of an RNase (ZC3H12A), which turnovers the mRNA of pro-inflammatory genes at the post-transcript level, were significantly upregulated in 3D UC-MSCs. 3D UC-MSCs reduced the secretion of many chemokines and growth factors, but increased the secretion of vascular endothelial growth factor. Compared with the vehicle and 2D UC-MSCs, 3D UC-MSCs significantly reduced hepatic IRI in rats, based on the plasma aminotransferase levels, liver damage scores, neutrophil infiltration, hepatocyte apoptosis and expression of inflammation-associated genes. These findings suggest that 3D UC-MSCs therapy is a promising treatment for hepatic IRI.

SUBMITTER: Sun Y

PROVIDER: S-EPMC5802716 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Spheroid-cultured human umbilical cord-derived mesenchymal stem cells attenuate hepatic ischemia-reperfusion injury in rats.

Sun Yi Y Wang Yang Y Zhou Liang L Zou Yizhou Y Huang Gengwen G Gao Ge G Ting Shi S Lei Xiong X Ding Xiang X

Scientific reports 20180206 1

Mesenchymal stem cell (MSC) transplantation is a promising treatment for ischemia-reperfusion injury (IRI). However, its effects on hepatic IRI were not consistent in the previous studies. 3D spheroid-cultured MSCs enhance their production of trophic and anti-inflammatory properties, but their effects on hepatic IRI remain unclear. In this study, we compared the 3D spheroid-cultured human umbilical derived MSCs (3D UC-MSCs) with 2D-cultured UC-MSCs (2D UC-MSCs) on treating hepatic IRI. The RNA s ...[more]

PMID: 29410537

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Project description:Mesenchymal stem cell (MSC) therapy is an innovative approach in diabetes due to its capacity to modulate tissue microenvironment and regeneration of glucose-responsive insulin-producing cells. In this study, we investigated the role of MSC-derived exosomes in pancreatic regeneration and insulin secretion in mice with streptozotocin-induced diabetes. Mesenchymal stem cells (MSCs) were isolated and characterized from umbilical cord blood (UCB). Exosomes were isolated and characterized from these MSCs. Diabetes was induced in male C57Bl/6 mice by streptozotocin (STZ; 40 mg/kg body weight, i.p.) for five consecutive days. The diabetic mice were administered (i.v.) with MSC (1 × 105 umbilical cord blood MSC cells/mice/day), their derived exosomes (the MSC-Exo group that received exosomes derived from 1 × 105 MSC cells/mice/day), or the same volume of PBS. Before administration, the potency of MSCs and their exosomes was evaluated in vitro by T cell activation experiments. After day 7 of the treatments, blood samples and pancreatic tissues were collected. Histochemistry was performed to check cellular architecture and β cell regeneration. In body weight, blood glucose level, and insulin level, cell proliferation assay was done to confirm regeneration of cells after MSC and MSC-Exo treatments. Hyperglycemia was also attenuated in these mice with a concomitant increase in insulin production and an improved histological structure compared to mice in the PBS-treated group. We found increased expression of genes associated with tissue regeneration pathways, including Reg2, Reg3, and Amy2b in the pancreatic tissue of mice treated with MSC or MSC-Exo relative to PBS-treated mice. MicroRNA profiling of MSC-derived exosomes showed the presence of miRs that may facilitate pancreatic regeneration by regulating the Extl3-Reg-cyclinD1 pathway. These results demonstrate a potential therapeutic role of umbilical cord blood MSC-derived exosomes in attenuating insulin deficiency by activating pancreatic islets' regenerative abilities.

Project description:BackgroundThis study was designed to determine the effect of human umbilical cord multipotent mesenchymal stromal cells (hUC-MSC) on acute ischemia/reperfusion (I/R) injury of spermatogenic cells.MethodThe testicular I/R rat model was established through 720° torsion for 1 h. hUC-MSC were intravenously injected 10 min before detorsion. Injury severity of spermatogenic cells was estimated by Johnsen's score. The proliferating of recipient spermatogonia was measured by the immunostaining of antibodies against Ki67, and all germ cells were detected with DDX4 antibody. And recipient spermatogenesis was assessed by staining spermatozoa with lectin PNA. The levels of inflammatory factors were measured by real-time PCR. And the Selectin-E expression, neutrophil infiltration in the testes was detected by immunostaining. Germ cells apoptosis was tested by TUNEL assay and western blot. Furthermore, the oxidative stress was tested by reactive oxidative species (ROS) levels. In vitro, the condition medium (CM) of hUC-MSC was used to culture human umbilical vein endothelial cells (HUVECs), so as to assess the paracrine effect of hUC-MSC on HUVECs. The protein chip was used to measure the relative concentration of the secretory proteins in the CM of hUC-MSC.ResulthUC-MSC greatly alleviated the testicular injury induced by testis I/R. The levels of proinflammatory factors were downregulated by hUC-MSC in vivo and in vitro. Neutrophil infiltration, ROS, and germ cell apoptosis in testicular tissues were greatly reduced in the group of hUC-MSC. Paracrine factors secreted by hUC-MSC including growth factors, cytokines, and anti-inflammatory cytokine were rich.ConclusionThis study demonstrated that intravenously injected hUC-MSC could protect the spermatogenic cells against I/R injury by reducing the inflammatory response, apoptosis, and acute oxidative injury. Paracrine mechanism of hUC-MSC may contribute to the protection of spermatogenic cells against I/R injury. Therefore, the present study provides a method for clinical treatment of attenuate I/R injury of spermatogenic cells.

Project description:Background:Cholestasis is a sign of hepatic ischemia-reperfusion injury (IRI), which is caused by the dysfunction of hepatocyte membrane transporters (HMTs). As transcriptional regulation of HMTs during oxidative stress is mediated by nuclear factor erythroid 2-related factor 2, we hypothesized that bardoxolone methyl (BARD), a nuclear factor erythroid 2-related factor 2 activator, can mitigate cholestasis associated with hepatic IRI. Methods:BARD (2 mg/kg) or the vehicle was intravenously administered into rats immediately before sham surgery, 60 min of ischemia (IR60), or 90 min of ischemia (IR90); tissue and blood samples were collected after 24 h to determine the effect on key surrogate markers of bile metabolism and expression of HMT genes (Mrp (multidrug resistance-associated protein) 2, bile salt export pump, Mrp3, sodium-taurocholate cotransporter, and organic anion-transporting polypeptide 1). Results:Significantly decreased serum bile acids were detected upon BARD administration in the IR60 group but not in the IR90 group. Hepatic tissue analyses revealed that BARD administration increased mRNA levels of Mrp2 and Mrp3 in the IR60 group, and it decreased those of bile salt export pump in the IR90 group. Protein levels of multidrug resistance-associated protein 2, multidrug resistance-associated protein 3, and sodium-taurocholate cotransporter were higher in the IR90 group relative to those in the sham or IR60 groups, wherein the difference was notable only when BARD was administered. Immunohistochemical and morphometric analyses showed that the area of expression for multidrug resistance-associated protein 2 and for sodium-taurocholate cotransporter was larger in the viable tissues than in the necrotic area, and the area for multidrug resistance-associated protein 3 was smaller; these differences were notable upon BARD administration. Conclusions:BARD may have the potential to change HMT regulation to mitigate cholestasis in hepatic IRI.

Dataset Information

Spheroid-cultured human umbilical cord-derived mesenchymal stem cells attenuate hepatic ischemia-reperfusion injury in rats.

Publications

Spheroid-cultured human umbilical cord-derived mesenchymal stem cells attenuate hepatic ischemia-reperfusion injury in rats.

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