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Induction of hepatocyte-like cells from human umbilical cord-derived mesenchymal stem cells by defined microRNAs.

ABSTRACT: Generating functional hepatocyte-like cells (HLCs) from mesenchymal stem cells (MSCs) is of great urgency for bio-artificial liver support system (BALSS). Previously, we obtained HLCs from human umbilical cord-derived MSCs by overexpressing seven microRNAs (HLC-7) and characterized their liver functions in vitro and in vivo. Here, we aimed to screen out the optimal miRNA candidates for hepatic differentiation. We sequentially removed individual miRNAs from the pool and examined the effect of transfection with remainder using RT-PCR, periodic acid-Schiff (PAS) staining and low-density lipoprotein (LDL) uptake assays and by assessing their function in liver injury models. Surprisingly, miR-30a and miR-1290 were dispensable for hepatic differentiation. The remaining five miRNAs (miR-122, miR-148a, miR-424, miR-542-5p and miR-1246) are essential for this process, because omitting any one from the five-miRNA combination prevented hepatic trans-differentiation. We found that HLCs trans-differentiated from five microRNAs (HLC-5) expressed high level of hepatic markers and functioned similar to hepatocytes. Intravenous transplantation of HLC-5 into nude mice with CCl4 -induced fulminant liver failure and acute liver injury not only improved serum parameters and their liver histology, but also improved survival rate of mice in severe hepatic failure. These data indicated that HLC-5 functioned similar to HLC-7 in vitro and in vivo, which have been shown to resemble hepatocytes. Instead of using seven-miRNA combination, a simplified five-miRNA combination can be used to obtain functional HLCs in only 7 days. Our study demonstrated an optimized and efficient method for generating functional MSC-derived HLCs that may serve as an attractive cell alternative for BALSS.

SUBMITTER: Zhou X

PROVIDER: S-EPMC5387126 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Induction of hepatocyte-like cells from human umbilical cord-derived mesenchymal stem cells by defined microRNAs.

Zhou Xia X Cui Lina L Zhou Xinmin X Yang Qiong Q Wang Lu L Guo Guanya G Hou Yu Y Cai Weile W Han Zheyi Z Shi Yongquan Y Han Ying Y

Journal of cellular and molecular medicine 20161122 5

Generating functional hepatocyte-like cells (HLCs) from mesenchymal stem cells (MSCs) is of great urgency for bio-artificial liver support system (BALSS). Previously, we obtained HLCs from human umbilical cord-derived MSCs by overexpressing seven microRNAs (HLC-7) and characterized their liver functions in vitro and in vivo. Here, we aimed to screen out the optimal miRNA candidates for hepatic differentiation. We sequentially removed individual miRNAs from the pool and examined the effect of tra ...[more]

PMID: 27874233

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Project description:Autism is a pervasive neurodevelopmental disorder. At present there are no defined mechanisms of pathogenesis and therapy is mostly limited to behavioral interventions. Stem cell transplantation may offer a unique treatment strategy for autism due to immune and neural dysregulation observed in this disease. This non-randomized, open-label, single center phase I/II trial investigated the safety and efficacy of combined transplantation of human cord blood mononuclear cells (CBMNCs) and umbilical cord-derived mesenchymal stem cells (UCMSCs) in treating children with autism.37 subjects diagnosed with autism were enrolled into this study and divided into three groups: CBMNC group (14 subjects, received CBMNC transplantation and rehabilitation therapy), Combination group (9 subjects, received both CBMNC and UCMSC transplantation and rehabilitation therapy), and Control group (14 subjects, received only rehabilitation therapy). Transplantations included four stem cell infusions through intravenous and intrathecal injections once a week. Treatment safety was evaluated with laboratory examinations and clinical assessment of adverse effects. The Childhood Autism Rating Scale (CARS), Clinical Global Impression (CGI) scale and Aberrant Behavior Checklist (ABC) were adopted to assess the therapeutic efficacy at baseline (pre-treatment) and following treatment.There were no significant safety issues related to the treatment and no observed severe adverse effects. Statistically significant differences were shown on CARS, ABC scores and CGI evaluation in the two treatment groups compared to the control at 24 weeks post-treatment (p < 0.05).Transplantation of CBMNCs demonstrated efficacy compared to the control group; however, the combination of CBMNCs and UCMSCs showed larger therapeutic effects than the CBMNC transplantation alone. There were no safety issues noted during infusion and the whole monitoring period.ClinicalTrials.gov: NCT01343511, Title "Safety and Efficacy of Stem Cell Therapy in Patients with Autism".

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Dataset Information

Induction of hepatocyte-like cells from human umbilical cord-derived mesenchymal stem cells by defined microRNAs.

Publications

Induction of hepatocyte-like cells from human umbilical cord-derived mesenchymal stem cells by defined microRNAs.

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