Human liver stem cell‐derived microvesicles accelerate hepatic regeneration in hepatectomized rats

Two distinct stem/progenitor cell populations of biliary origin have been identified in the adult liver and biliary tree. Hepatic Stem/progenitor Cells (HpSCs) are bipotent progenitor cells located within the canals of Hering and can be differentiated into mature hepatocytes and cholangiocytes; Biliary Tree Stem/progenitor Cells (BTSCs) are multipotent stem cells located within the peribiliary glands of large intrahepatic and extrahepatic bile ducts and able to differentiate into hepatic and pancreatic lineages. HpSCs and BTSCs are endowed in a specialized niche constituted by supporting cells and extracellular matrix compounds. The actual contribution of these stem cell niches to liver and biliary tree homeostatic regeneration is marginal; this is due to the high replicative capabilities and plasticity of mature parenchymal cells (i.e., hepatocytes and cholangiocytes). However, the study of human liver and biliary diseases disclosed how these stem cell niches are involved in the regenerative response after extensive and/or chronic injuries, with the activation of specific signaling pathways. The present review summarizes the contribution of stem/progenitor cell niches in human liver diseases, underlining mechanisms of activation and clinical implications, including fibrogenesis and disease progression.

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Current Perspectives Regarding Stem Cell-Based Therapy for Liver Cirrhosis

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2018/4197857 ◽

2018 ◽

Vol 2018 ◽

pp. 1-19 ◽

Cited By ~ 27

Author(s):

Kyeong-Ah Kwak ◽

Hyun-Jae Cho ◽

Jin-Young Yang ◽

Young-Seok Park

Keyword(s):

Liver Cirrhosis ◽

Stem Cell ◽

Mechanisms Of Action ◽

Clinical Applications ◽

Hepatic Regeneration ◽

Future Perspectives ◽

Cell Type ◽

Cell Based Therapy ◽

Preclinical And Clinical Studies ◽

Different Origins

Liver cirrhosis is a major cause of mortality and a common end of various progressive liver diseases. Since the effective treatment is currently limited to liver transplantation, stem cell-based therapy as an alternative has attracted interest due to promising results from preclinical and clinical studies. However, there is still much to be understood regarding the precise mechanisms of action. A number of stem cells from different origins have been employed for hepatic regeneration with different degrees of success. The present review presents a synopsis of stem cell research for the treatment of patients with liver cirrhosis according to the stem cell type. Clinical trials to date are summarized briefly. Finally, issues to be resolved and future perspectives are discussed with regard to clinical applications.

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Protective Effects of Human Liver Stem Cell-Derived Extracellular Vesicles in a Mouse Model of Hepatic Ischemia-Reperfusion Injury

Stem Cell Reviews and Reports ◽

10.1007/s12015-020-10078-7 ◽

2020 ◽

Author(s):

Alberto Calleri ◽

Dorotea Roggio ◽

Victor Navarro-Tableros ◽

Nicola De Stefano ◽

Chiara Pasquino ◽

...

Keyword(s):

Stem Cell ◽

Reperfusion Injury ◽

Extracellular Vesicles ◽

Human Liver ◽

Imaging System ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Control Group ◽

Hepatic Ischemia ◽

Hepatic Ischemia Reperfusion

AbstractHepatic ischemia-reperfusion injury (IRI) is observed in liver transplantation and hepato-biliary surgery and is associated with an inflammatory response. Human liver stem cell-derived extracellular vesicles (HLSC-EV) have been demonstrated to reduce liver damage in different experimental settings by accelerating regeneration and by modulating inflammation. The aim of the present study was to investigate whether HLSC-EV may protect liver from IRI in a mouse experimental model. Segmental IRI was obtained by selective clamping of intrahepatic pedicles for 90 min followed by 6 h of reperfusion. HLSC-EV were administered intravenously at the end of the ischemic period and histopathological and biochemical alterations were evaluated in comparison with controls injected with vehicle alone. Intra liver localization of labeled HLSC-EV was assessed by in in vivo Imaging System (IVIS) and the internalization into hepatocytes was confirmed by fluorescence analyses. As compared to the control group, administration of 3 × 109 particles (EV1 group) significantly reduced alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) release, necrosis extension and cytokines expression (TNF-α, CCL-2 and CXCL-10). However, the administration of an increased dose of HLSC-EV (7.5 × 109 particles, EV2 group) showed no significant improvement in respect to controls at enzyme and histology levels, despite a significantly lower cytokine expression. In conclusion, this study demonstrated that 3 × 109 HLSC-EV were able to modulate hepatic IRI by preserving tissue integrity and by reducing transaminases release and inflammatory cytokines expression. By contrast, a higher dose was ineffective suggesting a restricted window of biological activity.

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C-kit (stem cell factor receptor) expression in normal and diseased adult human liver

Journal of Hepatology ◽

10.1016/s0168-8278(02)80237-9 ◽

2002 ◽

Vol 36 ◽

pp. 70-71

Author(s):

Alberto Furlanetto ◽

Roberto Togni ◽

Stefano Negri ◽

Romano Colombari

Keyword(s):

Stem Cell ◽

Stem Cell Factor ◽

Human Liver ◽

Receptor Expression ◽

Adult Human

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Long Noncoding RNA CUDR Regulates HULC and β-Catenin to Govern Human Liver Stem Cell Malignant Differentiation

Molecular Therapy ◽

10.1038/mt.2015.166 ◽

2015 ◽

Vol 23 (12) ◽

pp. 1843-1853 ◽

Cited By ~ 50

Author(s):

Xin Gui ◽

Haiyan Li ◽

Tianming Li ◽

Hu Pu ◽

Dongdong Lu

Keyword(s):

Stem Cell ◽

Long Noncoding Rna ◽

Human Liver ◽

Noncoding Rna

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Pluripotent Stem Cell-Derived Human Liver Organoids Enter the Realm of High-Throughput Drug Screening

Gastroenterology ◽

10.1053/j.gastro.2020.12.005 ◽

2020 ◽

Author(s):

Salman R. Khetani

Keyword(s):

Stem Cell ◽

High Throughput ◽

Drug Screening ◽

Human Liver ◽

Pluripotent Stem Cell ◽

High Throughput Drug Screening ◽

Liver Organoids

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Expression of IGFBP-1 in normal and cirrhotic human livers

Journal of Endocrinology ◽

10.1677/joe.0.1410377 ◽

1994 ◽

Vol 141 (2) ◽

pp. 377-382 ◽

Cited By ~ 15

Author(s):

R J M Ross ◽

J Rodriguez-Arnao ◽

A Donaghy ◽

J Bentham ◽

A Clark ◽

...

Keyword(s):

Gene Expression ◽

Human Liver ◽

Chronic Liver ◽

Hepatic Regeneration ◽

Mrna Levels ◽

Insulin Levels ◽

Time Of Surgery ◽

Group 3 ◽

Group 2 ◽

Circulating Levels

Abstract Cirrhosis of the liver, a condition characterised by hepatocyte regeneration, is also associated with elevated insulin levels and insulin resistance. In animal models hepatic regeneration is associated with increased IGFBP-1 gene expression. Insulin is known to be an inhibitor of IGFBP-1 gene expression and circulating insulin levels in man demonstrate a negative correlation with IGFBP-1 levels. To further our understanding of the regulation of IGFBP-1 in cirrhosis we have studied steady state levels of IGFBP-1 mRNA in human liver from three groups of patients: Group 1, tissue obtained at the time of harvesting donor liver for orthotopic liver transplantation (n=4); group 2, patients undergoing major liver resection with no histological evidence of chronic liver disease (n=4); and group 3, patients undergoing orthotopic transplantation for chronic liver failure (n=9). Simultaneous samples of serum were taken at the time of surgery in some patients and in these patients IGFBP-1 mRNA levels were related to circulating levels of IGFBP-1 and insulin. IGFBP-1 mRNA was detectable in all the human liver samples with the greatest levels seen from the normal livers of group 2 patients. Insulin levels were elevated in the cirrhotic group 3 patients compared to a normal range as were IGFBP-1 levels. There was no relationship between circulating levels of IGFBP-1 and IGFBP-1 gene expression. In conclusion, IGFBP-1 mRNA is present in human adult liver at the time of surgery and also in cirrhotic liver despite high levels of insulin suggesting that there are factors other than insulin regulating IGFBP-1 gene expression. Journal of Endocrinology (1994) 141, 377–382

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