Amnion-Derived Mesenchymal Stromal/Stem Cell Paracrine Signals Potentiate Human Liver Organoid Differentiation: Translational Implications for Liver Regeneration

The prevalence of end-stage liver diseases has reached very high levels globally. The election treatment for affected patients is orthotopic liver transplantation, which is a very complex procedure, and due to the limited number of suitable organ donors, considerable research is being done on alternative therapeutic options. For instance, the use of cell therapy, such as the transplantation of hepatocytes to promote liver repair/regeneration, has been explored, but standardized protocols to produce suitable human hepatocytes are still limited. On the other hand, liver progenitor and multipotent stem cells offer potential cell sources that could be used clinically. Different studies have reported regarding the therapeutic effects of transplanted mesenchymal stromal/stem cells (MSCs) on end-stage liver diseases. Moreover, it has been shown that delivery of MSC-derived conditioned medium (MSC-CM) can reduce cell death and enhance liver proliferation in fulminant hepatic failure. Therefore, it is believed that MSC-CM contains many factors that probably support liver regeneration. In our work, we used an in vitro model of human liver organoids to study if the paracrine components secreted by human amnion-derived MSCs (hAMSCs) affected liver stem/progenitor cell differentiation. In particular, we differentiated liver organoids derived from bipotent EpCAM+ human liver cells and tested the effects of hAMSC secretome, derived from both two-dimensional (2D) and three-dimensional (3D) hAMSC cultures, on that model. Our analysis showed that conditioned medium (CM) produced by 3D hAMSCs was able to induce an over-expression of mature hepatocyte markers, such as ALB, NTCP, and CYP3A4, compared with both 2D hAMSC cultures and the conventional differentiation medium (DM). These data were confirmed by the over-production of ALB protein and over-activity of CYP3A4 observed in organoids grown in 3D hAMSC-CM. Liver repair dysfunction plays a role in the development of liver diseases, and effective repair likely requires the normal functioning of liver stem/progenitor cells. Herein, we showed that hAMSC-CM produced mainly by 3D cultures had the potential to increase hepatic stem/progenitor cell differentiation, demonstrating that soluble factors secreted by those cells are potentially responsible for the reaction. This work shows a potential approach to improve liver repair/regeneration also in a transplantation setting.

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Human Liver-Derived Stem Cells Improve Fibrosis and Inflammation Associated with Nonalcoholic Steatohepatitis

Stem Cells International ◽

10.1155/2019/6351091 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 6

Author(s):

Stefania Bruno ◽

Maria Beatriz Herrera Sanchez ◽

Chiara Pasquino ◽

Marta Tapparo ◽

Massimo Cedrino ◽

...

Keyword(s):

Stem Cells ◽

Nonalcoholic Steatohepatitis ◽

Stromal Cells ◽

Liver Diseases ◽

Human Liver ◽

Adult Liver ◽

Deficient Diet ◽

Immunodeficient Mice ◽

Feasible Alternative ◽

End Stage

Cell therapy may be regarded as a feasible alternative to whole organ transplantation to treat end-stage liver diseases. Human liver stem cells (HLSCs) are a population of cells easily obtainable and expandable from a human adult liver biopsy. HLSCs share with mesenchymal stromal cells the same phenotype, gene expression profile, and differentiation capabilities. In addition, HLSCs show a specific commitment to the hepatic phenotype. Injection of HLSCs into immunodeficient mice fed with a methionine-choline-deficient diet to induce nonalcoholic steatohepatitis ameliorates liver function and morphology. In particular, HLSC treatment induced a reduction of liver fibrosis and inflammation at morphological and molecular levels. Moreover, HLSCs were able to persist for up to 3 weeks after the injection. In conclusion, HLSCs have healing effects in a model of chronic liver disease.

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Contribution of Resident Stem Cells to Liver and Biliary Tree Regeneration in Human Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms19102917 ◽

2018 ◽

Vol 19 (10) ◽

pp. 2917 ◽

Cited By ~ 20

Author(s):

Diletta Overi ◽

Guido Carpino ◽

Vincenzo Cardinale ◽

Antonio Franchitto ◽

Samira Safarikia ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Progenitor Cells ◽

Human Liver ◽

Progenitor Cell ◽

Biliary Tree ◽

Tree Regeneration ◽

Multipotent Stem Cells ◽

Resident Stem Cells ◽

Stem Cell Niches

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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Post-meiotic male germ cell differentiation of mouse embryonic stem cells by exposure to conditioned medium

Fertility and Sterility ◽

10.1016/j.fertnstert.2019.07.385 ◽

2019 ◽

Vol 112 (3) ◽

pp. e101-e102

Author(s):

Aysha Trout ◽

Philip Xie ◽

Alessandra Parrella ◽

Zev Rosenwaks ◽

Gianpiero D. Palermo

Keyword(s):

Stem Cells ◽

Cell Differentiation ◽

Embryonic Stem Cells ◽

Germ Cell ◽

Conditioned Medium ◽

Embryonic Stem ◽

Mouse Embryonic Stem Cells ◽

Male Germ Cell ◽

Germ Cell Differentiation

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Growth factor-free cultured rat bone marrow derived mesenchymal stem cells towards hepatic progenitor cell differentiation

Biotechnology and Bioprocess Engineering ◽

10.1007/s12257-008-0080-x ◽

2008 ◽

Vol 13 (6) ◽

pp. 659-665 ◽

Cited By ~ 3

Author(s):

Tian Zhu Li ◽

Sang-Hyun Shin ◽

Hyun Hee Cho ◽

Jae Hyung Kim ◽

Hwal Suh

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Cell Differentiation ◽

Growth Factor ◽

Progenitor Cell ◽

Hepatic Progenitor Cell ◽

Rat Bone

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Evolving Cell-Based and Cell-Free Clinical Strategies for Treating Severe Human Liver Diseases

Cells ◽

10.3390/cells9020386 ◽

2020 ◽

Vol 9 (2) ◽

pp. 386 ◽

Cited By ~ 4

Author(s):

Viviana Cernigliaro ◽

Rossella Peluso ◽

Beatrice Zedda ◽

Lorenzo Silengo ◽

Emanuela Tolosano ◽

...

Keyword(s):

Stem Cells ◽

Liver Transplantation ◽

Extracellular Vesicles ◽

Liver Diseases ◽

Adult Stem Cells ◽

Embryonic Stem ◽

Hepatic Function ◽

Bioactive Molecules ◽

Cell Based Therapy ◽

End Stage

Liver diseases represent a major global health issue, and currently, liver transplantation is the only viable alternative to reduce mortality rates in patients with end-stage liver diseases. However, scarcity of donor organs and risk of recidivism requiring a re-transplantation remain major obstacles. Hence, much hope has turned towards cell-based therapy. Hepatocyte-like cells obtained from embryonic stem cells or adult stem cells bearing multipotent or pluripotent characteristics, as well as cell-based systems, such as organoids, bio-artificial liver devices, bioscaffolds and organ printing are indeed promising. New approaches based on extracellular vesicles are also being investigated as cell substitutes. Extracellular vesicles, through the transfer of bioactive molecules, can modulate liver regeneration and restore hepatic function. This review provides an update on the current state-of-art cell-based and cell-free strategies as alternatives to liver transplantation for patients with end-stage liver diseases.

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Mesenchymal Stem Cells Enhance Liver Regeneration via Improving Lipid Accumulation and Hippo Signaling

Stem Cells International ◽

10.1155/2018/7652359 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Yang Liu ◽

Faji Yang ◽

Jun Li ◽

Jinglin Wang ◽

Xun Wang ◽

...

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Mesenchymal Stem Cells ◽

Liver Regeneration ◽

Lipid Accumulation ◽

Liver Diseases ◽

Liver Lipid ◽

Hippo Signaling ◽

Mechanistic Target Of Rapamycin ◽

New Evidence

The liver has the potential to regenerate after injury. It is a challenge to improve liver regeneration (LR) after liver resection in clinical practice. Bone morrow-derived mesenchymal stem cells (MSCs) have shown to have a role in various liver diseases. To explore the effects of MSCs on LR, we established a model of 70% partial hepatectomy (PHx). Results revealed that infusion of MSCs could improve LR through enhancing cell proliferation and cell growth during the first 2 days after PHx, and MSCs could also restore liver synthesis function. Infusion of MSCs also improved liver lipid accumulation partly via mechanistic target of rapamycin (mTOR) signaling and enhanced lipid β-oxidation support energy for LR. Rapamycin-induced inhibition of mTOR decreased liver lipid accumulation at 24 h after PHx, leading to impaired LR. And after infusion of MSCs, a proinflammatory environment formed in the liver, evidenced by increased expression of IL-6 and IL-1β, and thus the STAT3 and Hippo-YAP pathways were activated to improve cell proliferation. Our results demonstrated the function of MSCs on LR after PHx and provided new evidence for stem cell therapy of liver diseases.

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Therapeutic applications of bone marrow-derived stem cells in liver transplantation for end-stage liver diseases

Chinese Science Bulletin ◽

10.1007/s11434-007-0392-9 ◽

2007 ◽

Vol 52 (18) ◽

pp. 2449-2456

Author(s):

HaiYing Luo ◽

YunFang Wang ◽

Wei Kong ◽

XueTao Pei

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Liver Transplantation ◽

Liver Diseases ◽

Therapeutic Applications ◽

End Stage

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Hypoxic Conditioned Medium From Human Adipose‐Derived Stem Cells Promotes Mouse Liver Regeneration Through JAK/STAT3 Signaling

Stem Cells Translational Medicine ◽

10.5966/sctm.2015-0191 ◽

2016 ◽

Vol 5 (6) ◽

pp. 816-825 ◽

Cited By ~ 37

Author(s):

Sang Chul Lee ◽

Hye Jin Jeong ◽

Sang Kuon Lee ◽

Say-June Kim

Keyword(s):

Stem Cells ◽

Liver Regeneration ◽

Conditioned Medium ◽

Mouse Liver ◽

Adipose Derived Stem Cells ◽

Stat3 Signaling

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Mesenchymal Stem Cells in the Adult Human Liver: Hype or Hope?

Cells ◽

10.3390/cells8101127 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1127 ◽

Cited By ~ 6

Author(s):

Irina V. Kholodenko ◽

Leonid K. Kurbatov ◽

Roman V. Kholodenko ◽

Garik V. Manukyan ◽

Konstantin N. Yarygin

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cell Therapy ◽

Progenitor Cells ◽

Liver Tissue ◽

Liver Diseases ◽

Human Liver ◽

Chronic Liver ◽

Attractive Alternative ◽

Short Supply

Chronic liver diseases constitute a significant economic, social, and biomedical burden. Among commonly adopted approaches, only organ transplantation can radically help patients with end-stage liver pathologies. Cell therapy with hepatocytes as a treatment for chronic liver disease has demonstrated promising results. However, quality human hepatocytes are in short supply. Stem/progenitor cells capable of differentiating into functionally active hepatocytes provide an attractive alternative approach to cell therapy for liver diseases, as well as to liver-tissue engineering, drug screening, and basic research. The application of methods generally used to isolate mesenchymal stem cells (MSCs) and maintain them in culture to human liver tissue provides cells, designated here as liver MSCs. They have much in common with MSCs from other tissues, but differ in two aspects—expression of a range of hepatocyte-specific genes and, possibly, inherent commitment to hepatogenic differentiation. The aim of this review is to analyze data regarding liver MSCs, probably another type of liver stem/progenitor cells different from hepatic stellate cells or so-called hepatic progenitor cells. The review presents an analysis of the phenotypic characteristics of liver MSCs, their differentiation and therapeutic potential, methods for isolating these cells from human liver, and discusses issues of their origin and heterogeneity. Human liver MSCs are a fascinating object of fundamental research with a potential for important practical applications.

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