Signalling pathways involved in the process of mesenchymal stem cells differentiating into hepatocytes

End‐stage liver disease can be the termination of acute or chronic liver diseases, with manifestations of liver failure; transplantation is currently an effective treatment for these. However, transplantation is severely limited due to the serious lack of donors, expense, graft rejection and requirement of long‐term immunosuppression. Mesenchymal stem cells (MSCs) have attracted considerable attention as therapeutic tools as they can be obtained with relative ease and expanded in culture, along with features of self‐renewal and multidirectional differentiation. Many scientific groups have sought to use MSCs differentiating into functional hepatocytes to be used in cell transplantation with liver tissue engineering to repair diseased organs. In most of the literature, hepatocyte differentiation refers to use of various additional growth factors and cytokines, such as hepatocyte growth factor (HGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), oncostatin M (OSM) and more, and most are involved in signalling pathway regulation and cell–cell/cell–matrix interactions. Signalling pathways have been shown to play critical roles in embryonic development, tumourigenesis, tumour progression, apoptosis and cell‐fate determination. However, mechanisms of MSCs differentiating into hepatocytes, particularly signalling pathways involved, have not as yet been completely illustrated. In this review, we have focused on progress of signalling pathways associated with mesenchymal stem cells differentiating into hepatocytes along with the stepwise differentiation procedure.

[1]  L. Gunhaga,et al.  Signaling pathways regulating ectodermal cell fate choices. , 2014, Experimental cell research.

[2]  F. O. Castro,et al.  Combined use of platelet rich plasma and vitamin C positively affects differentiation in vitro to mesodermal lineage of adult adipose equine mesenchymal stem cells. , 2014, Research in veterinary science.

[3]  M. Benderitter,et al.  Mesenchymal stem cell therapy induces glucocorticoid synthesis in colonic mucosa and suppresses radiation-activated T cells: new insights into MSC immunomodulation , 2013, Mucosal Immunology.

[4]  Wei Wu,et al.  Efficacy of HGF carried by ultrasound microbubble-cationic nano-liposomes complex for treating hepatic fibrosis in a bile duct ligation rat model, and its relationship with the diffusion-weighted MRI parameters. , 2013, Clinics and research in hepatology and gastroenterology.

[5]  C. Xiang,et al.  Menstrual blood-derived mesenchymal stem cells differentiate into functional hepatocyte-like cells , 2013, Journal of Zhejiang University SCIENCE B.

[6]  K. Lundin,et al.  Activin A and Wnt-dependent specification of human definitive endoderm cells. , 2013, Experimental cell research.

[7]  S. Strom,et al.  New potential cell source for hepatocyte transplantation: discarded livers from metabolic disease liver transplants. , 2013, Stem cell research.

[8]  W. Leeanansaksiri,et al.  Developing a New Two-Step Protocol to Generate Functional Hepatocytes from Wharton's Jelly-Derived Mesenchymal Stem Cells under Hypoxic Condition , 2013, Stem cells international.

[9]  A. Mandegary,et al.  Effect of EGF and FGF on the expansion properties of human umbilical cord mesenchymal cells , 2013, In Vitro Cellular & Developmental Biology - Animal.

[10]  H. Kim,et al.  Neural transdifferentiation of human bone marrow mesenchymal stem cells on hydrophobic polymer-modified surface and therapeutic effects in an animal model of ischemic stroke , 2013, Neuroscience.

[11]  M. Gupta,et al.  Supplementation of insulin–transferrin–selenium to embryo culture medium improves the in vitro development of pig embryos , 2013, Zygote.

[12]  N. Sebire,et al.  Placenta as a reservoir of stem cells: an underutilized resource? , 2013, British medical bulletin.

[13]  W. Cui,et al.  Application of three-dimensional culture conditions to human embryonic stem cell-derived definitive endoderm cells enhances hepatocyte differentiation and functionality. , 2013, Tissue engineering. Part A.

[14]  Tian-biao Zhou,et al.  Signaling pathways of prohibitin and its role in diseases , 2013, Journal of receptor and signal transduction research.

[15]  S. Lipton,et al.  Emerging role of protein-protein transnitrosylation in cell signaling pathways. , 2013, Antioxidants & redox signaling.

[16]  C. Steindler,et al.  TGFβ overrides HNF4α tumor suppressing activity through GSK3β inactivation: implication for hepatocellular carcinoma gene therapy. , 2013, Journal of hepatology.

[17]  L. Fabris,et al.  The balance between Notch/Wnt signaling regulates progenitor cells' commitment during liver repair: mystery solved? , 2013, Journal of hepatology.

[18]  Junji Xu,et al.  Mesenchymal stem cells derived from inflamed periodontal ligaments exhibit impaired immunomodulation. , 2012, Journal of clinical periodontology.

[19]  Jong Hoon Lee,et al.  Possibility of Undifferentiated Human Thigh Adipose Stem Cells Differentiating into Functional Hepatocytes , 2012, Archives of plastic surgery.

[20]  Wei-Jei Lee,et al.  Roles of hepatic progenitor cells activation, ductular reaction proliferation and Notch signaling in morbid obesity. , 2012, Hepato-gastroenterology.

[21]  D. Kimelman,et al.  Wnt/β-catenin signaling cell-autonomously converts non-hepatic endodermal cells to a liver fate , 2012, Biology Open.

[22]  S. Ranganathan,et al.  Calpain Induces N-terminal Truncation of β-Catenin in Normal Murine Liver Development , 2012, The Journal of Biological Chemistry.

[23]  J. Marrero,et al.  Interleukin-6 and oncostatin M are elevated in liver disease in conjunction with candidate hepatocellular carcinoma biomarker GP73. , 2012, Cancer biomarkers : section A of Disease markers.

[24]  X. Pei,et al.  Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF/EGFR/Akt pathway , 2012, Breast Cancer Research and Treatment.

[25]  R. Malekzadeh,et al.  In vitro differentiation of human bone marrow mesenchymal stem cells into hepatocyte-like cells. , 2011, Archives of Iranian medicine.

[26]  M. Zern,et al.  Bottom-up signaling from HGF-containing surfaces promotes hepatic differentiation of mesenchymal stem cells. , 2011, Biochemical and biophysical research communications.

[27]  Xiaoling Ma,et al.  Insulin–transferrin–selenium (ITS) improves maturation of porcine oocytes in vitro , 2011, Zygote.

[28]  M. Soleimani,et al.  Effects of TGF-β and b-FGF on the Potential of Peripheral Blood-Borne Stem Cells and Bone Marrow-Derived Stem Cells in Wound Healing in a Murine Model , 2011, Inflammation.

[29]  F. Zaibak,et al.  Stimulation of Activin A/Nodal signaling is insufficient to induce definitive endoderm formation of cord blood-derived unrestricted somatic stem cells , 2011, Stem Cell Research & Therapy.

[30]  D. Izquierdo,et al.  Effect of the addition of insulin-transferrin-selenium and/or L-ascorbic acid to the in vitro maturation of prepubertal bovine oocytes on cytoplasmic maturation and embryo development. , 2010, Theriogenology.

[31]  A. Rustgi,et al.  Dexamethasone Treatment Induces the Reprogramming of Pancreatic Acinar Cells to Hepatocytes and Ductal Cells , 2010, PloS one.

[32]  N Lin,et al.  Differentiation of bone marrow‐derived mesenchymal stem cells into hepatocyte‐like cells in an alginate scaffold , 2010, Cell proliferation.

[33]  N. Elvassore,et al.  A combining method to enhance the in vitro differentiation of hepatic precursor cells. , 2010, Tissue engineering. Part C, Methods.

[34]  C. Verfaillie,et al.  Differentiation of rat multipotent adult progenitor cells to functional hepatocyte-like cells by mimicking embryonic liver development , 2010, Nature Protocols.

[35]  R. Saraiva,et al.  Hepatocyte xenotransplantation for treating liver disease , 2010, Xenotransplantation.

[36]  R. Pedersen,et al.  Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions that recapitulate liver development , 2010, Hepatology.

[37]  M. Stampfli,et al.  Oncostatin M (OSM) primes IL-13- and IL-4-induced eotaxin responses in fibroblasts: regulation of the type-II IL-4 receptor chains IL-4Ralpha and IL-13Ralpha1. , 2009, Experimental cell research.

[38]  S. Montagnaro,et al.  Cryopreservation of feline epididymal spermatozoa from dead and alive animals and its use in assisted reproduction , 2009, Zygote.

[39]  M. Joglekar,et al.  Mesenchymal stem cells: immunobiology and role in immunomodulation and tissue regeneration. , 2009, Cytotherapy.

[40]  S. Islam,et al.  Cell therapy for liver disease. , 2009, Current opinion in molecular therapeutics.

[41]  I. Behrmann,et al.  Hypoxia‐inducible factor 1α is up‐regulated by oncostatin M and participates in oncostatin M signaling , 2009, Hepatology.

[42]  Q. Qu,et al.  [Expression of hepatocyte-enriched transcriptional factors during the differentiation of bone marrow mesenchymal stem cell-derived hepatocytes]. , 2009, Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae.

[43]  S. Ōmura,et al.  Role of dexamethasone and oncostatin M on the formation of vacuoles in human fetal liver cells. , 2009, Biological & pharmaceutical bulletin.

[44]  H. Masuyama,et al.  Relation between neonatal jaundice and oncostatin M, hepatocyte growth factor and soluble gp130 levels in umbilical cord , 2008, Acta obstetricia et gynecologica Scandinavica.

[45]  Ken Matsumoto,et al.  Wnt9a secreted from the walls of hepatic sinusoids is essential for morphogenesis, proliferation, and glycogen accumulation of chick hepatic epithelium. , 2008, Developmental biology.

[46]  J. Li,et al.  In Vitro Hepatic Differentiation of Mesenchymal Stem Cells from Human Fetal Bone Marrow , 2008, The Journal of international medical research.

[47]  D. Rickman,et al.  Stabilization of β‐catenin affects mouse embryonic liver growth and hepatoblast fate , 2007, Hepatology.

[48]  J. Fishman Infection in solid-organ transplant recipients. , 2007, The New England journal of medicine.

[49]  Nancy Cheng,et al.  Human hepatic stem cells from fetal and postnatal donors , 2007 .

[50]  M. Shen Nodal signaling: developmental roles and regulation , 2007, Development.

[51]  Stephen Dalton,et al.  Activin A Efficiently Specifies Definitive Endoderm from Human Embryonic Stem Cells Only When Phosphatidylinositol 3‐Kinase Signaling Is Suppressed , 2007, Stem cells.

[52]  A. Zorn,et al.  Molecular basis of vertebrate endoderm development. , 2007, International review of cytology.

[53]  Li-Xin Xiang,et al.  In vitro differentiation of hepatic progenitor cells from mouse embryonic stem cells induced by sodium butyrate , 2007, Journal of cellular biochemistry.

[54]  T. Tani,et al.  Acidic fibroblast growth factor promotes hepatic differentiation of monkey embryonic stem cells , 2007, In Vitro Cellular & Developmental Biology - Animal.

[55]  Roles and regulation , 2006, Veterinary Record.

[56]  A. Zorn,et al.  Molecular control of liver development. , 2006, Clinics in liver disease.

[57]  G. Forte,et al.  Hepatocyte Growth Factor Effects on Mesenchymal Stem Cells: Proliferation, Migration, and Differentiation , 2006, Stem cells.

[58]  R. Carithers,et al.  Practice Guidelines : Evaluation of the Patient for Liver Transplantation , 2005 .

[59]  S. Hwang,et al.  In vitro differentiation of human umbilical cord blood-derived mesenchymal stem cells into hepatocyte-like cells. , 2005, Biochemical and biophysical research communications.

[60]  S. Duncan,et al.  Embryonic development of the liver , 2005, Hepatology.

[61]  K. Zaret,et al.  Distinct populations of endoderm cells converge to generate the embryonic liver bud and ventral foregut tissues. , 2005, Developmental biology.

[62]  N. Segil,et al.  In vitro growth and differentiation of mammalian sensory hair cell progenitors: a requirement for EGF and periotic mesenchyme. , 2004, Developmental biology.

[63]  J. Luk,et al.  Expression of hepatocyte-like phenotypes in bone marrow stromal cells after HGF induction. , 2004, Biochemical and biophysical research communications.

[64]  S. Monga,et al.  Fibroblast growth factor enriches the embryonic liver cultures for hepatic progenitors. , 2004, The American journal of pathology.

[65]  Sabine Neuss,et al.  Functional Expression of HGF and HGF Receptor/c‐met in Adult Human Mesenchymal Stem Cells Suggests a Role in Cell Mobilization, Tissue Repair, and Wound Healing , 2004, Stem cells.

[66]  J. S. Sidhu,et al.  Phenobarbital responsiveness as a uniquely sensitive indicator of hepatocyte differentiation status: requirement of dexamethasone and extracellular matrix in establishing the functional integrity of cultured primary rat hepatocytes. , 2004, Experimental cell research.

[67]  Y. Sakai,et al.  Enhanced In Vitro Maturation of Fetal Mouse Liver Cells with Oncostatin M, Nicotinamide, and Dimethyl Sulfoxide , 2002, Cell transplantation.

[68]  A. Miyajima,et al.  Oncostatin M and hepatocyte growth factor induce hepatic maturation via distinct signaling pathways , 2001, FEBS letters.

[69]  T. Robak,et al.  Relationship between circulating interleukin-10 (IL-10) with interleukin-6 (IL-6) type cytokines (IL-6, interleukin-11 (IL-11), oncostatin M (OSM)) and soluble interleukin-6 (IL-6) receptor (sIL-6R) in patients with multiple myeloma. , 2000, European cytokine network.

[70]  Carmen Birchmeier,et al.  Requirement for beta-catenin in anterior-posterior axis formation in mice. , 2000 .

[71]  T. Mizuguchi,et al.  Effects of nicotinamide-related agents on the growth of primary rat hepatocytes and formation of small hepatocyte colonies. , 1999, Liver.

[72]  J. Gómez-Moreno,et al.  Infection in organ-transplant recipients. , 1998, The New England journal of medicine.

[73]  T. Jessell,et al.  Integrated FGF and BMP signaling controls the progression of progenitor cell differentiation and the emergence of pattern in the embryonic anterior pituitary. , 1998, Development.

[74]  Y. Inoue [Hepatocyte]. , 2020, Nihon rinsho. Japanese journal of clinical medicine.

[75]  M. Benito,et al.  Regulation of gene expression by interleukin‐6 in fetal rat hepatocyte primary cultures: Role of epidermal growth factor and dexamethasone , 1995, Hepatology.