A comparative analysis of the transcriptome and signal pathways in hepatic differentiation of human adipose mesenchymal stem cells

The specific features of the plasticity of adult stem cells are largely unknown. Recently, we demonstrated the hepatic differentiation of human adipose tissue‐derived mesenchymal stem cells (AT‐MSCs). To identify the genes responsible for hepatic differentiation, we examined the gene expression profiles of AT‐MSC‐derived hepatocytes (AT‐MSC‐Hepa) using several microarray methods. The resulting sets of differentially expressed genes (1639 clones) were comprehensively analyzed to identify the pathways expressed in AT‐MSC‐Hepa. Clustering analysis revealed a striking similarity of gene clusters between AT‐MSC‐Hepa and the whole liver, indicating that AT‐MSC‐Hepa were similar to liver with regard to gene expression. Further analysis showed that enriched categories of genes and signaling pathways such as complementary activation and the blood clotting cascade in the AT‐MSC‐Hepa were relevant to liver‐specific functions. Notably, decreases in Twist and Snail expression indicated that mesenchymal‐to‐epithelial transition occurred in the differentiation of AT‐MSCs into hepatocytes. Our data show a similarity between AT‐MSC‐Hepa and the liver, suggesting that AT‐MSCs are modulated by their environmental conditions, and that AT‐MSC‐Hepa may be useful in basic studies of liver function as well as in the development of stem cell‐based therapy.

[1]  T. Ochiya,et al.  Adipose tissue‐derived mesenchymal stem cells as a source of human hepatocytes , 2007, Hepatology.

[2]  Héctor Peinado,et al.  Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? , 2007, Nature Reviews Cancer.

[3]  J V Castell,et al.  Human mesenchymal stem cells from adipose tissue: Differentiation into hepatic lineage. , 2007, Toxicology in vitro : an international journal published in association with BIBRA.

[4]  A. Sakurada,et al.  Genome-wide profiling of promoter methylation in human , 2006, Oncogene.

[5]  T. Ochiya,et al.  Recapitulation of in vivo gene expression during hepatic differentiation from murine embryonic stem cells , 2005, Hepatology.

[6]  W. Chiu,et al.  Isolation and Characterization of Neurogenic Mesenchymal Stem Cells in Human Scalp Tissue , 2005, Stem cells.

[7]  Klaus H. Kaestner,et al.  The initiation of liver development is dependent on Foxa transcription factors , 2005, Nature.

[8]  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.

[9]  T. Ochiya,et al.  Direct hepatic fate specification from mouse embryonic stem cells , 2005, Hepatology.

[10]  Min-Jeong Seo,et al.  Differentiation of human adipose stromal cells into hepatic lineage in vitro and in vivo. , 2005, Biochemical and biophysical research communications.

[11]  F. Claas,et al.  Isolation of Mesenchymal Stem Cells of Fetal or Maternal Origin from Human Placenta , 2004, Stem cells.

[12]  D. Zipori.  Mesenchymal stem cells: harnessing cell plasticity to tissue and organ repair. , 2004, Blood cells, molecules & diseases.

[13]  Shinya Kuroda,et al.  Mesenchymal-epithelial transition during somitic segmentation is regulated by differential roles of Cdc42 and Rac1. , 2004, Developmental cell.

[14]  J. Massagué,et al.  Epithelial-Mesenchymal Transitions Twist in Development and Metastasis , 2004, Cell.

[15]  H. Klüter,et al.  Critical Parameters for the Isolation of Mesenchymal Stem Cells from Umbilical Cord Blood , 2004, Stem cells.

[16]  S. Ramaswamy,et al.  Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis , 2004, Cell.

[17]  Zhiping Weng,et al.  Computational inference of transcriptional regulatory networks from expression profiling and transcription factor binding site identification. , 2004, Nucleic acids research.

[18]  R. Costa,et al.  Transcription factors in liver development, differentiation, and regeneration , 2003, Hepatology.

[19]  Chava Kimchi-Sarfaty,et al.  P-glycoprotein: from genomics to mechanism , 2003, Oncogene.

[20]  V. Ribeiro,et al.  CYP3A4 and MDR1 Alleles in a Portuguese Population , 2003, Clinical chemistry and laboratory medicine.

[21]  Steven C. Lawlor,et al.  MAPPFinder: using Gene Ontology and GenMAPP to create a global gene-expression profile from microarray data , 2003, Genome Biology.

[22]  Min Zhu,et al.  Human adipose tissue is a source of multipotent stem cells. , 2002, Molecular biology of the cell.

[23]  Y. Sakai,et al.  Maturation of fetal hepatocytes in vitro by extracellular matrices and oncostatin M: Induction of tryptophan oxygenase , 2002, Hepatology.

[24]  Steven C. Lawlor,et al.  GenMAPP, a new tool for viewing and analyzing microarray data on biological pathways , 2002, Nature Genetics.

[25]  N. Fisk,et al.  Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. , 2001, Blood.

[26]  H. Lorenz,et al.  Multilineage cells from human adipose tissue: implications for cell-based therapies. , 2001, Tissue engineering.

[27]  W. Janssen,et al.  Adult Bone Marrow Stromal Cells Differentiate into Neural Cells in Vitro , 2000, Experimental Neurology.

[28]  M. Relling,et al.  Pharmacogenomics: translating functional genomics into rational therapeutics. , 1999, Science.

[29]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[30]  K. Zaret,et al.  GATA transcription factors as potentiators of gut endoderm differentiation. , 1998, Development.

[31]  J. Rossant,et al.  Regulation of a transcription factor network required for differentiation and metabolism. , 1998, Science.

[32]  G Cossu,et al.  Muscle regeneration by bone marrow-derived myogenic progenitors. , 1998, Science.

[33]  G. Granneman,et al.  Use of In Vitro and In Vivo Data to Estimate the Likelihood of Metabolic Pharmacokinetic Interactions , 1997, Clinical pharmacokinetics.

[34]  P. Watkins.  Noninvasive tests of CYP3A enzymes. , 1994, Pharmacogenetics.

[35]  Friedenstein Aj,et al.  Marrow microenvironment transfer by heterotopic transplantation of freshly isolated and cultured cells in porous sponges. , 1982 .

[36]  T. Takayama,et al.  Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion , 2005 .

[37]  A. Friedenstein,et al.  Marrow microenvironment transfer by heterotopic transplantation of freshly isolated and cultured cells in porous sponges. , 1982, Experimental hematology.