title: Endothelial cells control pancreatic cell fate at defined stages through EGFL7 signaling.
abstract: Although endothelial cells have been shown to affect mouse pancreatic development, their precise function in human development remains unclear. Using a coculture system containing human embryonic stem cell (hESC)-derived progenitors and endothelial cells, we found that endothelial cells play a stage-dependent role in pancreatic development, in which they maintain pancreatic progenitor (PP) self-renewal and impair further differentiation into hormone-expressing cells. The mechanistic studies suggest that the endothelial cells act through the secretion of EGFL7. Consistently, endothelial overexpression of EGFL7 in vivo using a transgenic mouse model resulted in an increase of PP proliferation rate and a decrease of differentiation toward endocrine cells. These studies not only identified the role of EGFL7 as the molecular handle involved in the crosstalk between endothelium and pancreatic epithelium, but also provide a paradigm for using hESC stepwise differentiation to dissect the stage-dependent roles of signals controlling organogenesis.
authors.affiliation: Departments of Surgery and Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Der-I
authors.initials: DI
authors.lastname: Kao
authors.affiliation: Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Lauretta A
authors.initials: LA
authors.lastname: Lacko
authors.affiliation: Howard Hughes Medical Institute, Ansary Stem Cell Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Bi-Sen
authors.initials: BS
authors.lastname: Ding
authors.affiliation: Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Huang
authors.affiliation: Departments of Surgery and Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Phung
authors.affiliation: Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Gu
authors.affiliation: Howard Hughes Medical Institute, Ansary Stem Cell Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Stuhlmann
authors.affiliation: Departments of Surgery and Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: shc2034@med.cornell.edu.
authors.forename: Shuibing
authors.initials: S
authors.lastname: Chen
mesh_terms: D002135:Calcium-Binding Proteins; D002450:Cell Communication; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D018920:Coculture Techniques; D066255:EGF Family of Proteins; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D010179:Pancreas / Q000166:cytology* / Q000196:embryology; D010641:Phenotype; D015398:Signal Transduction; D055153:Stem Cell Niche; D015534:Trans-Activators / Q000378:metabolism; D059467:Transcriptome
chemical_list: D002135:Calcium-Binding Proteins; D066255:EGF Family of Proteins; C527877:EGFL7 protein, human; D016228:Endothelial Growth Factors; D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein