title: Fulfilling Koch's postulates in glycoscience: HCELL, GPS and translational glycobiology.
abstract: Glycoscience-based research that is performed expressly to address medical necessity and improve patient outcomes is called "translational glycobiology". In the 19th century, Robert Koch proposed a set of postulates to rigorously establish causality in microbial pathogenesis, and these postulates can be reshaped to guide knowledge into how naturally-expressed glycoconjugates direct molecular processes critical to human well-being. Studies in the 1990s indicated that E-selectin, an endothelial lectin that binds sialofucosylated carbohydrate determinants, is constitutively expressed on marrow microvessels, and investigations in my laboratory indicated that human hematopoietic stem cells (HSCs) uniquely express high levels of a specialized glycoform of CD44 called "hematopoietic cell E-/L-selectin ligand" (HCELL) that functions as a highly potent E-selectin ligand. To assess the role of HCELL in directing HSC migration to marrow, a method called "glycosyltransferase-programmed stereosubstitution" (GPS) was developed to custom-modify CD44 glycans to enforce HCELL expression on viable cell surfaces. Human mesenchymal stem cells (MSCs) are devoid of E-selectin ligands, but GPS-based glycoengineering of CD44 on MSCs licenses homing of these cells to marrow in vivo, providing direct evidence that HCELL serves as a "bone marrow homing receptor". This review will discuss the molecular basis of cell migration in historical context, will describe the discovery of HCELL and its function as the bone marrow homing receptor, and will inform on how glycoengineering of CD44 serves as a model for adapting Koch's postulates to elucidate the key roles that glycoconjugates play in human biology and for realizing the immense impact of translational glycobiology in clinical medicine.
authors.affiliation: Department of Dermatology and Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA Harvard Skin Disease Research Center Program of Excellence in Glycosciences, Harvard Medical School, 77 Avenue Louis Pasteur, Room 671, Boston, MA 02115, USA rsackstein@partners.org.
authors.forename: Robert
authors.initials: R
authors.lastname: Sackstein
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology*; D002465:Cell Movement; D019040:E-Selectin / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D054794:Glycomics / Q000266:history* / Q000639:trends; D016695:Glycosyltransferases / Q000235:genetics / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology; D015202:Protein Engineering / Q000266:history / Q000379:methods; D015398:Signal Transduction; D057170:Translational Research, Biomedical / Q000639:trends
chemical_list: D019040:E-Selectin; D016695:Glycosyltransferases; D018960:Hyaluronan Receptors; C497483:CD44 protein, human; C546936:SELE protein, human
keywords: cell migration; exofucosylation; fucosyltransferase; hematopoietic stem cell; mesenchymal stem cell