title: Brief Report: Elastin Microfibril Interface 1 and Integrin-Linked Protein Kinase Are Novel Markers of Islet Regenerative Function in Human Multipotent Mesenchymal Stromal Cells.
abstract: Multipotent mesenchymal stromal cell (MSC) transplantation is proposed as a novel therapy for treating diabetes by promoting the regeneration of damaged islets. The clinical promise of such treatments may be hampered by a high degree of donor-related variability in MSC function and a lack of standards for comparing potency. Here, we set out to identify markers of cultured human MSCs directly associated with islet regenerative function. Stromal cultures from nine separate bone marrow donors were demonstrated to have differing capacities to reduce hyperglycemia in the NOD/SCID streptozotocin-induced diabetic model. Regenerative (R) and non-regenerative (NR) MSC cultures were directly compared using isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics. A total of 1,410 proteins were quantified resulting in the identification of 612 upregulated proteins and 275 downregulated proteins by ± 1.2-fold in R-MSC cultures. Elastin microfibril interface 1 (EMILIN-1), integrin-linked protein kinase (ILK), and hepatoma-derived growth factor (HDGF) were differentially expressed in R-MSCs, and Ingenuity Pathway Analyses revealed each candidate as known regulators of integrin signaling. Western blot validation of EMILIN-1, ILK, and HDGF not only showed significantly higher abundance levels in R-MSCs, as compared with NR-MSCs, but also correlated with passage-induced loss of islet-regenerative potential. Generalized estimating equation modeling was applied to examine the association between each marker and blood glucose reduction. Both EMILIN-1 and ILK were significantly associated with blood glucose lowering function in vivo. Our study is the first to identify EMILIN-1 and ILK as prospective markers of islet regenerative function in human MSCs. Stem Cells 2016;34:2249-2255.
authors.affiliation: Regulatory Research Division, Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Jessie R
authors.initials: JR
authors.lastname: Lavoie
authors.affiliation: Regulatory Research Division, Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Marybeth M
authors.initials: MM
authors.lastname: Creskey
authors.affiliation: Regulatory Research Division, Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Gauri
authors.initials: G
authors.lastname: Muradia
authors.affiliation: Department of Physiology and Pharmacology, Molecular Medicine Research Group, Krembil Centre for Stem Cell Biology, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Bell
authors.affiliation: Department of Physiology and Pharmacology, Molecular Medicine Research Group, Krembil Centre for Stem Cell Biology, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sherman
authors.affiliation: Biostatistics Unit, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Gao
authors.affiliation: Faculty of Medicine, Department of Cellular and Molecular Medicine, Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research and Regenerative Medicine Program and University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.affiliation: Regulatory Research Division, Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Cyr
authors.affiliation: Department of Physiology and Pharmacology, Molecular Medicine Research Group, Krembil Centre for Stem Cell Biology, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Hess
authors.affiliation: Regulatory Research Division, Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Rosu-Myles
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000628:therapy; D006801:Humans; D006943:Hyperglycemia / Q000473:pathology; D016023:Integrins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007515:Islets of Langerhans / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D016513:Mice, SCID; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D040901:Proteomics; D012038:Regeneration; D015203:Reproducibility of Results; D013311:Streptozocin; D014019:Tissue Donors; D000099200:Scaffold Protein ILK
chemical_list: D015415:Biomarkers; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D017346:Protein Serine-Threonine Kinases; D013311:Streptozocin; D000099200:Scaffold Protein ILK; C030340:elastin microfibril interface located protein; C051610:hepatoma-derived growth factor
keywords: Biologic marker; Diabetes mellitus; Multipotent mesenchymal stromal cells; Regeneration; Type 1