title: Microvesicles but Not Exosomes from Pathfinder Cells Stimulate Functional Recovery of the Pancreas in a Mouse Streptozotocin-Induced Diabetes Model.
abstract: Pathfinder cells (PCs), a novel cell type derived from the pancreas of adult rats, have been demonstrated to stimulate recovery of tissue structure and function in two animal models of acute tissue damage to date-streptozotocin (STZ)-induced diabetes and ischemia-reperfusion damage to the kidney. In repaired tissue, PCs and their progeny typically represent only 0.02% of the repaired tissue, suggesting that they act via a paracrine mechanism on native cells in the damaged area. Extracellular vesicles are strong candidates for mediating such a paracrine effect. Therefore, we studied the effects of two PC-derived extracellular vesicle fractions on tissue repair in the STZ diabetes model, one containing primarily microvesicles and the second containing predominantly exosomes. Treatment of STZ-induced diabetic mice with the microvesicles preparation led to blood glucose, insulin, glucagon, and C-peptide levels similar to those found with PC treatment. Furthermore, analysis of the histopathology of the pancreas indicated islet regeneration. In contrast, the exosome fraction demonstrated no repair activity, and STZ diabetic mice treated with exosome preparations had blood glucose values that were indistinguishable from those of vehicle-only treated controls. Therefore, we conclude that exosomes play no part in PC action as detected by this assay, whereas microvesicles provide all or a large component of the paracrine activity of PCs. Because they act to stimulate repair of multiple tissues, PC-derived microvesicles may similarly have the potential to stimulate repair of many damaged tissues, identifying a very significant cell-free therapeutic opportunity in regenerative medicine.
authors.affiliation: 1 Institute of Cancer Sciences, University of Glasgow , Wolfson Wohl Cancer Research Centre, Glasgow, United Kingdom .
authors.forename: Dagmara
authors.initials: D
authors.lastname: McGuinness
authors.affiliation: 1 Institute of Cancer Sciences, University of Glasgow , Wolfson Wohl Cancer Research Centre, Glasgow, United Kingdom .
authors.forename: Diana F
authors.initials: DF
authors.lastname: Anthony
authors.affiliation: 1 Institute of Cancer Sciences, University of Glasgow , Wolfson Wohl Cancer Research Centre, Glasgow, United Kingdom .
authors.forename: Vladimira
authors.initials: V
authors.lastname: Moulisova
authors.affiliation: 1 Institute of Cancer Sciences, University of Glasgow , Wolfson Wohl Cancer Research Centre, Glasgow, United Kingdom .
authors.forename: Alasdair I
authors.initials: AI
authors.lastname: MacDonald
authors.affiliation: 1 Institute of Cancer Sciences, University of Glasgow , Wolfson Wohl Cancer Research Centre, Glasgow, United Kingdom .
authors.forename: Alan
authors.initials: A
authors.lastname: MacIntyre
authors.affiliation: 1 Institute of Cancer Sciences, University of Glasgow , Wolfson Wohl Cancer Research Centre, Glasgow, United Kingdom .
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Thomson
authors.affiliation: 2 Invitek Corporation , Hayward, California.
authors.forename: Abhijeet
authors.initials: A
authors.lastname: Nag
authors.affiliation: 3 University of Edinburgh, School of Informatics , Edinburgh, United Kingdom .
authors.forename: R Wayne
authors.initials: RW
authors.lastname: Davies
authors.affiliation: 1 Institute of Cancer Sciences, University of Glasgow , Wolfson Wohl Cancer Research Centre, Glasgow, United Kingdom .
authors.forename: Paul G
authors.initials: PG
authors.lastname: Shiels
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D055252:Cell-Derived Microparticles / Q000378:metabolism / Q000637:transplantation*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology / Q000601:surgery*; D055354:Exosomes / Q000378:metabolism / Q000637:transplantation*; D005260:Female; D005934:Glucagon / Q000097:blood; D007328:Insulin / Q000097:blood; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D019899:Paracrine Communication; D051381:Rats; D020127:Recovery of Function; D012038:Regeneration; D015398:Signal Transduction; D013311:Streptozocin; D013997:Time Factors
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D013311:Streptozocin; D005934:Glucagon