title: Collagen IV-modified scaffolds improve islet survival and function and reduce time to euglycemia.
abstract: Islet transplantation on extracellular matrix (ECM) protein-modified biodegradable microporous poly(lactide-co-glycolide) scaffolds is a potential curative treatment for type 1 diabetes mellitus (T1DM). Collagen IV-modified scaffolds, relative to control scaffolds, significantly decreased the time required to restore euglycemia from 17 to 3 days. We investigated the processes by which collagen IV-modified scaffolds enhanced islet function and mediated early restoration of euglycemia post-transplantation. We characterized the effect of collagen IV-modified scaffolds on islet survival, metabolism, and insulin secretion in vitro and early- and intermediate-term islet mass and vascular density post-transplantation and correlated these with early restoration of euglycemia in a syngeneic mouse model. Control scaffolds maintained native islet morphologies and architectures as well as collagen IV-modified scaffolds in vivo. The islet size and vascular density increased, while β-cell proliferation decreased from day 16 to 113 post-transplantation. Collagen IV-modified scaffolds promoted islet cell viability and decreased early-stage apoptosis in islet cells in vitro-phenomena that coincided with enhanced islet metabolic function and glucose-stimulated insulin secretion. These findings suggest that collagen IV-modified scaffolds promote the early restoration of euglycemia post-transplantation by enhancing islet metabolism and glucose-stimulated insulin secretion. These studies of ECM proteins, in particular collagen IV, and islet function provide key insights for the engineering of a microenvironment that would serve as a platform for enhancing islet transplantation as a viable clinical therapy for T1DM.
authors.affiliation: 1 Department of Biomedical Engineering, Northwestern University , Evanston, Illinois.
authors.forename: Woon Teck
authors.initials: WT
authors.lastname: Yap
authors.forename: David M
authors.initials: DM
authors.lastname: Salvay
authors.forename: Michael A
authors.initials: MA
authors.lastname: Silliman
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhang
authors.forename: Zachary G
authors.initials: ZG
authors.lastname: Bannon
authors.forename: Dixon B
authors.initials: DB
authors.lastname: Kaufman
authors.forename: William L
authors.initials: WL
authors.lastname: Lowe
authors.forename: Lonnie D
authors.initials: LD
authors.lastname: Shea
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000737:chemistry* / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D024141:Collagen Type IV