Extracellular Matrix Components in the Pathogenesis of Type 1 Diabetes
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Type 1 diabetes (T1D) results from progressive immune cell-mediated destruction of pancreatic β cells. As immune cells migrate into the islets, they pass through the extracellular matrix (ECM). This ECM is composed of different macromolecules localized to different compartments within and surrounding islets; however, the involvement of this ECM in the development of human T1D is not well understood. Here, we summarize our recent findings from human and mouse studies illustrating how specific components of the islet ECM that constitute basement membranes and interstitial matrix of the islets, and surprisingly, the intracellular composition of islet β cells themselves, are significantly altered during the pathogenesis of T1D. Our focus is on the ECM molecules laminins, collagens, heparan sulfate/heparan sulfate proteoglycans, and hyaluronan, as well as on the enzymes that degrade these ECM components. We propose that islet and lymphoid tissue ECM composition and organization are critical to promoting immune cell activation, islet invasion, and destruction of islet β cells in T1D.
KeywordsExtracellular matrix Hyaluronan Hyaladherins Laminin Heparan sulfate Cathepsins Heparanase Islet Islet infiltration Diabetes Immune regulation
The basement membrane work was supported by the European Foundation for the Study of Diabetes/Juvenile Diabetes Research Foundation (JDRF)/Novo Nordisk A/S (BD21070), JDRF (1-2005-903), and German Research Foundation Collaborative Research Center (CRC) (1009 and SO285/9-1) (L.S.). The heparan sulfate work was supported by a National Health and Medical Research Council of Australia (NH & MRC)/JDRF Special Program Grant in Type 1 Diabetes (#418138; to C.R.P.), a NHMRC Project Grant (#1043284; to C.J.S.), and a research grant from the Roche Organ Transplantation Research Foundation (ROTRF)/JDRF (#477554991; to C.J.S.). The hyaluronan work was supported by JDRF nPOD grant 25-2010-648, and NIH/NIAID grants U01 AI101990 and U01 AI101984 (T.N.W.). This research was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative type 1 diabetes research project sponsored by JDRF. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at http://www.jdrfnpod.org/for-partners/npod-partners/.
Compliance with Ethics Guidelines
Conflict of Interest
Marika Bogdani declares that she has no conflict of interest.
Eva Korpos declares that she has no conflict of interest.
Charmaine J. Simeonovic has received research support through a grant from The Australian National University, is currently a shareholder of Beta Therapeutics, and currently has two patents pending.
Christopher R. Parish has received research support through a grant from The Australian National University, is currently a shareholder of Beta Therapeutics, and currently has two patents pending.
Lydia Sorokin declares that she has no conflict of interest.
Thomas N. Wight declares that he has no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human subjects performed by any of the authors. Studies with animals were approved by the relevant institution’s Animal Care and Use Committee and have been previously published.
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