R2-DB19-0725-SUPPLEMENTARY_INFORMATION.docx (9.71 MB)
Dextran Sulfate Protects Pancreatic β-Cells, Reduces Autoimmunity and Ameliorates Type 1 Diabetes
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posted on 2020-05-07, 14:12 authored by Ada AdminAda Admin, Geming Lu, Francisco Rausell-Palamos, Jiamin Zhang, Zihan Zheng, Tuo Zhang, Shelley Valle, Carolina Rosselot, Cecilia Berrouet, Patricia Conde, Matthew P. Spindler, John G. Graham, Dirk Homann, Adolfo Garcia-OcañaA failure in self-tolerance leads to autoimmune
destruction of pancreatic β-cells and type 1 diabetes (T1D). Low molecular
weight dextran sulfate (DS) is a sulfated semi-synthetic polysaccharide with demonstrated
cytoprotective and immunomodulatory properties in vitro. However, whether DS can protect pancreatic β-cells,
reduce autoimmunity and ameliorate T1D is unknown. Here we report that DS, but
not dextran, protects human β-cells against cytokine-mediated cytotoxicity in vitro. DS also protects mitochondrial
function and glucose-stimulated insulin secretion and reduces chemokine
expression in human islets in a pro-inflammatory environment. Interestingly, daily
treatment with DS significantly reduces diabetes incidence in pre-diabetic non-obese
diabetic (NOD) mice, and most importantly, reverses diabetes in early-onset
diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate
(HS)/heparan sulfate proteoglycan (HSPG) expression and preserves β-cell mass
and plasma insulin in these mice. DS administration also increases the
expression of the inhibitory co-stimulatory molecule programmed death-1 (PD-1) in
T-cells, reduces interferon-γ+ CD4+ and CD8+ T-cells and enhances the number of
FoxP3+ cells. Collectively, these studies demonstrate that the action of one
single molecule, DS, on β-cell protection, extracellular matrix preservation
and immunomodulation can reverse diabetes in NOD mice highlighting its
therapeutic potential for the treatment of T1D.