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Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes
Andrew F. Ziolkowski, … , Christopher R. Parish, Charmaine J. Simeonovic
Andrew F. Ziolkowski, … , Christopher R. Parish, Charmaine J. Simeonovic
Published December 19, 2011
Citation Information: J Clin Invest. 2012;122(1):132-141. https://doi.org/10.1172/JCI46177.
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Research Article Metabolism

Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes

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Abstract

The autoimmune type 1 diabetes (T1D) that arises spontaneously in NOD mice is considered to be a model of T1D in humans. It is characterized by the invasion of pancreatic islets by mononuclear cells (MNCs), which ultimately leads to destruction of insulin-producing β cells. Although T cell dependent, the molecular mechanisms triggering β cell death have not been fully elucidated. Here, we report that a glycosaminoglycan, heparan sulfate (HS), is expressed at extraordinarily high levels within mouse islets and is essential for β cell survival. In vitro, β cells rapidly lost their HS and died. β Cell death was prevented by HS replacement, a treatment that also rendered the β cells resistant to damage from ROS. In vivo, autoimmune destruction of islets in NOD mice was associated with production of catalytically active heparanase, an HS-degrading enzyme, by islet-infiltrating MNCs and loss of islet HS. Furthermore, in vivo treatment with the heparanase inhibitor PI-88 preserved intraislet HS and protected NOD mice from T1D. Our results identified HS as a critical molecular requirement for islet β cell survival and HS degradation as a mechanism for β cell destruction. Our findings suggest that preservation of islet HS could be a therapeutic strategy for preventing T1D.

Authors

Andrew F. Ziolkowski, Sarah K. Popp, Craig Freeman, Christopher R. Parish, Charmaine J. Simeonovic

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Figure 1

HS is highly expressed within pancreatic islets in situ, and HS loss in vitro correlates with β cell death.

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HS is highly expressed within pancreatic islets in situ, and HS loss in ...
(A) Detection of HS in NOD/SCID pancreatic islets in situ by Alcian blue histochemistry and immunohistochemistry using HepSS-1 anti-HS mAb. No background staining with isotype control mouse IgM was observed. Scale bars: 50 μm. (B) Intra-islet HS content (quantified by Image J with Color Deconvolution plugin) showed that the area of intraislet staining with Alcian blue was significantly higher in islets in situ (n = 50) than after isolation (n = 45; P < 0.0001). (C) Isolated BALB/c islet showing loss of intraislet HS by Alcian blue staining. Scale bar: 50 μm. (D) Intracellular HS staining was further reduced in BALB/c islet β cells during culture, as demonstrated by FACS staining using HepSS-1 (anti-HSlo; blue histogram) and 10E4 (anti-HShi; pink histogram) mAbs or an isotype control IgM (green histogram); black histogram denotes islet cell autofluorescence. Loss of β cell viability after culture for 2 days, as measured by Sytox green uptake (dead/dying cells), is shown at right. SSC-W, side scatter width. (E) Loss of intracellular HShi and HSlo and increase of cell surface HShi and HSlo was seen in β cells cultured for 2 days. *P = 0.0022; #P < 0.0001; **P = 0.0225; ##P = 0.0202. (F) Loss of intracellular HS during culture for 2 days, as in E, correlated with a significant increase in percent Sytox green+ β cells (P < 0.0001). Data are mean ± SEM (n = 6).

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