Important role of heparan sulfate in postnatal islet growth and insulin secretion

Takahashi, Ikuo; Noguchi, Naoya; Nata, Koji; Yamada, Shuhei; Kaneiwa, Tomoyuki; Mizumoto, Shuji; Ikeda, Takayuki; Sugihara, Kazushi; Asano, Masahide; Yoshikawa, Takeo; Yamauchi, Akiyo; Shervani, Nausheen J.; Uruno, Akira; Kato, Ichiro; Unno, Michiaki; Sugahara, Kazuyuki; Takasawa, Shin; Okamoto, Hiroshi; Sugawara, Akira

doi:10.1016/j.bbrc.2009.03.140

Cited by 82 publications

(85 citation statements)

References 18 publications

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“…In addition to playing a critical role in β cell survival, HS may also perform other homeostatic functions as a reservoir and coreceptor for essential growth factors (50) and has previously been reported to regulate the postnatal development of β cell function (26). Under conditions of autoimmune disease, we demonstrated here that islet HS acts as a critical target for destruction by heparanase.…”

Section: Figuresupporting

confidence: 50%

“…24, 25, and Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI46177DS1). The direct detection methods we used to localize HS in islets represent a technical advance over the indirect approach of identifying HS "stubs" after heparitinase treatment of pancreas sections (26).…”

Section: Hs Is Highly Expressed In Mouse Islets In Situmentioning

confidence: 99%

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

Ziolkowski

Popp²,

Freeman³

et al. 2012

J. Clin. Invest.

140

194

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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.

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Section: Figuresupporting

confidence: 50%

Section: Hs Is Highly Expressed In Mouse Islets In Situmentioning

confidence: 99%

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

Ziolkowski

Popp²,

Freeman³

et al. 2012

J. Clin. Invest.

140

194

View full text Add to dashboard Cite

show abstract

“…S3). Moreover, it is also reported that HSPGs are involved in the postnatal b-cell proliferation or b-cell function (Takahashi et al, 2009). To test whether the HSPGs have a role in pancreatic differentiation, we generated Hspg2-knockdown SK7 ES cells.…”

Section: Heparan Sulfate Proteoglycan Is Involved In Pancreatic Diffementioning

confidence: 99%

Synthesized basement membranes direct the differentiation of mouse embryonic stem cells into pancreatic lineages

Higuchi

Shiraki

Yamane

et al. 2010

Journal of Cell Science

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SummaryWe previously reported that embryonic stem (ES) cells cultured on M15 cells, a mesoderm-derived supportive cell line, were efficiently differentiated towards an endodermal fate, finally adopting the specific lineages of various digestive organs such as the pancreas and liver. We show here that the endoderm-inducing activity of M15 cells is in part mediated through the extracellular matrices, and that laminin 5 is one of the crucial components. In an attempt to establish a feeder-free ES-cell procedure for pancreatic differentiation, we used a synthesized basement membrane (sBM) substratum using an HEK293 cell line stably expressing laminin-511. On the sBM, mouse ES or induced pluripotent stem (iPS) cells sequentially differentiated into the definitive endoderm, pancreatic progenitor cells, and then insulin-expressing pancreatic b-cells in vitro. Knockdown of ES cells with integrin b1 (Itgb1) reduces differentiation towards pancreatic cells. Heparan sulfate proteoglycan 2 (HSPG2) knockdown and heparitinase treatment synergistically decreased the number of Pdx1-expressing cells. These findings indicate that components of the basement membrane have an important role in the differentiation of definitive endoderm lineages. This novel procedure will be useful for the study of pancreatic differentiation of ES or iPS cells and the generation of potential sources of surrogate cells for regenerative medicine.

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“…These mice also responded to glucose challenge with increased blood glucose levels and their plasma insulin levels were reduced. These findings demonstrate that -cell specific EXTL3 knockout can affect the regulation of postnatal islet maturation via ablation or reduction or alteration of HS proteoglycan biosynthesis (Takahashi, Noguchi et al 2009). These encouraging data might lead to the formation of a basis from which the effects of Reg could be explained.…”

Section: Studies In Search Of a Reg Receptormentioning

confidence: 81%

The Role of Reg Proteins, a Family of Secreted C-Type Lectins, in Islet Regeneration and as Autoantigens in Type 1 Diabetes

Gürr¹

2011

Type 1 Diabetes - Pathogenesis, Genetics and Immunotherapy

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Important role of heparan sulfate in postnatal islet growth and insulin secretion

Cited by 82 publications

References 18 publications

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

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

Synthesized basement membranes direct the differentiation of mouse embryonic stem cells into pancreatic lineages

The Role of Reg Proteins, a Family of Secreted C-Type Lectins, in Islet Regeneration and as Autoantigens in Type 1 Diabetes

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