Mesenchymal Stem Cells and Islet Cotransplantation in Diabetic Rats: Improved Islet Graft Revascularization and Function by Human Adipose Tissue-Derived Stem Cells Preconditioned With Natural Molecules
Mesenchymal Stem Cells and Islet Cotransplantation in Diabetic Rats: Improved Islet Graft Revascularization and Function by Human Adipose Tissue-Derived Stem Cells Preconditioned With Natural Molecules
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DOI：
10.3727/096368912x637046
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发表时间：
2012-01-01
影响因子：
3.3
通讯作者：
Ventura, Carlo
中科院分区：
文献类型：
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作者：
Cavallari, Giuseppe;Olivi, Elena;Ventura, Carlo
缺氧在限制肝内移植胰岛的植入、存活和功能方面起重要作用。间充质干细胞（MSCs）最近被用于胰岛移植的动物模型，不仅可以减少同种异体移植排斥反应，而且可以促进血管重建。在不同的可能来源中，脂肪组织代表了一种新的和良好的MSC来源。此外，最近有报道称，在小鼠杂交移植后，脂肪组织来源的干细胞（ASCs）能够改善胰岛移植物的血管重建。在这种情况下，我们以前已经表明，丁酸和视黄酸的透明质酸酯可以显着提高人MSC（hMSC）的拯救潜力。在这里，我们评估是否离体预处理的人ASCs（hASCs）与透明质酸（HA），丁酸（BU），和维甲酸（RA）的混合物可能会导致优化移植物血运重建后胰岛/干细胞肝内共移植在同基因糖尿病大鼠。我们证明了暴露于分子混合物的hASC能够增加血管内皮生长因子（VEGF）的分泌以及血管生成基因（包括VEGF、KDR（激酶插入结构域受体）和肝细胞生长因子（HGF））的转录。与移植等体积的胰岛和对照hASC的大鼠相比，移植与预处理的hASC共培养的胰岛的大鼠表现出更好的血糖控制。与预处理的hASCs共移植也与体内胰岛血管重建增强相关，正如移植物形态学分析所强调的那样。所观察到的胰岛移植物血运重建和功能的增加表明，我们的干细胞预处理方法可能是一种新的策略，以显着提高胰岛-hMSCs共移植的疗效。
Hypoxia plays an important role in limiting the engraftment, survival, and function of intrahepatically transplanted islets. Mesenchymal stem cells (MSCs) were recently used in animal models of islet transplantation not only to reduce allograft rejection but also to promote revascularization. Among different possible origins, adipose tissue represents a novel and good source of MSCs. Moreover, the capability of adipose tissue-derived stem cells (ASCs) to improve islet graft revascularization was recently reported after hybrid transplantation in mice. Within this context, we have previously shown that hyaluronan esters of butyric and retinoic acids can significantly enhance the rescuing potential of human MSCs (hMSCs). Here we evaluated whether ex vivo preconditioning of human ASCs (hASCs) with a mixture of hyaluronic (HA), butyric (BU), and retinoic (RA) acids may result in optimization of graft revascularization after islet/stem cell intrahepatic cotransplantation in syngeneic diabetic rats. We demonstrated that hASCs exposed to the mixture of molecules are able to increase the secretion of vascular endothelial growth factor (VEGF) as well as the transcription of angiogenic genes, including VEGF, KDR (kinase insert domain receptor), and hepatocyte growth factor (HGF). Rats transplanted with islets cocultured with preconditioned hASCs exhibited a better glycemic control than rats transplanted with an equal volume of islets and control hASCs. Cotransplantation with preconditioned hASCs was also associated with enhanced islet revascularization in vivo, as highlighted by graft morphological analysis. The observed increase in islet graft revascularization and function suggests that our method of stem cell preconditioning may represent a novel strategy to remarkably improve the efficacy of islets-hMSCs cotransplantation.