Islet-like cell aggregates generated from human adipose tissue derived stem cells ameliorate experimental diabetes in mice.
Islet-like cell aggregates generated from human adipose tissue derived stem cells ameliorate experimental diabetes in mice.
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DOI：
10.1371/journal.pone.0020615
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Bhonde RR
中科院分区：
文献类型：
--
作者：
Chandra V;Swetha G;Muthyala S;Jaiswal AK;Bellare JR;Nair PD;Bhonde RR
1型糖尿病是由胰腺中产生胰岛素的β细胞自身免疫性破坏引起的。目前可用的治疗方法包括将供体胰腺中分离出的胰岛移植到患者体内。然而，这种方法受到免疫抑制手段不足的限制，无法防止胰岛排斥，而且重要的是，可供移植的胰岛供应有限。现在考虑将自体成体干细胞用于糖尿病的细胞替代疗法，因为它有可能产生新的胰岛，这些胰岛在基因上是接受治疗个体的一部分。采用胰岛在免疫隔离装置中封装的方法将无需使用免疫抑制剂。
在本研究中，我们探索了人脂肪组织来源的成体干细胞（h - ASCs）分化为功能性胰岛样细胞聚集体（ICAs）的潜力。我们的阶段特异性分化方案允许中胚层的h - ASCs转化为定型内胚层（Hnf3β、TCF2和Sox17）以及PDX1、Ngn3、NeuroD、Pax4阳性的胰腺内胚层，后者在体外进一步成熟以分泌胰岛素。这些ICAs被证明能以葡萄糖依赖的方式产生人C肽，表现出体外功能。将成熟的ICAs封装在免疫隔离的生物相容性胶囊中并移植到链脲佐菌素诱导的糖尿病小鼠体内，在3 - 4周内使血糖恢复接近正常水平。在实验小鼠的血清中检测到人C肽，浓度为1155±165 pM，证明了我们的分化方法的有效性。
h - ASC是用于细胞替代疗法的理想的个人干细胞群，因为它们数量丰富、容易获取且来源于自体。我们的研究结果提供了证据，表明h - ASCs可以被诱导分化为具有生理功能的功能性胰岛样细胞聚集体，这可能为1型糖尿病的细胞替代疗法提供一种替代胰岛的来源。
Type 1 Diabetes Mellitus is caused by auto immune destruction of insulin producing beta cells in the pancreas. Currently available treatments include transplantation of isolated islets from donor pancreas to the patient. However, this method is limited by inadequate means of immuno-suppression to prevent islet rejection and importantly, limited supply of islets for transplantation. Autologous adult stem cells are now considered for cell replacement therapy in diabetes as it has the potential to generate neo-islets which are genetically part of the treated individual. Adopting methods of islet encapsulation in immuno-isolatory devices would eliminate the need for immuno-suppressants. In the present study we explore the potential of human adipose tissue derived adult stem cells (h-ASCs) to differentiate into functional islet like cell aggregates (ICAs). Our stage specific differentiation protocol permit the conversion of mesodermic h-ASCs to definitive endoderm (Hnf3β, TCF2 and Sox17) and to PDX1, Ngn3, NeuroD, Pax4 positive pancreatic endoderm which further matures in vitro to secrete insulin. These ICAs are shown to produce human C-peptide in a glucose dependent manner exhibiting in-vitro functionality. Transplantation of mature ICAs, packed in immuno-isolatory biocompatible capsules to STZ induced diabetic mice restored near normoglycemia within 3–4 weeks. The detection of human C-peptide, 1155±165 pM in blood serum of experimental mice demonstrate the efficacy of our differentiation approach. h-ASC is an ideal population of personal stem cells for cell replacement therapy, given that they are abundant, easily available and autologous in origin. Our findings present evidence that h-ASCs could be induced to differentiate into physiologically competent functional islet like cell aggregates, which may provide as a source of alternative islets for cell replacement therapy in type 1 diabetes.
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