In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion
In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion
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DOI：
10.1172/jci200316502
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发表时间：
2003-03-01
影响因子：
15.9
通讯作者：
Hussain, MA
中科院分区：
文献类型：
--
作者：
Ianus, A;Holz, GG;Hussain, MA
骨髓含有具有分化为神经元、内皮、上皮和肌肉表型的非造血组织细胞的能力的细胞。在这里，我们证明，骨髓来源的细胞填充胰岛的朗格汉斯。将来自雄性小鼠的骨髓细胞移植到致死性照射的受体雌性小鼠中，所述骨髓细胞使用CRE-LoxP系统表达增强的绿色荧光蛋白（EGFP）（如果胰岛素基因被活跃转录）。移植后4 - 6周，受体小鼠在胰岛中显示Y染色体和EGFP双阳性细胞。供体或受体小鼠的骨髓细胞和循环外周血有核细胞均未检测到任何增强型绿色荧光蛋白。从胰岛纯化的EGFP阳性细胞表达胰岛素、葡萄糖转运蛋白2（GLUT 2）和通常在胰腺β细胞中发现的转录因子。此外，在体外，这些骨髓来源的细胞表现出-胰腺β细胞-葡萄糖依赖性和肠促胰岛素增强的胰岛素分泌。这些结果表明，骨髓含有能够分化为功能上有能力的胰腺内分泌β细胞的细胞，并且代表了基于细胞的糖尿病治疗的来源。用CRE-LoxP系统产生的结果还表明，体内细胞融合不太可能解释骨髓来源的细胞向分化的细胞表型的“转分化”。
Bone marrow harbors cells that have the capacity to differentiate into cells of nonhematopoietic tissues of neuronal, endothelial, epithelial, and muscular phenotype. Here we demonstrate that bone marrow-derived cells populate pancreatic islets of Langerhans. Bone marrow cells from male mice that express, using a CRE-LoxP system, an enhanced green fluorescent protein (EGFP) if the insulin gene is actively transcribed were transplanted into lethally irradiated recipient female mice. Four to six weeks after transplantation, recipient mice revealed Y chromosome and EGFP double-positive cells in their pancreatic islets. Neither bone marrow cells nor circulating peripheral blood nucleated cells of donor or recipient mice had any detectable EGFP. EGFP-positive cells purified from islets express insulin, glucose transporter 2 (GLUT2), and transcription factors typically found in pancreatic beta cells. Furthermore, in vitro these bone marrow-derived cells exhibit - as do pancreatic beta cells - glucose-dependent and incretin-enhanced insulin secretion. These results indicate that bone marrow harbors cells that have the capacity to differentiate into functionally competent pancreatic endocrine beta cells and that represent a source for cell-based treatment of diabetes mellitus. The results generated with the CRE-LoxP system also suggest that in vivo cell fusion is an unlikely explanation for the "transdifferentiation" of bone marrow-derived cells into differentiated cell phenotypes.