Xenotransplanted Embryonic Kidney Provides a Niche for Endogenous Mesenchymal Stem Cell Differentiation into Erythropoietin-Producing Tissue
Xenotransplanted Embryonic Kidney Provides a Niche for Endogenous Mesenchymal Stem Cell Differentiation into Erythropoietin-Producing Tissue
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DOI：
10.1002/stem.1101
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发表时间：
2012-06-01
期刊：
影响因子：
5.2
通讯作者：
Kobayashi, Eiji
中科院分区：
文献类型：
--
作者：
Matsumoto, Kei;Yokoo, Takashi;Kobayashi, Eiji
最近的研究结果表明，干细胞可以分化成成熟的组织时，提供了一个小生境含有相同的因素，在正常的发育程序。通过异种移植类似的发育器官可以提供器官发育的生态位。然而，这一过程有许多技术、安全和伦理问题。在这里，我们建立了异种移植模型，控制内源性间充质干细胞（MSC）分化成成熟的促红细胞生成素（EPO）生产组织中提供的一个小生境发展中的xenometanephros。将大鼠后肾移植到小鼠网膜中，以及类似地将猪后肾移植到猫网膜中，导致宿主细胞的募集和EPO的产生。EPO表达细胞没有分化整合血管，因为他们不共表达内皮标志物（Tie-2和VE-钙粘蛋白）。相反，表达EPO的细胞显示来自循环宿主细胞，如在嵌合小鼠的生长移植物中增强的绿色荧光蛋白（EGFP）表达所示，所述嵌合小鼠具有来自在EPO启动子控制下表达EGFP的转基因小鼠的骨髓。这些结果表明，异种移植的发育器官中供体细胞的募集和分化在物种之间可能是一致的。通过将人骨髓来源的MSC和内皮祖细胞注射到NOD/SCID小鼠中，鉴定负责EPO表达的细胞为MSC。此外，使用来自转基因ER-E2 F1自杀诱导型小鼠的后肾，可以消除异种组织成分，留下自体产生EPO的组织。我们的研究结果可能会减轻由于长期免疫抑制引起的不良反应，并有助于减轻伦理问题。干细胞2012;30：12281235
Recent findings have demonstrated that stem cells can differentiate into mature tissue when supplied with a niche containing factors identical to those in the normal developmental program. A niche for the development of an organ can be provided by xenotransplantation of a similar developing organ. However, this process has many technical, safety, and ethical concerns. Here, we established xenotransplantation models that control endogenous mesenchymal stem cell (MSC) differentiation into mature erythropoietin (EPO)-producing tissue in a niche provided by a developing xenometanephros. Transplantation of rat metanephroi into mouse omentum, and similarly pig metanephroi into cat omentum, led to the recruitment of host cells and EPO production. EPO-expressing cells were not differentiated from integrating vessels because they did not coexpress endothelial markers (Tie-2 and VE-cadherin). Instead, EPO-expressing cells were shown to be derived from circulating host cells, as shown by enhanced green fluorescent protein (EGFP) expression in the grown transplants of chimeric mice bearing bone marrow from a transgenic mouse expressing EGFP under the control of the EPO promoter. These results suggest that donor cell recruitment and differentiation in a xenotransplanted developing organ may be consistent between species. The cells responsible for EPO expression were identified as MSCs by injecting human bone marrow-derived MSCs and endothelial progenitor cells into NOD/SCID mice. Furthermore, using metanephroi from transgenic ER-E2F1 suicide-inducible mice, the xenotissue component could be eliminated, leaving autologous EPO-producing tissue. Our findings may alleviate adverse effects due to long-lasting immunosuppression and help mitigate ethical concerns. STEM CELLS2012;30:12281235