Human embryonic stem cell-derived mesenchymal stromal cell transplantation in a rat hind limb injury model.
Human embryonic stem cell-derived mesenchymal stromal cell transplantation in a rat hind limb injury model.
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DOI：
10.3109/14653240903067299
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发表时间：
2009
期刊：
影响因子：
4.5
通讯作者：
Laukkanen MO
中科院分区：
文献类型：
--
作者：
Laurila JP;Laatikainen L;Castellone MD;Trivedi P;Heikkila J;Hinkkanen A;Hematti P;Laukkanen MO
间充质基质/干细胞（MSC）已用于各种临床前实验和越来越多的人体临床试验。尽管许多研究显示了不同的植入水平，但移植后 MSC 的确切命运以及组织对其植入的反应尚未得到详细研究。在目前的工作中，我们研究了移植后大鼠后肢缺血性损伤模型中人间充质干细胞的分布，并分析了受体组织对移植细胞的反应。我们利用生物发光成像、荧光显微镜和大鼠后肢缺血模型中的基因/蛋白质表达分析来追踪移植的 MSC 的体内命运。我们还通过移植物与受体表达分析监测移植细胞的活力，并通过组织学染色确定移植的血管生成和增殖作用。根据成像分析，只有一小部分细胞在损伤部位持续存在较长时间。有趣的是，受体与移植物表达研究表明，移植组织中大鼠来源的血管生成因子的合成增加，而没有人来源的 mRNA 或蛋白质合成。更重要的是，尽管缺乏强大的植入或生长因子分泌，移植过程却发挥了显着的促血管生成和促增殖作用，我们证明这是由血管生成和有丝分裂信号通路介导的。我们的结果显示，间充质干细胞移植对颞组织产生即时反应，这可能代表了一种新颖的间接旁分泌机制，可以在受损组织中观察到细胞移植的有益效果。
Mesenchymal stromal/stem cells (MSCs) have been used in a wide variety of preclinical experiments and in an increasing number of human clinical trials. Although many of these studies have shown different levels of engraftment, the exact fate of MSCs after transplantation and the tissue response to their engraftment has not been investigated in detail. In the present work we studied the distribution of human MSCs in a rat hind limb ischemic injury model immediately after transplantation and also analyzed the recipient tissue response to transplanted cells. We tracked the in vivo fate of the transplanted MSCs utilizing bioluminescence imaging, fluorescence microscopy, and gene/protein expression analysis in rat hind limb ischemia model. We also monitored the viability of transplanted cells by graft vs. recipient expression analysis and determined the angiogenic and proliferative effect of transplantation by histological staining. According to imaging analysis only a small portion of cells persisted for extended period of time at the site of injury. Interestingly, recipient versus graft expression studies showed increased synthesis of rat-origin angiogenic factors and no human-origin mRNA or protein synthesis in transplanted tissues. More importantly, despite the lack of robust engraftment or growth factor secretion the transplantation procedure exerted a significant pro-angiogenic and pro-proliferative effect, which we showed was mediated by angiogenic and mitogenic signaling pathways. Our results show an immediate temporal tissue effect in response to MSC transplantation that may represent a novel indirect paracrine mechanism for the beneficial effects of cell transplantation observed in injured tissues.
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