Widespread distribution and muscle differentiation of human fetal mesenchymal cells after intrauterine transplantation in dystrophic mdx mouse
Widespread distribution and muscle differentiation of human fetal mesenchymal cells after intrauterine transplantation in dystrophic mdx mouse
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DOI：
10.1634/stemcells.2006-0694
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发表时间：
2007-01-01
期刊：
影响因子：
5.2
通讯作者：
Fisk, Nicholas M.
中科院分区：
文献类型：
--
作者：
Chan, Jerry;Waddington, Simon N.;Fisk, Nicholas M.
杜氏肌营养不良症（DMD）是一种常见的X-连锁疾病，由于缺乏肌营养不良蛋白的肌肉。受影响的男孩患有无法治愈的进行性肌肉无力，导致过早死亡。干细胞移植可能是治愈性的，但由于需要全身递送和免疫排斥而受到阻碍。为了解决DMD中干细胞治疗的这些障碍，我们研究了胎儿对胎儿移植策略。我们研究了人胎儿间充质干细胞（hfMSCs）向胚胎（E）14-16天的MF 1小鼠的肌内、血管内和腹膜内递送，以确定全身递送的最合适途径。肌内注射导致局部植入，而腹膜内和血管内递送导致全身扩散。然而，血管内递送导致移植小鼠意外死亡。将hfMSC移植到E14-16 mdx小鼠中导致在多个器官中广泛的长期植入（19周），与非肌肉组织相比，肌肉组织的偏好（0.71%对0.15%，p <0.01），以及骨骼肌和心肌中hfMSC的肌源性分化的证据。这是第一次报告子宫内移植的本体相关的hfMSCs到完全免疫功能正常的营养不良胎鼠，与系统性传播的内皮屏障，导致广泛的长期植入在多个器官隔室。虽然低水平的嵌合体不能治愈DMD，但这种方法可能适用于其他严重的间充质或酶缺乏综合征，其中低水平的蛋白质表达可能改善疾病病理。
Duchenne muscular dystrophy (DMD) is a common X-linked disease resulting from the absence of dystrophin in muscle. Affected boys suffer from incurable progressive muscle weakness, leading to premature death. Stem cell transplantation may be curative, but is hampered by the need for systemic delivery and immune rejection. To address these barriers to stem cell therapy in DMD, we investigated a fetal-to-fetal transplantation strategy. We investigated intramuscular, intravascular, and intraperitoneal delivery of human fetal mesenchymal stem cells (hfMSCs) into embryonic day (E) 14-16 MF1 mice to determine the most appropriate route for systemic delivery. Intramuscular injections resulted in local engraftment, whereas both intraperitoneal and intravascular delivery led to systemic spread. However, intravascular delivery led to unexpected demise of transplanted mice. Transplantation of hfMSCs into E14-16 mdx mice resulted in widespread long-term engraftment (19 weeks) in multiple organs, with a predilection for muscle compared with nonmuscle tissues (0.71% vs. 0.15%, p < .01), and evidence of myogenic differentiation of hfMSCs in skeletal and myocardial muscle. This is the first report of intrauterine transplantation of ontologically relevant hfMSCs into fully immunocompetent dystrophic fetal mice, with systemic spread across endothelial barriers leading to widespread long-term engraftment in multiple organ compartments. Although the low-level of chimerism achieved is not curative for DMD, this approach may be useful in other severe mesenchymal or enzyme deficiency syndromes, where low-level protein expression may ameliorate disease pathology.