Intrinsic cell memory reinforces myogenic commitment of pericyte-derived iPSCs
Intrinsic cell memory reinforces myogenic commitment of pericyte-derived iPSCs
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DOI：
10.1002/path.2845
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发表时间：
2011-04-01
影响因子：
7.3
通讯作者：
Sampaolesi, Maurilio
中科院分区：
文献类型：
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作者：
Quattrocelli, Mattia;Palazzolo, Giacomo;Sampaolesi, Maurilio
中成血管细胞（MAB）是肌肉来源的周细胞的一个子集，能够恢复小鼠和狗的营养不良表型。然而，它们的寿命是有限的，并且在25-30次群体倍增后就会衰老。最近，由重编程成纤维细胞产生的诱导多能干细胞（iPSC）已被证明在针对 SM/C-2.6 抗原进行分选时具有体外和体内生肌潜力。此外，来自 mdx-iPSC (DYS-HAC) 细胞的嵌合小鼠表现出肌营养不良蛋白的组织特异性表达。然而，肌源性分化方案和不同细胞来源产生的 iPSC 的潜力仍然存在悬而未决的问题。在这里，我们表明，由前瞻性分选的 MAB (MAB-iPSC) 产生的 iPSC 与成纤维细胞衍生的 iPSC (f-iPSC) 一样具有多能性。然而，畸胎瘤形成和遗传细胞操作分析均发现 MAB-iPSC 具有持久的表观遗传记忆，从而产生更强的肌源性承诺。横纹肌组织占 MAB-iPSC 畸胎瘤的 70%。此外，转染 Pax3 和 Pax7 可在 MAB-iPSC 中诱导比 f-iPSC 更强的肌原性分化。从MAB-iPSCs分化库中可以分选出大量的CD56(+)祖细胞，移植到α sg-KO小鼠体内后，可以有效参与骨骼肌再生并恢复α sg表达。我们的数据强烈表明，iPSC 是一个异质群体，当由肌源性成体干细胞生成时，它们表现出更强的承诺，为创建针对肌营养不良症的定制细胞方案铺平了道路。版权。 (C) 2011 年英国和爱尔兰病理学会。由约翰·威利父子有限公司出版
Mesoangioblasts (MABs) are a subset of muscle-derived pericytes able to restore dystrophic phenotype in mice and dogs. However, their lifespan is limited and they undergo senescence after 25-30 population doublings. Recently, induced pluripotent stem cells (iPSCs) generated from reprogrammed fibroblasts have been demonstrated to have in vitro and in vivo myogenic potential when sorted for the SM/C-2.6 antigen. Furthermore, chimeric mice from mdx-iPSCs (DYS-HAC) cells showed tissue-specific expression of dystrophin. Nevertheless, myogenic differentiation protocols and the potential of iPSCs generated from different cell sources still present unanswered questions. Here we show that iPSCs generated from prospectively sorted MABs (MAB-iPSCs) are pluripotent as fibroblast-derived iPSCs (f-iPSCs). However, both teratoma formation and genetic cell manipulation assays identify a durable epigenetic memory in MAB-iPSCs, resulting in stronger myogenic commitment. Striated muscle tissue accounts for up to 70% of MAB-iPSC teratomas. Moreover, transfection with Pax3 and Pax7 induces a more robust myogenic differentiation in MAB-iPSCs than in f-iPSCs. A larger amount of CD56(+) progenitors can be sorted from the MAB-iPSCs differentiating pool and, after transplantation into alpha sg-KO mice, can efficiently participate to skeletal muscle regeneration and restore alpha sg expression. Our data strongly suggest that iPSCs are a heterogeneous population and, when generated from myogenic adult stem cells, they exhibit a stronger commitment, paving the way for creating custom-made cell protocols for muscular dystrophies. Copyright. (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.