Transplanted Mouse Embryonic Stem-Cell-Derived Motoneurons Form Functional Motor Units and Reduce Muscle Atrophy
Transplanted Mouse Embryonic Stem-Cell-Derived Motoneurons Form Functional Motor Units and Reduce Muscle Atrophy
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DOI：
10.1523/jneurosci.1761-08.2008
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发表时间：
2008-11-19
影响因子：
5.3
通讯作者：
Brownstone, Robert M.
中科院分区：
文献类型：
--
作者：
Yohn, Damien C.;Miles, Gareth B.;Brownstone, Robert M.
由于运动神经元（MN）损伤导致的长时间肌肉去神经支配导致神经肌肉接头（NMJ）的萎缩和变性，这可造成不可逆的损伤。在这项研究中，我们问是否移植的胚胎干细胞（ES）分化成MN可以形成功能性突触与宿主肌肉，如果是这样，他们对肌肉有什么影响。移植到成年小鼠的横断胫神经后，ES细胞衍生的MN与失神经支配的宿主肌肉形成功能性突触，这导致产生平均强直力的能力为非损伤对照的44%。ES细胞衍生的运动单位（MU）的平均力值和范围类似于控制肌肉。I型纤维的数量和肌群的抗疲劳性增加，去神经相关的肌肉萎缩显着减少。这些结果证明了ES细胞衍生的MN不仅能够掺入成体宿主组织中，而且还能够在靶组织中产生变化。通过提供在胚胎发育期间正常激活的信号并将细胞置于具有其靶组织的环境中，ES细胞分化成MN，其产生类似于内源性MN的MU输出的功能性MU输出。这表明这些信号与移植物环境中存在的信号相结合，导致旨在产生正常范围MU力的程序激活。
Prolonged muscle denervation resulting from motor neuron (MN) damage leads to atrophy and degeneration of neuromuscular junctions (NMJs), which can impart irreversible damage. In this study, we ask whether transplanted embryonic stem (ES) cells differentiated into MNs can form functional synapses with host muscle, and if so what effects do they have on the muscle. After transplantation into transected tibial nerves of adult mice, ES-cell-derived MNs formed functional synapses with denervated host muscle, which resulted in the ability to produce average tetanic forces of 44% of nonlesioned controls. ES-cell-derived motor units (MUs) had mean force values and ranges similar to control muscles. The number of type I fibers and fatigue resistance of the MUs were increased, and denervation-associated muscle atrophy was significantly reduced. These results demonstrate the capacity for ES-cell-derived MNs not only to incorporate into the adult host tissue, but also to exert changes in the target tissue. By providing the signals normally active during embryonic development and placing the cells in an environment with their target tissue, ES cells differentiate into MNs that give rise to functional MU output which resembles the MU output of endogenous MNs. This suggests that these signals combined with those present in the graft environment, lead to the activation of a program intended to produce a normal range of MU forces.