Transplantation of enteric nervous system stem cells rescues nitric oxide synthase deficient mouse colon
Transplantation of enteric nervous system stem cells rescues nitric oxide synthase deficient mouse colon
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DOI：
10.1038/ncomms15937
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发表时间：
2017-07-03
影响因子：
16.6
通讯作者：
Thapar, Nikhil
中科院分区：
文献类型：
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作者：
McCann, Conor J.;Cooper, Julie E.;Thapar, Nikhil
肠神经系统神经病变引起广泛的严重肠道动力障碍。使用肠神经干细胞（ENSC）细胞替代丢失的神经元是这些生命限制性疾病的可能疗法。在这里，我们显示了在人类肠神经病的小鼠模型，神经元型一氧化氮合酶（nNOS（-/-））缺陷的小鼠模型中，ENSC移植后肠道运动的救援，其显示结肠中的缓慢传输。我们进一步表明，将ENSC移植到结肠中可以挽救受损的结肠运动，形成广泛的移植细胞网络，包括nNOS（+）神经元的发育和随后的氮能反应的恢复。此外，移植后的非细胞自主机制恢复了在nNOS（-/-）结肠中减少的Cajal间质细胞的数量。这些结果提供了第一个直接证据，即ENSC移植可以调节肠神经肌肉合胞体，以恢复功能，在器官水平上，在运动障碍性胃肠道疾病模型。
Enteric nervous system neuropathy causes a wide range of severe gut motility disorders. Cell replacement of lost neurons using enteric neural stem cells (ENSC) is a possible therapy for these life-limiting disorders. Here we show rescue of gut motility after ENSC transplantation in a mouse model of human enteric neuropathy, the neuronal nitric oxide synthase (nNOS(-/-)) deficient mouse model, which displays slow transit in the colon. We further show that transplantation of ENSC into the colon rescues impaired colonic motility with formation of extensive networks of transplanted cells, including the development of nNOS(+) neurons and subsequent restoration of nitrergic responses. Moreover, post-transplantation non-cell-autonomous mechanisms restore the numbers of interstitial cells of Cajal that are reduced in the nNOS(-/-) colon. These results provide the first direct evidence that ENSC transplantation can modulate the enteric neuromuscular syncytium to restore function, at the organ level, in a dysmotile gastrointestinal disease model.