目前开发干细胞疗法作为神经肠疾病的新治疗方法的努力受到无法获得用于研究人肠中细胞移植的模型系统的限制。我们建议,当皮下或腹内移植到小鼠中时,异种移植模型支持胎儿人类肠道中的肠神经系统(ENS)发育。
将胎儿人小肠和大肠移植到小肠系膜和免疫缺陷小鼠的皮下组织中长达4个月。使用免疫组织化学研究了肠道细胞结构和ENS发育。
在腹部和皮下移植中,肠道发育正常,形成成熟的上皮和间充质层。ENS在两个含有肠神经元和神经胶质的神经节丛中形成图案,包括胆碱能和硝能神经元亚型。肠壁中存在Cajal的c-Kit免疫反应性间质细胞。
腹部异种移植物代表了支持胎儿人类肠的生长和发育的新型模型。这种体内方法将是研究ENS成熟的有用方法,神经肠道疾病的病理生理学,以及用于治疗肠神经病变的神经元干细胞的长期存活和功能分化。
Current efforts to develop stem cell therapy as a novel treatment for neurointestinal diseases are limited by the unavailability of a model system to
study cell transplantation in the human intestine. We propose that xenograft models support enteric nervous system (ENS) development in the fetal human intestine when transplanted into mice subcutaneously or intra-abdominally.
Fetal human small and large intestine were grafted onto the small intestinal mesentery and into the subcutaneous tissue of immunodeficient mice for up to 4 months. Intestinal cytoarchitecture and ENS development were studied using immunohistochemistry.
In both abdominal and subcutaneous grafts, the intestine developed normally with formation of mature epithelial and mesenchymal layers. The ENS was patterned in two ganglionated plexuses containing enteric neurons and glia, including cholinergic and nitrergic neuronal subtypes. c-Kit-immunoreactive interstitial cells of Cajal were present in the gut wall.
Abdominal xenografts represent a novel model that supports the growth and development of fetal human intestine. This in vivo approach will be a useful method to
study maturation of the ENS, the pathophysiology of neurointestinal diseases, and the long-term survival and functional differentiation of neuronal stem cells for the treatment of enteric neuropathies.