Development of novel therapeutics targeting the function of intestinal cells of Cajal in gastrointestinal motility disorder

Cajal间质细胞（Interstitial cells of Cajal，ICCs）是胃肠道内与神经丛相连的细胞网络。最近的研究提供了证据表明，ICC在肠道中起着起搏细胞的作用，负责产生自发性电活动。我们已经表明，ICCs的缺陷和自发突变大鼠的肠收缩活动的减少，在c-kit的酪氨酸激酶结构域的小缺失。我们还发现慢性假性肠梗阻肌病患者的ICC缺乏。大多数类型的慢性假性肠梗阻对常规促肠动力药物无反应。因此，需要通过靶向与ICC的增殖、分化和功能的调节相关的分子来开发新的治疗方法。我们正在研究ICC的增殖、分化和功能的调节机制。我们建立了小鼠小肠ICC的体外培养体系和小肠基质细胞系。干细胞因子（SCF）是c-kit的配体，刺激交配后第8天胚胎ICCs的增殖。SCF并没有刺激出生后第6天的新生儿ICC的增殖，但它们的存活需要SCF。我们已经开发了来源于小鼠小肠的基质细胞系。转染c-kit互补DNA的基质细胞有向ICC分化的趋势。我们将识别可以靶向诱导分化的分子。

Interstitial cells of Cajal (ICCs) are found as networks of cells associated with neuronal plexuses in gastrointestinal tract. Recent studies have provided evidence that ICCs function in the gut as pacemaker cells responsible for the generation of spontaneous electrical activity. We have shown the deficiency of ICCs and the decrease in the contractile activity of the intestine in spontaneous mutant rats with a small deletion at the tyrosine kinase domain of c-kit. We have also shown the deficiency of ICCs in patients with a myopathic form of chronic intestinal pseudo-obstruction. Most types of chronic intestinal pseudo-obstruction do not respond to conventional prokinetic drugs. Therefore, methods of novel therapeutics need to be developed by targeting the molecules associated with the regulation of proliferation, differentiation and function of ICCs. We are investigating the mechanism of the regulation of proliferation, differentiation and function of ICCs. We have established in vitro culture system for ICCs isolated from mouse intestine and intestinal stromal cell line. Stem cell factor (SCF), which is a ligand of c-kit, stimulated the proliferation of ICCs from day-8 postcoitus embryos. SCF did not stimulate the proliferation of ICCs from day-6 postpartum neonates but SCF was needed for their survival. We have developed stromal cell lines originating from the small intestine of the mouse. The stromal cells transfected with c-kit complementary DNA showed the tendency to differentiate to ICCs. We are going to identify the molecules that can be targeted to induce differentiation.