长脉冲胃电刺激促进Cajal间质细胞修复的机制研究

Gastrointestinal motility disorders were related with lack of or serious injury of ICC in the gastrointestinal tract. Gastric electrical stimulation (GES), as a potential treatment method of gastric motility disorders, was increasingly being taken seriously. Long pulse GES could recover the dysrhythmia of the gastric slow waves and improve the delayed gastric emptying, but its specific mechanism was not clear. Our previous study for the first time found that GES could repair injured ICC through the transformation of the ICC phenotype(NSFC，30670775). Recent studies had found that the repair of ICC could be achieved by promoting the development of the ICC precursor cell and increasing the survival and proliferation of mature ICC in addition to the transformation of the ICC phenotype. Our study, with diabetic gastroparesis rat as a model, will explore whether GES repair injured ICC through the complement of the ICC precursor cells or promoting survival and proliferation of ICC. Furthermore, we will research whether GES promote the repair of ICC by affecting the SCF/Kit, Insulin/IGF-I pathway and regulating related factors for survival and proliferation of ICC, and seek the best GES parameters.Further study on the mechanisms of GES promoting the repair of the ICC is needed, to provide a new theoretical basis for the GES treatment of gastric motility disorders.

胃肠动力障碍性疾病与胃肠道ICC缺失或严重损伤有关。胃电刺激（GES）作为一种非常有潜力的治疗胃动力障碍性疾病的方法越来越受到重视，长脉冲GES可恢复紊乱的胃慢波电节律及改善延迟的胃排空，但具体机制不明确。我们前期研究首次从ICC表型转化角度发现GES对损伤的ICC有修复作用（NSFC，30670775）。近期研究发现，除ICC表型转化外，ICC修复可通过促进ICC前体细胞发展，增加成熟ICC存活和增殖途径而达到，因此GES修复ICC的机制需进一步深入研究。本研究以糖尿病胃轻瘫大鼠为模型，探讨GES是否通过ICC前体细胞补充或促进ICC存活和增殖修复损伤的ICC；进一步研究GES能否通过影响SCF/Kit、Insulin/IGF-I通路及调节ICC生存增殖的相关因子而促进ICC修复；并寻求最佳GES参数。深入研究GES促进ICC修复的机制，为GES治疗胃动力障碍疾病提供新的理论依据。

Cajal间质细胞（interstitial cells of Cajal, ICC）是一类起源于间充质干细胞的特殊细胞，以网络状结构分布于胃肠神经末梢和平滑肌细胞之间。目前已经证实，ICC是胃肠道起搏细胞，具有产生、传播慢波的功能。大量的国内外研究认为许多胃肠动力紊乱疾病如糖尿病胃轻瘫、特发性胃轻瘫、慢传输型便秘等与胃肠道ICC网络缺失或严重损伤有关。近年来，胃电刺激（gastric electrical stimulation, GES）作为一种有潜力的治疗胃动力障碍性疾病的方法受到人们的关注。然而，其具体机制还不明确。本研究就不同参数的胃电刺激（GES1：5.5cpm, 100ms, 4mA; GES2：5.5cpm, 300ms, 4mA; GES3：5.5cpm, 550ms, 2mA）是否可以促进糖尿病胃轻瘫大鼠模型ICC网络修复进行研究，检测胃电刺激对ICC及影响ICC生存相关细胞和分子的影响。我们发现（1）与正常组相比，糖尿病组大鼠胃功能明显降低，但胃电刺激组较糖尿病组明显改善（2）ICC在超微结构在糖尿病组损伤明显和c-Kit标记蛋白的表达也显著降低，而胃电刺激组较糖尿病组两者均有明显改善；（3）SCF/c-Kit信号的表达在糖尿病组显著降低，在GES组未见明显改变；（4）同糖尿病组相比，胃电刺激组可见显著增多的c-Kit+/Ki67+增值细胞；（5）与糖尿病组相比，在胃电刺激组可见明显增多的α-SMA+/IGF-1R+细胞和IGF-1的表达水平；（6）在糖尿病组，可促进ICC生存的nNOS和5-HT2B的表达明显降低，而胃电刺激组较糖尿病组有显著升高。因此，我们推测长脉冲胃电刺激可以改善糖尿病大鼠延迟的胃排空和损伤的肌肉收缩，可能与GES促进胃组织中ICC再生相关。GES影响ICC的重塑机制可能与GES促进SCF/c-Kit信号、IGF-1信号及促使ICC生存的分子表达相关。这些结果提示GES具有促进糖尿病胃组织ICC生存的相关蛋白表达，维持ICC完整结构，进而可以改善糖尿病患者胃功能，这将为未来临床治疗糖尿病胃轻瘫非药物途径提供了可能。