Establishment of the novel and basic technique for inducing human ES cells to differentiate into connective tissue-type mast cells and their utilization in clinical practice

在人类中，肥大细胞(MC)在先天免疫中发挥核心作用，并作为过敏反应的细胞介质发挥作用。在婴儿期，天然免疫系统的建立在很大程度上是基于对新抗原的接触和识别。由于MC通常位于具有战略意义的身体屏障上，如皮肤、血管和粘膜组织，它们是婴儿发育免疫中的第一个反应物之一。然而，大多数MC数据仅来自于小鼠和大鼠的实验。人类MC数据非常有限。人类MC研究的一个特殊问题是难以获得用于体外研究的人类材料。如上所述，我已经建立了从非人类灵长类ES细胞中产生功能性MC的方法。最近，在JSPS的资助下，我们成功地建立了一种类似的方法来从hESCs中获得定量的功能成熟的肥大细胞，为人类MC的发育及其功能的研究提供了多种可能性。在本研究中，我发现hESC来源的MC的发育可能有两条途径：在诱导的最初阶段，他们首先形成同时表达糜乳酶和类胰蛋白酶的CT-MC，然后在相对较晚的阶段从多潜能的造血祖细胞分化为M-MC。这与我们在猴子胚胎干细胞来源的MC发育中发现的非常相似，这表明在人类和非人类灵长类动物中，早期胚胎/胎儿阶段MC发育的独特途径是常见的。这也为研究人巨噬细胞介导的婴儿先天免疫系统的首次建立提供了良好的模型。我们的发现是迄今为止世界上第一个人类/非人类灵长类ES来源的功能性MC的报道，应该会开辟MC发育的一个新的研究领域。

In human being, mast cells (MC) play a central role in innate immune and function as cellular mediators of allergy. During infancy, the establishment of innate immuno-system is largely based on the encountering and recognizing of new antigens. Since MCs are typically located at strategically important body barriers, such as skin, vascular and mucosal tissues, they are one of the first reactors in the developmental immunes in infants. However, most of MC data derive solely from experiments in mice and rats. Human MC data are very limited. A particular problem of human MC research is the difficulty in obtaining human material for in vitro studies.I have already established method to generate fuctional MCs from non-human primate ES cells, as reported above. More recently, by the financial supporting from JSPS, we have successfully established a similar method to produce quantitative functionally mature mast cells from hESCs, providing a large variety of possibilities in research on human MC development and their functions. In the present study, I found hESC-derived MC development might be along to two pathpawys : At primary time of induction, they first develop CT-MC that both express chymase and tryptase, and then from multipotential hematopoietic progenitor cells at a comparatively later stage they develop M-MC. This is quite similar to what we have found in monkey ESC-derived MC development, suggesting a unique pathway of MC development during early embryonic/fetal stages is common in human and non-human primates. It also offers a good model to investigate the first establishment of innate immune system mediated by human MCs in infants. Our finding is so far the first report of human/non-human primate ES derived functional MCs in the world, and should open a new research field on MC development.