Human enteric nervous system progenitor dynamics during development and disease

肠道的正常功能是由一个复杂的神经网络控制的，即肠神经系统（ENS），也被称为“第二大脑”。ENS是在子宫内由称为ENS祖细胞和雪旺细胞前体（scp）的特殊细胞群产生的。这些祖先在产生ENS时的错误，通常是由于我们的DNA缺陷（突变），导致出生时出现肠道神经病变，其特征是肠道中缺乏神经。最常见的肠道神经病变是先天性巨结肠病，这是一种危及生命的肠道疾病，大约每5000名新生儿中就有1名受到影响。巨结肠疾病中肠神经的缺乏通常是由RET基因突变引起的，RET基因对ENS祖细胞的正常功能很重要。引人注目的是，RET突变似乎不影响SCPs，这是ENS细胞的另一个补充来源。因此，为了更好地了解HSCR的病因，研究ENS祖细胞/ scp如何产生肠神经以及RET突变如何影响这一过程是很重要的。为了解决这一问题，我们建议使用人类干细胞产生健康的和ret突变的ENS祖细胞和scp，并在培养皿中培养。然后，我们将详细研究ret突变细胞群注射到从人类患者和小鼠分离的肠道组织中并在培养皿中生长后的行为。对突变细胞和健康细胞的比较将有助于我们了解巨结肠疾病的问题所在，并最终有助于开发针对这种毁灭性儿童疾病的治疗方法。

The proper function of our gut is controlled, in an involuntary fashion, by a complex network of nerves, the enteric nervous system (ENS), also known as the 'second brain'. The ENS is produced in utero by specialised cell populations known as ENS progenitors and Schwann cell precursors (SCPs). Mistakes in the generation of the ENS by these progenitors, often due to defects in our DNA (mutations), lead to birth conditions called enteric neuropathies that are marked by lack of nerves in the gut. The most common enteric neuropathy is Hirschsprung disease, which is a life-threatening intestinal disorder affecting approximately 1 in 5,000 newborn children. The lack of enteric nerves in Hirschsprung disease is usually caused by mutations in a gene called RET, which is important for the proper function of ENS progenitors. Strikingly, RET mutations do not seem to affect SCPs, the other complementary source of ENS cells. To better understand the causes of HSCR, it is therefore important to examine how ENS progenitors/SCPs produce enteric nerves and how RET mutations affect this process. To address this issue, we propose to use human stem cells to generate healthy and RET-mutant ENS progenitors and SCPs, and kept in culture in a petri dish. We will then study in detail the behaviour of the RET-mutant cell populations after their injection in gut tissue isolated from human patients and mice, and grown in the petri dish. Comparison of mutant and healthy cells will help us understand what goes wrong in Hirschsprung disease and will ultimately assist the development of therapies against this devastating childhood disease.