Generation of functional adrenocortical organoids from mice and humans and their preclinical testing as cell-based therapy for adrenal insufficiency

肾上腺是内分泌系统的一部分，它们的功能是向血液系统释放激素。每个肾上腺由两个不同的部分组成，外皮质和内髓质。肾上腺皮质对生命是必不可少的，因为它产生类固醇激素：糖皮质激素(如皮质醇)调节身体新陈代谢，帮助我们对抗感染，而盐皮质激素(如醛固酮)主要影响血压。肾上腺皮质紊乱会导致肾上腺分泌过多或不足的激素；当糖皮质激素，有时是盐皮质激素不能产生足够量时，就会发生肾上腺功能不全。肾上腺功能不全可由肾上腺功能、自身免疫性疾病或腺体结核感染所必需的基因突变引起；最近，也有报道称，SARS-CoV-2(新冠肺炎冠状病毒病的病原体)可感染肾上腺，在某些患者中导致肾上腺功能不全。肾上腺功能不全的治疗是用药物来替代丢失的激素，患者必须在他们的余生中服用这些药物。这些治疗方法远非完美，对于专科医生和患者来说，患者的整体管理都可能非常具有挑战性；例如，患者可能会出现突然的严重症状，尤其是由于疾病、发烧、手术或脱水而产生的压力，因此必须始终携带医疗警告卡或标签，以确保快速治疗，以防止休克、癫痫或昏迷。科学家们正在努力为肾上腺功能不全患者开发新的治疗方法，在基因和细胞治疗领域已经取得了重要的临床前步骤。我们的实验室对肾上腺的生物学有着长期的兴趣，最近，通过一项开创性的研究，我们能够从先天性肾上腺疾病患者的尿液中提取细胞来生成功能性肾上腺细胞。这个项目的总体目标是首次建立肾上腺类器官：这些是在培养皿中产生的微型器官，它们保留了产生它们的组织的生理功能，因此可以被认为是起源组织的化身，在这种情况下是肾上腺皮质。该项目将使我们能够全面描述小鼠和人类的肾上腺有机化合物，无论男女，都是从年轻和年长的捐赠者那里建立的。至关重要的是，当功能长期保持时，有机类化合物可能会被用来取代患者不起作用的腺体；为了测试这一点，我们将使用一个适当的临床前模型，即一个基因已经被移除的小鼠，并非常准确地概括了罕见的遗传性疾病先天性肾上腺增生。这个模型是由我们在英国爱丁堡大学的合作者创建并描述的。在这里，器官类物质将被移植到肾脏的外部，我们将评估先天性肾上腺增生症(糖皮质激素和盐皮质激素缺乏)的基本特征是否可以逆转。我们相信，这个项目将在未来5-10年内加速将前景看好的BASE研究转化为患者。

The adrenal glands are part of the endocrine system, and their function is to release hormones into the blood system. Each adrenal gland is composed of two distinct parts, an outer cortex and an inner medulla. The adrenal cortex is essential for life as it produces steroid hormones: glucocorticoids (such as cortisol) regulate body metabolism and help us fight infections, and mineralocorticoids (such as aldosterone) mainly affect blood pressure. Adrenal cortex disorders can cause our adrenal glands to produce too much or not enough hormones; adrenal insufficiency occurs when glucocorticoids, and sometimes mineralocorticoids, cannot be generated in sufficient amounts. Adrenal insufficiency can be caused by mutations in genes essential for adrenal function, autoimmune disease, or tuberculosis infection of the glands; more recently, it has also been reported that SARS-CoV-2 (the causative agent for Coronavirus disease COVID-19) can infect the adrenal glands and cause adrenal insufficiency in some patients. Adrenal insufficiency is treated with medication to replace the missing hormones, and patients must take these medications for the rest of their life. These treatments are far from perfect, and the overall management of patients can be very challenging for specialists and patients alike; for example, patients may have sudden severe symptoms, especially when stressed as a result of an illness, fever, surgery, or dehydration and therefore must always carry a medical alert card or tag in order to ensure rapid treatment to prevent shock, seizure, or coma. Scientists are striving to develop novel curative treatments for patients with adrenal insufficiency, and important pre-clinical steps have been achieved in the field of gene- and cell-based therapies. Our laboratory has a long-lasting interest in the biology of the adrenal gland and recently, with a ground-breaking study, we have been able to generate functional adrenal cells starting from cells extracted from urine of patients with inborn adrenal disorders. The overall goal of this project is to establish, for the first time, adrenal organoids: these are mini organs generated in a dish, that retain the physiological function of the tissue they are generated from, and hence, can be considered 'avatars' of the tissue of origin, the adrenal cortex in this case. This project would allow us to fully characterise adrenal organoids in mice and humans, in both sexes and established from young and older donors. Crucially, when function is retained long-term, organoids could potentially be used to replace the patients' non-functioning gland; to test this, we will use an appropriate pre-clinical model, namely mice where a gene has been removed and recapitulating quite accurately the rare genetic disorder Congenital Adrenal Hyperplasia. This model has been generated and characterised by our collaborators at the University of Edinburgh, UK. Here, organoids will be transplanted in the external part of the kidneys, and we will assess whether the cardinal features of the Congenital Adrenal Hyperplasia (deficiency in glucocorticoids and mineralocorticoids) can be reversed. We believe this project will accelerate the translation of promising bench research to the patient over the next 5-10 years.