Thyroid Follicular Cell Signaling and Development in Humans

项目摘要 甲状腺从前内胚层发育是发育的一个重要步骤，它允许 人类在子宫中12周左右甲状腺激素的产生。不幸的是，在大约4000名新生儿中 影响这一发育途径的基因突变会导致需要终生的先天性甲状腺功能减退症 甲状腺激素替代疗法。因此，更好地了解甲状腺滤泡细胞的发育可能 导致基因编辑和细胞疗法可以治疗先天性 甲减(CH)。我们在这一领域的工作利用了定向差异化方法，并确定了 骨形态发生蛋白和成纤维细胞生长因子是甲状腺滤泡细胞系的关键介质 跨物种的发展导致了功能正常的小鼠甲状腺滤泡细胞，可以拯救甲状腺机能亢进的小鼠。 在这项提案中，我们现在将我们的注意力完全转向人类甲状腺滤泡细胞的发育，并提出 允许功能性人甲状腺滤泡细胞临床前发展的三个具体目标 来源于人类诱导多能干细胞(IPSCs)，在第一个目标中，我们将利用一种新的谱系追踪 了解发育中的人甲状腺滤泡如何获得细胞命运的方法学，并确保 在iPSC中的过程与体内的过程相似。在第二个目标中，我们将证明人类甲状腺滤泡细胞 来源于ipscs的干细胞在体外完全能够产生甲状腺激素，并可以移植到 免疫缺陷的甲亢小鼠挽救他们的甲状腺功能减退症。最后，在第三个目标中，我们将演示Pre 临床上，来自CH患者的IPSCs可以通过基因纠正并通过移植重新引入 才能正常运作。这些目标的共同完成将提供对IPSC可能性的关键洞察 衍生细胞疗法治疗慢性脑出血，提高对内皮细胞发育的认识 人类体内的衍生组织。

Project Summary The development of the thyroid gland from anterior endoderm is an essential step in development that allows for the production of thyroid hormones around week 12 in utero in humans. Unfortunately, in about 1/4000 births genetic mutations that affect this development pathway lead to congenital hypothyroidism requiring lifelong thyroid hormone replacement therapy. Thus, a better understanding of thyroid follicular cell development could lead to a process where genetic editing and cellular therapy could provide treatment for congenital hypothyroidism (CH). Our work in this area has utilized a directed differentiation approach and has identified bone morphogenic protein and fibroblast growth factor as key mediators of thyroid follicular cell lineage development across species resulting in functional murine thyroid follicular cells that can rescue athyreotic mice. In this proposal, we now turn our attention exclusively to human thyroid follicular cell development and propose three Specific Aims that will allow for the pre-clinical development of functioning human thyroid follicular cells derived from human induced pluripotent stem cells (iPSCs), In the first Aim we will utilize a novel lineage tracing methodology to understand how developing human thyroid follicular acquire their cell fate and to ensure that the process in iPSC parallels that in vivo. In the second Aim we will prove that the human thyroid follicular cells derived from iPSCs are fully able to produce thyroid hormones in vitro and can be transplanted into immunodeficient athyreotic mice to rescue their hypothyroidism. Finally, in the third Aim we will demonstrate pre- clinically that derived iPSCs from a patient with CH can be genetically corrected and re-introduced via transplant to function normally. Together completion of these Aims will provide key insight into the possibilities of iPSC derived cellular therapy for the treatment of CH and enhance our understanding of the development endodermal- derived tissues in humans.