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重要步骤， 人类在子宫内12周左右产生甲状腺激素。不幸的是，在大约1/4000的新生儿中 影响这一发育途径的基因突变导致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， 导致基因编辑和细胞疗法可以为先天性 甲状腺功能减退症（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作为甲状腺滤泡细胞谱系的关键介质 跨物种的发育，导致功能性鼠甲状腺滤泡细胞，可以拯救甲状腺功能不全的小鼠。 在这个建议中，我们现在把我们的注意力完全转向人类甲状腺滤泡细胞的发育，并建议 三个特定目标，将允许临床前开发功能性人类甲状腺滤泡细胞 来源于人诱导多能干细胞（iPSC），在第一个目的中，我们将利用一种新的谱系追踪方法， 方法来了解如何发展人类甲状腺滤泡获得他们的细胞命运，并确保 在iPSC中的过程与在体内的过程平行。在第二个目的中，我们将证明人甲状腺滤泡细胞 来自iPSC的细胞完全能够在体外产生甲状腺激素，并且可以移植到 免疫缺陷型甲状腺功能不全小鼠来挽救它们的甲状腺功能减退症。最后，在第三个目标中，我们将演示预- 在临床上，来自CH患者的iPSC可以通过移植进行遗传校正和重新引入， 才能正常工作这些目标的共同完成将为iPSC的可能性提供关键的见解 衍生的细胞疗法治疗CH，并提高我们对发展内胚层- 人类的衍生组织。

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.