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诱导多能干细胞衍生甲状旁腺类器官类似于甲状旁腺的形态和功能。

Induced Pluripotent Stem Cell-Derived Parathyroid Organoids Resemble Parathyroid Morphology and Function.

机构信息

Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, İstanbul, 34755, Turkey.

Department of Veterinary Obstetrics and Gynecology, Faculty of Veterinary Medicine, University of Fırat, Elazığ, 23119, Turkey.

出版信息

Adv Sci (Weinh). 2024 Nov;11(43):e2407567. doi: 10.1002/advs.202407567. Epub 2024 Sep 27.

DOI:10.1002/advs.202407567
PMID:39331961
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11578294/
Abstract

The primary role of the parathyroid glands is to maintain calcium homeostasis through the secretion of parathyroid hormone (PTH). The limited proliferative capacity and differentiation of parathyroid cells hinder the generation of cell therapy options. In this study, parathyroid organoids are successfully generated from human-induced pluripotent stem cells (hiPSCs). At the end of the 20 days of differentiation, the parathyroid organoids exhibited distinct parathyroid morphology. Stereomicroscope, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) analysis demonstrated the 3D arrangement of the cell layers in which intracellular structures of parathyroid cells resemble human parathyroid cellular morphology. Comprehensive molecular analyses, including RNA sequencing (RNA-Seq) and liquid chromatography/mass spectrometry (LC-MS/MS), confirmed the expression of key parathyroid-related markers. Protein expression of CasR, CxCr4, Gcm2, and PTH are observed in parathyroid organoids. Parathyroid organoids secrete PTH, demonstrate active intercellular calcium signaling, and induce osteogenic differentiation via their secretome. The tissue integration potential of parathyroid organoids is determined by transplantation into parathyroidectomized rats. The organoid transplanted animals showed significant elevations in PTH-related markers (CasR, CxCr4, Foxn1, Gcm2, and PTH). PTH secretion is detected in organoid-transplanted animals. The findings represent a significant advancement in parathyroid organoid culture and may offer a cellular therapy for treating PTH-related diseases, including hypoparathyroidism.

摘要

甲状旁腺的主要作用是通过分泌甲状旁腺激素 (PTH) 来维持钙稳态。甲状旁腺细胞的增殖能力有限，分化能力差，这阻碍了细胞治疗方案的产生。在这项研究中，成功地从人诱导多能干细胞 (hiPSC) 中生成了甲状旁腺类器官。在分化的第 20 天结束时，甲状旁腺类器官表现出明显的甲状旁腺形态。体视显微镜、扫描电子显微镜 (SEM) 和透射电子显微镜 (TEM) 分析表明，细胞层呈 3D 排列，其中甲状旁腺细胞的细胞内结构类似于人甲状旁腺细胞形态。全面的分子分析，包括 RNA 测序 (RNA-Seq) 和液相色谱/质谱 (LC-MS/MS)，证实了关键的甲状旁腺相关标志物的表达。在甲状旁腺类器官中观察到 CasR、CxCr4、Gcm2 和 PTH 的蛋白表达。甲状旁腺类器官分泌 PTH，表现出活跃的细胞间钙信号，并通过其分泌组诱导成骨细胞分化。甲状旁腺类器官的组织整合潜力通过移植到甲状旁腺切除大鼠中来确定。类器官移植动物的 CasR、CxCr4、Foxn1、Gcm2 和 PTH 等与 PTH 相关的标志物显著升高。在类器官移植动物中检测到 PTH 的分泌。这些发现代表了甲状旁腺类器官培养的重大进展，可能为治疗包括甲状旁腺功能减退症在内的与 PTH 相关的疾病提供细胞治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b60d/11578294/80a483907df2/ADVS-11-2407567-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b60d/11578294/23f50d6fbbf2/ADVS-11-2407567-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b60d/11578294/365bbbd4f8e4/ADVS-11-2407567-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b60d/11578294/92697a9305d8/ADVS-11-2407567-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b60d/11578294/930ca461c94b/ADVS-11-2407567-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b60d/11578294/b1f363c898ef/ADVS-11-2407567-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b60d/11578294/80a483907df2/ADVS-11-2407567-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b60d/11578294/23f50d6fbbf2/ADVS-11-2407567-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b60d/11578294/365bbbd4f8e4/ADVS-11-2407567-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b60d/11578294/92697a9305d8/ADVS-11-2407567-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b60d/11578294/930ca461c94b/ADVS-11-2407567-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b60d/11578294/b1f363c898ef/ADVS-11-2407567-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b60d/11578294/80a483907df2/ADVS-11-2407567-g006.jpg

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