In vitro bone-like nodules generated from patient-derived iPSCs recapitulate pathological bone phenotypes
In vitro bone-like nodules generated from patient-derived iPSCs recapitulate pathological bone phenotypes
复制标题
DOI：
10.1038/s41551-019-0410-7
复制
发表时间：
2019-07-01
影响因子：
28.1
通讯作者：
Toguchida, Junya
中科院分区：
文献类型：
--
作者：
Kawai, Shunsuke;Yoshitomi, Hiroyuki;Toguchida, Junya
通过体外生成骨样结节来重现骨形成通常用于了解骨发育。然而，目前的骨诱导技术速度缓慢且难以重现。在这里，我们报告了通过使用视黄酸（RA）诱导人类诱导多能干细胞（hiPSC）成骨分化为成骨细胞样和骨细胞样细胞，在植入小鼠颅骨缺损时形成人类骨组织，在十天内形成了骨样结节。我们还表明，骨形成的诱导取决于通过 RA 受体 RAR α 和 RAR β 的细胞信号传导，它们同时激活 BMP（骨形态发生蛋白）和 Wnt 信号传导途径。此外，通过使用患者来源的 hiPSC，骨样结节重现了成骨不完美表型，这种表型可以通过纠正致病突变以及部分通过 mTOR（雷帕霉素的机械靶标）抑制剂来挽救。诱导骨结节的方法可以作为研究健康骨和病理骨形成的快速且可重复的模型。
The recapitulation of bone formation via the in vitro generation of bone-like nodules is frequently used to understand bone development. However, current bone-induction techniques are slow and difficult to reproduce. Here, we report the formation of bone-like nodules within ten days, via the use of retinoic acid (RA) to induce the osteogenic differentiation of human induced pluripotent stem cells (hiPSCs) into osteoblast-like and osteocyte-like cells that create human bone tissue when implanted in calvarial defects in mice. We also show that the induction of bone formation depends on cell signalling through the RA receptors RAR alpha and RAR beta, which simultaneously activate the BMP (bone morphogenetic protein) and Wnt signalling pathways. Moreover, by using patient-derived hiPSCs, the bone-like nodules recapitulated the osteogenesis-imperfecta phenotype, which was rescued via the correction of disease-causing mutations and partially by an mTOR (mechanistic target of rapamycin) inhibitor. The method of inducing bone nodules may serve as a fast and reproducible model for the study of the formation of both healthy and pathological bone.