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患者由来iPS細胞を用いた進行性骨化性線維異形成症における異所性骨化形成の解析

使用患者来源的 iPS 细胞分析进行性骨化性纤维发育不良的异位骨化

基本信息

批准号：
20J23707
负责人：
孫麗萍
金额：
$ 1.6万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for JSPS Fellows
财政年份：
2020
资助国家：
日本
起止时间：
2020-04-24 至 2023-03-31
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-20J23707/
关键词：
FOP Heterotopic Ossification Energy Metabolism OXPHOS FAPs Heterotopic ossification Energy metabolism mTOR signaling

项目摘要

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by the mutation of ACVR1, which was symptomized by heterotopic ossification (HO) in soft tissues via endochondral ossification. Utilizing FOP patient-specific iPSCs, Activin A was identified as an evocator of HO by activating mTORC1 in our previous study. However, how the activated mTORC1 induces aberrant chondrogenesis is still unknown. According to the reported study, mTORC1 plays a special role in nutrient and growth factor response as well as stress to metabolic processes. Mitochondrial biogenesis is activated by mTORC1, which leads to upregulation of energy production by OXPHOS. Here we discussed that energy metabolism during aberrant chondrogenesis of FOP-iMSCs was studied to explore a new therapeutic strategy for FOP disease. In summary, we identified Activin A-induced chondrogenesis required OXPHOS as a major energy source and therefore the inhibition of OXPHOS could suppress chondrogenesis in vitro.　And utilizing FOP-ACVR1 mice, we demonstrated mitochondrial biogenesis was strongly activated during chondrogenesis of fibro/adipogenic precursors (FAPs), a small population of muscle-resident progenitors, reported as the cells of origin of pathological cartilage formation in soft tissue. Importantly, we also identified the inhibition of OXPHOS can suppress FAPs-derived chondrocyte differentiation in vivo. All these findings revealed the features of mitochondrial biogenesis and OXPHOS activity during the formation of heterotopic cartilage and will provide a novel perspective on FOP therapy.

进行性骨化纤维发育不良（FOP）是一种罕见的由ACVR1基因突变引起的遗传病，其症状表现为软骨内成骨导致软组织异位骨化（HO）。在我们之前的研究中，利用FOP患者特异性的iPSCs，激活素A通过激活mTORC1被鉴定为HO的促因子。然而，活化的mTORC1如何诱导异常软骨形成仍是未知的。根据报道的研究，mTORC1在营养和生长因子反应以及应激代谢过程中起特殊作用。线粒体生物发生由mTORC1激活，从而导致OXPHOS能量产生的上调。在这里，我们讨论了在FOP- imscs异常软骨形成过程中的能量代谢，以探索一种新的治疗FOP疾病的策略。综上所述，我们发现激活素a诱导的软骨形成需要OXPHOS作为主要的能量来源，因此抑制OXPHOS可以在体外抑制软骨形成。利用FOP-ACVR1小鼠，我们证明了线粒体生物发生在纤维/脂肪生成前体细胞（FAPs）的软骨形成过程中被强烈激活，FAPs是一小群肌肉祖细胞，据报道是软组织病理软骨形成的起源细胞。重要的是，我们还发现抑制OXPHOS可以抑制体内faps衍生的软骨细胞分化。这些发现揭示了异位软骨形成过程中线粒体生物发生和OXPHOS活性的特征，并将为FOP治疗提供新的视角。