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Abstract：
BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by a gain-of-function mutation in ACVR1, which is a bone morphogenetic protein (BMP) type I receptor. Moreover, it causes progressive heterotopic ossification (HO) in connective tissues. Using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) and mouse models, we elucidated the underlying mechanisms of FOP pathogenesis and identified a candidate drug for FOP.
METHODS: In the current study, healthy mesenchymal stem/stromal cells derived from iPSCs (iMSCs) expressing ACVR2B-Fc (iMSCACVR2B-Fc), which is a neutralizing receptobody, were constructed. Furthermore, patient-derived iMSCs and FOP mouse model (ACVR1R206H, female) were used to confirm the inhibitory function of ACVR2B-Fc fusion protein secreted by iMSCACVR2B-Fc on BMP signaling pathways and HO development, respectively.
RESULTS: We found that secreted ACVR2B-Fc attenuated BMP signaling initiated by Activin-A and BMP-9 in both iMSCs and FOP-iMSCs in vitro. Transplantation of ACVR2B-Fc-expressing iMSCs reduced primary HO in a transgenic mouse model of FOP. Notably, a local injection of ACVR2B-Fc-expressing iMSCs and not an intraperitoneal injection improved the treadmill performance, suggesting compound effects of ACVR2B-Fc and iMSCs.
CONCLUSIONS: These results offer a new perspective for treating FOP through stem cell therapy.
METHODS: In the current study, healthy mesenchymal stem/stromal cells derived from iPSCs (iMSCs) expressing ACVR2B-Fc (iMSCACVR2B-Fc), which is a neutralizing receptobody, were constructed. Furthermore, patient-derived iMSCs and FOP mouse model (ACVR1R206H, female) were used to confirm the inhibitory function of ACVR2B-Fc fusion protein secreted by iMSCACVR2B-Fc on BMP signaling pathways and HO development, respectively.
RESULTS: We found that secreted ACVR2B-Fc attenuated BMP signaling initiated by Activin-A and BMP-9 in both iMSCs and FOP-iMSCs in vitro. Transplantation of ACVR2B-Fc-expressing iMSCs reduced primary HO in a transgenic mouse model of FOP. Notably, a local injection of ACVR2B-Fc-expressing iMSCs and not an intraperitoneal injection improved the treadmill performance, suggesting compound effects of ACVR2B-Fc and iMSCs.
CONCLUSIONS: These results offer a new perspective for treating FOP through stem cell therapy.
摘要：
背景：进行性骨化性纤维异型增生（FOP）是一种罕见的遗传性疾病，由ACVR1的功能获得突变引起，ACVR1是一种骨形态发生蛋白（BMP）I型受体。此外，在结缔组织中引起进行性异位骨化(HO)。使用FOP患者来源的诱导多能干细胞（FOP-iPSCs）和小鼠模型，我们阐明了FOP发病的潜在机制,并确定了FOP的候选药物.
方法：在目前的研究中，源自表达ACVR2B-Fc（iMSCACVR2B-Fc）的iPSCs（iMSCs）的健康间充质干细胞/基质细胞，这是一个中和的接受体，是建造的。此外，患者来源的iMSCs和FOP小鼠模型(ACVR1R206H，雌性）用于证实iMSCACVR2B-Fc分泌的ACVR2B-Fc融合蛋白对BMP信号通路和HO发育的抑制功能，分别。
结果:我们发现分泌的ACVR2B-Fc在体外减弱iMSC和FOP-iMSC中由激活素A和BMP-9引发的BMP信号传导。表达ACVR2B-Fc的iMSC的移植减少了FOP的转基因小鼠模型中的原代HO。值得注意的是,局部注射表达ACVR2B-Fc的iMSC而不是腹膜内注射改善了跑步机性能，提示ACVR2B-Fc和iMSC的复合作用。
结论：这些结果为通过干细胞疗法治疗FOP提供了新的视角。
方法：在目前的研究中，源自表达ACVR2B-Fc（iMSCACVR2B-Fc）的iPSCs（iMSCs）的健康间充质干细胞/基质细胞，这是一个中和的接受体，是建造的。此外，患者来源的iMSCs和FOP小鼠模型(ACVR1R206H，雌性）用于证实iMSCACVR2B-Fc分泌的ACVR2B-Fc融合蛋白对BMP信号通路和HO发育的抑制功能，分别。
结果:我们发现分泌的ACVR2B-Fc在体外减弱iMSC和FOP-iMSC中由激活素A和BMP-9引发的BMP信号传导。表达ACVR2B-Fc的iMSC的移植减少了FOP的转基因小鼠模型中的原代HO。值得注意的是,局部注射表达ACVR2B-Fc的iMSC而不是腹膜内注射改善了跑步机性能，提示ACVR2B-Fc和iMSC的复合作用。
结论：这些结果为通过干细胞疗法治疗FOP提供了新的视角。
