我校王军平教授和汤勇博士团队在《Theranostics》发表研究成果——巨核细胞来源的TGF-β1通过耦联骨生成和H型血管生成改善放射性骨骼损伤
发布人:zhangyilin 发布时间:10/20/2020 9:08:23 AM  浏览次数:1669次
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巨核细胞来源的TGF-β1通过耦联骨生成和H型血管生成改善放射性骨骼损伤

汤勇,王军平

 

骨是一种特殊的器官,由成骨细胞(OBs)和破骨细胞(OCs)维持动态平衡。在骨重塑过程中,OCs介导的骨吸收和OBs介导的骨形成通过内分泌和旁分泌途径促进其前体的迁移和分化。充足的血供可以运输OBs增殖和分化所必需的营养物质。因此,血管生成和骨形成的有机结合对骨代谢平衡至关重要。

放射性骨骼损伤是放疗常见的副作用,常导致病理性骨折等并发症。辐照诱导骨形成受损的机制非常复杂,涉及细胞周期阻滞、OBs分化减少和OBs凋亡增加。此外,照射还会导致血管内皮细胞减少,从而阻碍骨血供,加重骨损伤。目前尚无针对性辐射性骨质疏松症的治疗药物。

造血系统与骨骼系统有着密切的关系。巨核细胞是血小板前体细胞,可以通过分泌各种生长因子来调节骨代谢平衡。既往研究显示,缺乏GATA-1或NF-E2的小鼠,巨核细胞数量显著增加,伴有骨小梁数量和骨皮质厚度增加。然而,巨核细胞在稳态条件下和辐照后如何调节骨形成尚不清楚。

鉴于巨核细胞对机体骨代谢调控的重要影响,我们进一步深入研究了巨核细胞在放射性骨损伤救治中的作用。体外研究发现,一方面,巨核细胞能促进成骨细胞的增殖、分化,减轻辐照诱导的细胞凋亡;另一方面,巨核细胞促进了内皮祖细胞的分化和血管管腔形成。体内研究发现,巨核细胞数量减少会引起骨量和骨强度的减弱,CD31hiEmcnhi血管内皮细胞数量也同时减少。使用TPO或髓腔内注射升高巨核细胞,有效缓解了辐照诱导的骨损伤。深入研究发现,骨髓腔内TGF-β1主要来源于巨核细胞。巨核细胞来源的TGF-β1通过依赖Smad2/3的方式促进成骨祖细胞的增殖和分化,以及依赖Hif-1α/VEGF途径促进血管形成。

研究结果于2020年1月在权威杂志《Theranostics》(IF=8.579)上进行发表,这是本课题组首次发表关于巨核细胞功能研究的原创性成果。该研究进一步丰富了人们对巨核细胞在骨代谢中的独特调控作用,同时也为放射行骨损伤的救治提供了新的线索。

 

附:英文摘要

Megakaryocytes promote bone formation through coupling osteogenesis with angiogenesis by secreting TGF-β1

Yong Tang, Mengjia Hu, Yang Xu, Fang Chen, Shilei Chen, Mo Chen, Yan Qi, Mingqiang Shen, Cheng Wang, Yukai Lu, Zihao Zhang, Hao Zeng, Yong Quan, Fengchao Wang, Yongping Su, Dongfeng Zeng, Song Wang, Junping Wang.

Abstract

Rationale: The hematopoietic system and skeletal system have a close relationship, and megakaryocytes (MKs) may be involved in maintaining bone homeostasis. However, the exact role and underlying mechanism of MKs in bone formation during steady-state and stress conditions are still unclear.

 

Methods: We first evaluated the bone phenotype with MKs deficiency in bone marrow by using c-Mpl-deficient mice and MKs-conditionally deleted mice. Then, osteoblasts (OBs) proliferation and differentiation and CD31hiEmcnhi tube formation were assessed. The expression of growth factors related to bone formation in MKs was detected by RNA-sequencing and enzyme-linked immunosorbent assays (ELISAs). Mice with specific depletion of TGF-β1 in MKs were used to further verify the effect of MKs on osteogenesis and angiogenesis. Finally, MKs treatment of irradiation-induced bone injury was tested in a mouse model.

 

Results: We found that MKs deficiency significantly impaired bone formation. Further investigations revealed that MKs could promote OBs proliferation and differentiation, as well as CD31hiEmcnhi vessels formation, by secreting high levels of TGF-β1. Consistent with these findings, mice with specific depletion of TGF-β1 in MKs displayed significantly decreased bone mass and strength. Importantly, treatment with MKs or thrombopoietin (TPO) substantially attenuated radioactive bone injury in mice by directly or indirectly increasing the level of TGF-β1 in bone marrow. MKs-derived TGF-β1 was also involved in suppressing apoptosis and promoting DNA damage repair in OBs after irradiation exposure.

 

Conclusions: Our findings demonstrate that MKs contribute to bone formation through coupling osteogenesis with angiogenesis by secreting TGF-β1, which may offer a potential therapeutic strategy for the treatment of irradiation-induced osteoporosis.

Key words: megakaryocyte, bone formation, angiogenesis, irradiation, TGF-β1

 

全文链接:https://www.thno.org/v10p2229.htm

 


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