Bone morphogenetic protein 4 inhibits rat stem/progenitor Leydig cell development and regeneration via SMAD-dependent and SMAD-independent signaling.
Bone morphogenetic protein 4 inhibits rat stem/progenitor Leydig cell development and regeneration via SMAD-dependent and SMAD-independent signaling.
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DOI：
10.1038/s41419-022-05471-8
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发表时间：
2022-12-13
影响因子：
9
通讯作者：
Ge, Ren-Shan
中科院分区：
文献类型：
--
作者：
Li, Xiaoheng;Fang, Yinghui;Chen, Lanlan;Quan, Hehua;Wang, Yiyan;Ge, Ren-Shan
骨形态发生蛋白4（BMP 4）是转化生长因子β超家族的重要成员。BMP 4在Leydig细胞谱系中表达。我们推测BMP 4可能调控间质干/祖细胞的发育。发现BMP 4受体BMPR 1A、BMPR 1B和BMPR 2在青春期前睾丸的前体Leydig细胞和分离的细胞中表达。1和10 ng/mL的BMP 4在24 h处理时显著降低雄激素产生并下调类固醇生成相关基因和蛋白表达，这可能是通过激活SMAD信号通路（增加SMAD 1/5磷酸化和SMAD 4）实现的。0.1 ng/mL及更高浓度的BMP 4在处理24 h后显著降低了CD 90+干Leydig细胞的EdU标记指数，并在培养7天后显著降低了曲细精管表面上EdU+干Leydig细胞的数量。0.01 ng/mL及更高浓度的BMP 4显著阻断干Leydig细胞向成体细胞的分化，如通过3D曲细精管培养3周后睾酮分泌减少和Lhcgr、Scarb 1、Cyp 11 a1、Hsd 11b 1和Insl 3及其功能的下调所示，并且这种效应通过与BMP 4拮抗剂noggin和doxomorphine的共同处理而逆转。此外，BMP 4还通过SMAD非依赖性信号通路（ERK 1/2和AMPK）阻断干Leydig细胞分化。乙二甲烷磺酸盐（EDS）单次注射可导致睾酮降低，治疗后可恢复。在EDS治疗后Leydig细胞再生的体内模型中，从消除后第14天至第28天睾丸内注射BMP 4显著降低血清睾酮水平，并下调Scarb 1、星星、Hsd 11 b1和Insl 3及其蛋白的表达，这可能是通过SMAD依赖性和SMAD非依赖性（ERK 1/2和AMPK）信号通路实现的。总之，BMP 4在Leydig细胞谱系的细胞中表达，并通过SMAD依赖性和SMAD非依赖性信号通路阻断干/祖Leydig细胞进入成年Leydig细胞。
Bone morphogenetic protein 4 (BMP4) is an important member of the transforming growth factor-β superfamily. BMP4 is expressed in the Leydig cell lineage. We hypothesized that BMP4 might regulate the development of stem/progenitor Leydig cells. The BMP4 receptors, BMPR1A, BMPR1B, and BMPR2 were found to be expressed in progenitor Leydig cells of prepubertal testis and isolated cells. BMP4 at 1 and 10 ng/mL significantly reduced androgen production and down-regulated steroidogenesis-related gene and protein expression possibly by activating the SMAD signaling pathway (increasing SMAD1/5 phosphorylation and SMAD4) at 24 h treatment. BMP4 at 0.1 ng/mL and higher concentrations markedly reduced the EdU labeling index of CD90+ stem Leydig cells after 24 h treatment and significantly reduced the number of EdU+ stem Leydig cells on the surface of seminiferous tubules after 7 days of culture. BMP4 at 0.01 ng/mL and higher concentrations significantly blocked the differentiation of stem Leydig cells into adult cells, as shown by the reduction of testosterone secretion and the downregulation of Lhcgr, Scarb1, Cyp11a1, Hsd11b1, and Insl3 and their function after 3D seminiferous tubule culture for 3 weeks, and this effect was reversed by co-treatment with the BMP4 antagonists noggin and doxomorphine. In addition, BMP4 also blocked stem Leydig cell differentiation through SMAD-independent signaling pathways (ERK1/2 and AMPK). Ethanedimethane sulfonate (EDS) single injection can result in reduction of testosterone, restoration can happen post treatment. In an in vivo model of Leydig cell regeneration following EDS treatment, intratesticular injection of BMP4 from day 14 to day 28 post-elimination significantly reduced serum testosterone levels and down-regulated the expression of Scarb1, Star, Hsd11b1, and Insl3 and its proteins, possibly through SMAD-dependent and SMAD-independent (ERK1/2 and AMPK) signaling pathways. In conclusion, BMP4 is expressed in cells of the Leydig cell lineage and blocks entry of stem/progenitor Leydig cells into adult Leydig cells through SMAD-dependent and SMAD-independent signaling pathways.
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影响因子：
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作者：
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DOI：
10.1083/jcb.200409107
发表时间：
2004-12-06
期刊：
The Journal of cell biology
影响因子：
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通讯作者：
Podestá EJ