VEGFA Family Isoforms Regulate Spermatogonial Stem Cell Homeostasis in Vivo
VEGFA Family Isoforms Regulate Spermatogonial Stem Cell Homeostasis in Vivo
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DOI：
10.1210/en.2011-1323
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发表时间：
2012-02-01
期刊：
影响因子：
4.8
通讯作者：
McLean, Derek J.
中科院分区：
文献类型：
--
作者：
Caires, Kyle C.;de Avila, Jeanene M.;McLean, Derek J.
本研究的目的是探讨血管内皮生长因子A（VEGFA）亚型在体内精原干细胞（SSC）命运决定中的调控作用。出生后1-180天睾丸发育过程中VEGF亚型、受体和辅助受体的表达模式和细胞特异性分布表明VEGF调节早期生殖细胞稳态的非血管功能。出生后不久出现的未分化精原细胞的人群VEGF受体激活呈阳性，免疫组化分析表明。因此，我们假设VEGF的促血管生成亚型（VEGFA（164））刺激SSC自我更新，而VEGF的抗血管生成亚型（VEGFA（165）B）诱导SSC分化。为了检验这一假设，我们使用移植来测定从出生后第3-5天每天用1）媒介物、2）VEGFA（164）、3）VEGFA（165）B、4）IgG对照、5）抗VEGFA（164）和6）抗VEGFA（165）B处理的新生小鼠获得的SSC的干细胞活性。SSC移植分析表明，VEGFA（164）支持自我更新，而VEGFA（165）B刺激小鼠SSC体内分化。SSC相关因子的基因表达分析和生殖细胞群的形态测定分析证实了治疗对调节SSC生物活性的影响。这些发现表明VEGF在睾丸发育中的非血管作用，并表明VEGFA（164）和VEGFA（165）B亚型之间的微妙平衡协调了SSC的细胞命运决定。未来的体内和体外实验将集中于阐明VEGFA亚型调节SSC稳态的机制。（内分泌学153：887-900，2012）
The objective of the present study was to investigate vascular endothelial growth factor A (VEGFA) isoform regulation of cell fate decisions of spermatogonial stem cells (SSC) in vivo. The expression pattern and cell-specific distribution of VEGF isoforms, receptors, and coreceptors during testis development postnatal d 1-180 suggest a nonvascular function for VEGF regulation of early germ cell homeostasis. Populations of undifferentiated spermatogonia present shortly after birth were positive for VEGF receptor activation as demonstrated by immuno-histochemical analysis. Thus, we hypothesized that proangiogenic isoforms of VEGF (VEGFA(164)) stimulate SSC self-renewal, whereas antiangiogenic isoforms of VEGF (VEGFA(165)b) induce differentiation of SSC. To test this hypothesis, we used transplantation to assay the stem cell activity of SSC obtained from neonatal mice treated daily from postnatal d 3-5 with 1) vehicle, 2) VEGFA(164), 3) VEGFA(165)b, 4) IgG control, 5) anti-VEGFA(164), and 6) anti-VEGFA(165)b. SSC transplantation analysis demonstrated that VEGFA(164) supports self-renewal, whereas VEGFA(165)b stimulates differentiation of mouse SSC in vivo. Gene expression analysis of SSC-associated factors and morphometric analysis of germ cell populations confirmed the effects of treatment on modulating the biological activity of SSC. These findings indicate a nonvascular role for VEGF in testis development and suggest that a delicate balance between VEGFA(164) and VEGFA(165)b isoforms orchestrates the cell fate decisions of SSC. Future in vivo and in vitro experimentation will focus on elucidating the mechanisms by which VEGFA isoforms regulate SSC homeostasis. (Endocrinology 153: 887-900, 2012)