Spermatogonial Stem Cell Numbers Are Reduced by Transient Inhibition of GDNF Signaling but Restored by Self-Renewing Replication when Signaling Resumes.
Spermatogonial Stem Cell Numbers Are Reduced by Transient Inhibition of GDNF Signaling but Restored by Self-Renewing Replication when Signaling Resumes.
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DOI：
10.1016/j.stemcr.2021.01.015
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发表时间：
2021-03-09
影响因子：
5.9
通讯作者：
Wright WW
中科院分区：
文献类型：
--
作者：
Parker N;Laychur A;Sukwani M;Orwig KE;Oatley JM;Zhang C;Rutaganira FU;Shokat K;Wright WW
人类男性不育的一个原因是睾丸中缺乏精原干细胞(SSCs)，这些支持细胞既不能产生足够数量的GDNF，也不能形成形成血-睾丸屏障(BTB)的Sertoli-Sertoli连接。这些患者提出了这样一个问题：如果恢复正常信号，由于GDNF刺激不足而耗尽的SSCs池是否会扩大。在这里，我们使用一种可逆地抑制GDNF信号的化学遗传方法，将成年小鼠的SSC数量减少了90%。信号恢复导致所有剩余的SSCs立即复制，但它们主要形成分化的前体精原细胞。随后，自我续订复制会恢复SSC编号。在修复过程中，睾丸GDNF水平不升高。然而，随着SSC和祖细胞数量的增加，SSC的复制减少，这表明这些细胞之间存在重要的调控相互作用。最后，SSCs和粗线期精母细胞的连续丢失会导致BTB的溶解，从而概括了一些不育男性的另一个重要特征。当GDNF信号被抑制时，SSC迅速丢失如果信号恢复，耗尽的SSC池通过自我更新复制恢复，睾丸GDNF水平在恢复期间没有增加，SSC复制随着干细胞数量的增加而减少，Wright和他的同事研究了成年精原干细胞(SSCs)在被抑制的GDNF信号9天后的恢复。信号恢复后，SSC复制立即产生祖细胞。然后，自我续订复制将恢复SSC编号。在修复过程中，睾丸GDNF水平不升高。然而，复制的SSCs的比例随着它们数量的增加而减少，这表明它们之间的相互作用调节着恢复。
One cause of human male infertility is a scarcity of spermatogonial stem cells (SSCs) in testes with Sertoli cells that neither produce adequate amounts of GDNF nor form the Sertoli-Sertoli junctions that form the blood-testis barrier (BTB). These patients raise the issue of whether a pool of SSCs, depleted due to inadequate GDNF stimulation, will expand if normal signaling is restored. Here, we reduce adult mouse SSC numbers by 90% using a chemical-genetic approach that reversibly inhibits GDNF signaling. Signal resumption causes all remaining SSCs to replicate immediately, but they primarily form differentiating progenitor spermatogonia. Subsequently, self-renewing replication restores SSC numbers. Testicular GDNF levels are not increased during restoration. However, SSC replication decreases as numbers of SSCs and progenitors increase, suggesting important regulatory interactions among these cells. Finally, sequential loss of SSCs and then pachytene spermatocytes causes dissolution of the BTB, thereby recapitulating another important characteristic of some infertile men. SSCs are rapidly lost when GDNF signaling is inhibited If signaling resumes the depleted SSC pool is restored by self-renewing replication Testicular GDNF levels are not increased during restoration SSC replication decreases as stem cell numbers increase Wright and colleagues investigate the restoration of adult spermatogonial stem cells (SSCs) following 9 days of inhibited GDNF signaling. Immediately after signaling resumes, SSC replication generates progenitors. Then, self-renewing replication restores SSC numbers. Testicular GDNF levels are not increased during restoration. However, the fraction of replicating SSCs decreases as their numbers increase, suggesting that interactions among them regulate restoration.
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影响因子：
8.8
作者：
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通讯作者：
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影响因子：
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