Autologous transplantation of spermatogonial stem cells restores fertility in congenitally infertile mice
Autologous transplantation of spermatogonial stem cells restores fertility in congenitally infertile mice
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DOI：
10.1073/pnas.1914963117
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发表时间：
2020-04-07
影响因子：
11.1
通讯作者：
Shinohara, Takashi
中科院分区：
文献类型：
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作者：
Kanatsu-Shinohara, Mito;Ogonuki, Narumi;Shinohara, Takashi
血睾屏障（BTB）被认为是精子发生不可或缺的，因为它为减数分裂创造了一个特殊的环境，并保护单倍体细胞免受免疫系统的侵害。BTB将生精小管分为近腔室和基底室。精原干细胞（SSCs）具有独特的能力，移植到曲细精管后可通过BTB从近腔室迁移到基底室。在这里，我们分析了Cldn 11的作用，BTB的主要组成部分，在精子发生使用精原细胞移植。Cldn 11缺陷小鼠由于在精母细胞阶段精子发生停止而不育。Cldn 11缺陷型SSC未能有效地定殖野生型睾丸，并且经历Cldn 3和Cldn 5双重消耗的Cldn 11缺陷型SSC显示出最小的定殖，这表明SSC上的claudin是迁移所必需的。然而，CLDN 11缺陷的Sertoli细胞使SSC归巢效率增加>3倍，表明Sertoli细胞中的CLDN 11抑制SSC通过BTB的迁移。与完整Cldn 11缺陷睾丸中的内源性精原干细胞相反，来自WT或Cldn 11缺陷睾丸的精原干细胞在Cldn 11缺陷睾丸中再生精子。这种自体移植的成功似乎取决于去除用于受体制备的内源性生殖细胞，其重新编程支持细胞中的claudin表达模式。与这一想法一致，在体内消耗Cldn 3/5再生内源性精子发生在Cldn 11缺陷小鼠。因此，SSC和Sertoli细胞表达中协调的claudin表达对于SSC归巢和精子发生的再生是必需的，并且自体干细胞移植可以挽救自我更新组织的先天性缺陷。
The blood-testis barrier (BTB) is thought to be indispensable for spermatogenesis because it creates a special environment for meiosis and protects haploid cells from the immune system. The BTB divides the seminiferous tubules into the adluminal and basal compartments. Spermatogonial stem cells (SSCs) have a unique ability to transmigrate from the adluminal compartment to the basal compartment through the BTB upon transplantation into the seminiferous tubule. Here, we analyzed the role of Cldn11, a major component of the BTB, in spermatogenesis using spermatogonial transplantation. Cldn11-deficient mice are infertile due to the cessation of spermatogenesis at the spermatocyte stage. Cldn11-deficient SSCs failed to colonize wild-type testes efficiently, and Cldn11-deficient SSCs that underwent double depletion of Cldn3 and Cldn5 showed minimal colonization, suggesting that claudins on SSCs are necessary for transmigration. However, Cldn11-deficient Sertoli cells increased SSC homing efficiency by >3-fold, suggesting that CLDN11 in Sertoli cells inhibits transmigration of SSCs through the BTB. In contrast to endogenous SSCs in intact Cldn11-deficient testes, those from WT or Cldn11-deficient testes regenerated sperm in Cldn11-deficient testes. The success of this autologous transplantation appears to depend on removal of endogenous germ cells for recipient preparation, which reprogrammed claudin expression patterns in Sertoli cells. Consistent with this idea, in vivo depletion of Cldn3/5 regenerated endogenous spermatogenesis in Cldn11-deficient mice. Thus, coordinated claudin expression in both SSCs and Sertoli cells expression is necessary for SSC homing and regeneration of spermatogenesis, and autologous stem cell transplantation can rescue congenital defects of a self-renewing tissue.