Autologous transplantation of spermatogonial stem cells restores fertility in congenitally infertile mice.

Abstract

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 <i>Cldn11</i>, a major component of the BTB, in spermatogenesis using spermatogonial transplantation. <i>Cldn11</i>-deficient mice are infertile due to the cessation of spermatogenesis at the spermatocyte stage. <i>Cldn11</i>-deficient SSCs failed to colonize wild-type testes efficiently, and <i>Cldn11</i>-deficient SSCs that underwent double depletion of <i>Cldn3</i> and <i>Cldn5</i> showed minimal colonization, suggesting that claudins on SSCs are necessary for transmigration. However, <i>Cldn11</i>-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 <i>Cldn11</i>-deficient testes, those from WT or <i>Cldn11</i>-deficient testes regenerated sperm in <i>Cldn11</i>-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 <i>Cldn3</i>/<i>5</i> regenerated endogenous spermatogenesis in <i>Cldn11</i>-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.