Adenosine may regulate the integrity of the testicular peritubular wall: evidence from cellular studies.

In brief: How the integrity of the multilayered human testicular peritubular wall compartment is maintained was unknown. We found that in isolated human testicular peritubular cells, adenosine enhanced the levels of the adherens junction protein cadherin-11, prevented cell migration, and thus may reinforce the structural and functional integrity of the architecture of the human peritubular wall in situ. Abstract: In the human testis, seminiferous tubules are surrounded by several layers of peritubular cells and extracellular matrix. How the integrity of this small compartment is maintained remains unknown. Isolated and cultured human testicular peritubular cells (HTPCs) provide an opportunity to study aspects of the peritubular wall compartment. Previous studies have shown that HTPCs are targeted by extracellular purines, including adenosine. A proteomic analysis revealed that adenosine was negatively linked, among others, to "(positive) regulation of cell migration" and "focal adhesion" pathways and positively linked to "single organismal cell-cell adhesion" pathways. We therefore hypothesized that adenosine may contribute to the integrity of the peritubular wall compartment and tested this in functional assays. We found that adenosine significantly reduced HTPCs migration, accompanied by significantly decreased single-cell velocity, while cell number and proliferation remained unaffected. Changes in cell-cell and cell-substrate adhesion may underlie this effect, pointing to a role for cadherin-11 (CDH11), the major adherens junction protein of HTPCs. Its role in cell motility was shown upon siRNA-mediated knockdown of CDH11, which enhanced HTPC migration. Immunocytochemistry and western blotting revealed that adenosine increased CDH11 protein levels. Involvement of ADORA2B receptors was indicated by a comparable action of the selective adenosine receptor agonist BAY60-6583. Collectively, these results suggest that adenosine, by increasing the abundance of CDH11, suppresses cell migration. If transferable to the in-situ situation, locally produced adenosine may reinforce the structural integrity of the multilayered architecture of the peritubular wall.