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Abstract Porcine organs and human induced pluripotent stem cell (iPSC)-derived organoids as alternative organs for human transplantation have garnered attention, but both face technical challenges. Interspecies chimeric organ production using human iPSCs shows promise in overcoming these challenges. Our group successfully generated chimeric renal organoids using human iPSC-derived nephron progenitor cells (NPCs) and fetal mouse kidneys. However, the current technology is limited to rodents. Therefore, this study focused on producing human-pig chimeric renal organoids, as pigs are the most promising species for xenotransplantation. Modification of existing culture systems enables continuous renal development in both species, resulting in the successful creation of human-pig chimeric renal organoids. Moreover, this method can be applied to generate humanized xenogeneic kidneys for future clinical applications. This study provides evidence that optimizing culture conditions enables the early-stage kidney development beyond species barriers, thus laying the foundation for accelerating research on humanized xenogeneic kidney fabrication for clinical purposes.

Abstract In mammals, females undergo reproductive cessation with age, whereas male fertility gradually declines but persists almost throughout life. However, the detailed effects of ageing on germ cells during and after spermatogenesis, in the testis and epididymis, respectively, remain unclear. Here we comprehensively examined the in vivo male fertility and the overall organization of the testis and epididymis with age, focusing on spermatogenesis, and sperm function and fertility, in mice. We first found that in vivo male fertility decreased with age, which is independent of mating behaviors and testosterone levels. Second, overall sperm production in aged testes was decreased; about 20% of seminiferous tubules showed abnormalities such as germ cell depletion, sperm release failure, and perturbed germ cell associations, and the remaining 80% of tubules contained lower number of germ cells because of decreased proliferation of spermatogonia. Further, the spermatozoa in aged epididymides exhibited decreased total cell numbers, abnormal morphology/structure, decreased motility, and DNA damage, resulting in low fertilizing and developmental rates. We conclude that these multiple ageing effects on germ cells lead to decreased in vivo male fertility. Our present findings are useful to better understand the basic mechanism behind the ageing effect on male fertility in mammals including humans.

Abstract The mammalian spermatozoa produced in the testis require functional maturation in the epididymis for their full competence. Epididymal sperm maturation is regulated by lumicrine signalling pathways in which testis-derived secreted signals relocate to the epididymis lumen and promote functional differentiation. However, the detailed mechanisms of lumicrine regulation are unclear. Herein, we demonstrate that a small secreted protein, NELL2-interacting cofactor for lumicrine signalling (NICOL), plays a crucial role in lumicrine signalling in mice. NICOL is expressed in male reproductive organs, including the testis, and forms a complex with the testis-secreted protein NELL2, which is transported transluminally from the testis to the epididymis. Males lacking Nicol are sterile due to impaired NELL2-mediated lumicrine signalling, leading to defective epididymal differentiation and deficient sperm maturation but can be restored by NICOL expression in testicular germ cells. Our results demonstrate how lumicrine signalling regulates epididymal function for successful sperm maturation and male fertility.