When it comes to male fertility, the spotlight often falls on sperm. Yet germ cell production and transport require other cell types in the testicles to run smoothly. Peritubular myoid (PTM) cells, which give structure to the seminiferous tubes and contract to help spermatozoa move through these tubules, are one of these key ingredients. 

Ryan Flannigan, a reproductive surgeon and scientist at the University of British Columbia, wanted to better understand the mechanisms involved in impaired sperm production. To achieve this, Flannigan explained, “We use human tissue samples from very generous patients that allow us to use some of their tissue for research, but for all of the experiments that we’re looking to do and technologies we’re looking to develop, it’s certainly a limited resource.”

Scientists can address these constraints by generating populations of different testicular cell types using human-derived cells. While many lab-created testicular cells are available, PTM cells were a missing piece. Recently, Flannigan and his colleagues differentiated PTM cells from human induced pluripotent stem cells (hiPSC) for the first time and reported the feat in Advanced Biology (1).

“Fundamentally speaking, it is interesting to study peritubular myoid cell development and differentiation,” said reproductive biologist Ina Dobrinski at the University of Calgary who did not participate in this study. And to that end, she agreed with Flannigan; the human-derived material is exceedingly limited, and that makes his achievement significant. 

During development, PTM cells derive from the same progenitor cells as Leydig cells, which are responsible for producing testosterone. Flannigan’s team modified a protocol for differentiating Leydig cells from hiPSC (2). Next, they looked at the genes expressed by the resulting cells and compared them to those of PTM cells obtained from a patient’s testicular biopsy to confirm that they had derived cells with PTM-like transcriptomes. 

“What we're really focusing on now is being able to use these cell populations as the substrate for optimizing three-dimensional architecture within the testicle,” Flannigan said. He added that these in vitro generated cells could help researchers better understand human spermatogenesis or even lead to a regenerative platform for fertility treatments.

Currently, Flannigan and his colleagues employ 3D bioprinting techniques to pursue these goals. They use microfluidic 3D bioprinters to deposit specific human testicular cell types within bioink, a liquid composed of various proteins including collagen. “Then, we can design where we want to place those cells relative to the other cells,” Flannigan explained. His team has previously bioprinted testicular tubules using human adult testicular cells from a patient and shown that the structures maintained cell viability after printing (3). “Having that ability to have those [in vitro generated cell] populations allows us to move that technology forward,” he said.

While Dobrinski said that we might still be far from building a testis niche with direct clinical applications such as fertility preservation, cultivating PTM cells in the lab constitutes a significant piece of the puzzle. 

References

1. Robinson, M. et al. Differentiation of Peritubular Myoid-Like Cells from Human Induced Pluripotent Stem Cells. Adv Biol (Weinh)  7, e2200322 (2023).
2. Chen, X. et al. Differentiation of human induced pluripotent stem cells into Leydig-like cells with molecular compounds. Cell Death Dis  4, 220 (2019). 
3. Robinson, M. et al. Using clinically derived human tissue to 3-dimensionally bioprint personalized testicular tubules for in vitro culturing: first report. F&S Sci  3, 130-139 (2022).