Stem cell researchers from the Whitehead Institute in Cambridge, Massachusetts have used a novel, stepwise cell reprogramming protocol to convert skin cells into embryonic Sertoli-like cells.
Sertoli cells are found in the testes of men and they provide vital support, protection, and nutrition to developing sperm cells. Sertoli cells also possess “trophic” properties, which simply mean that they secrete factors that help cells grow and survive. In fact, Sertoli cells have been used to protect and promote the growth, and survival of non-testicular cellular grafts in transplantations. Mature Sertoli cells, however, do not divide, and primary immature Sertoli cells have the unfortunate tendency to degenerate during prolonged culture in the laboratory. Therefore, it is desirable to find some kind of alternative source of Sertoli cells independent of the donor testis cells, but for basic research and clinical applications.
Whitehead Institute Founding Member Rudolf Jaenisch said, “The idea is if you could make Sertoli cells from a skin cell, they’d be accessible for supporting the spermatogenesis process when conducting in vitro fertilization assays or protecting other cell types such as neurons when co-transplanted in vivo. Otherwise, you could get proliferating cells only from fetal testis.”
Researchers in the Jaenisch lab seem to have overcome the supply and lifespan challenges of cultured Sertoli cells by means of using cellular reprogramming to direct one mature cell type, in this case a skin cell, into immature Sertoli cells. The process of cellular reprogramming, otherwise known as trans-differentiation, reprograms a cell directly from one mature cell type to another without first de-differentiating the cell back to an embryonic stem-cell stage. Unlike other reprogramming methods that generate induced pluripotent stem cells (iPSCs), trans-differentiation does not rely on the use of genes that can cause cancer.
The Whitehead Institute scientists trans-differentiated mouse skin cells into embryonic Sertoli-like cells by dividing the trans-differentiation process into two main steps that mimic Sertoli cell development inside the testes. This first step involves the progression transformed skin fibroblasts from their free-moving, unorganized mesenchymal state into an organized, sheet-like epithelial state. For the second step, the cells were induced so that they acquired the ability to attract each so that they formed aggregates that are very similar to those observed in co-cultures of embryonic Sertoli cells and germ cells.
Next, Jaenisch’s lab workers invented a cocktail that consisted of five different transcription factors that specifically activate the developmental program for embryonic Sertoli cells. The cells that resulted from this induction behaved in ways that were reminiscent of embryonic Sertoli cells. They aggregated, formed tubular structures similar to seminiferous tubules found in the testes, and secreted a host of Sertoli-specific factors. When these reprogrammed cells were injected into the testis of fetal mice, the trans-differentiated cells properly migrated to the right location and integrated into the seminiferous tubules. The injected cells behaved exactly like endogenous embryonic Sertoli cells, even though they expressed a few genes differently.
Yossi Buganim, a postdoctoral researcher in the Jaenisch lab and first author of the Cell Stem Cell paper said: “The injected trans-differentiated cells were closely interacting with the native germ cells, which shows [sic] that they definitely do not have any bad effect on the germ cells. Instead, they enable those germ cells to survive.”
Buganim also showed that when their embryonic Sertoli-like cells made from trans-differentiated skin cells were used to sustain other cultured cells in a Petri dish, the cells thrived and lived longer than cells sustained by actual native Sertoli cells. The reprogrammed Sertoli cells supported and nourished the cultured cells and acted like tried and true Sertoli cells.
These encouraging results from their cell culture work have inspired Buganim to investigate if the embryonic Sertoli-like cells retain their enhanced supportive capacity after transplantation into the brain. Once in the brain, the cells could potentially sustain ailing neurons. If these cells truly have this ability, they could have clinical applications. Such applications would include the support and protection of implanted neurons in regenerative therapies for neurodegenerative disorders such as ALS and Parkinson’s disease.