Testicular organoids to study cell–cell interactions in the mammalian testis

Abstract

BackgroundOver the last ten years, three‐dimensional organoid culture has garnered renewed interest, as organoids generated from primary cells or stem cells with cell associations and functions similar to organs in vivo can be a powerful tool to study tissue‐specific cell–cell interactions in vitro. Very recently, a few interesting approaches have been put forth for generating testicular organoids for studying the germ cell niche microenvironment.AimTo review different model systems that have been employed to study germ cell biology and testicular cell–cell interactions and discuss how the organoid approach can address some of the shortcomings of those systems.Results and ConclusionTesticular organoids that bear architectural and functional similarities to their in vivo counterparts are a powerful model system to study cell–cell interactions in the germ cell niche. Organoids enable studying samples in humans and other large animals where in vivo experiments are not possible, allow modeling of testicular disease and malignancies and may provide a platform to design more precise therapeutic interventions.

A Novel Organoid Model of In Vitro Spermatogenesis Using Human Induced Pluripotent Stem Cells

“…This is in keeping with primary SSC studies showing that SSC resistance to retinoic acid stimulation is contingent on the topography of testis tissue facilitating short range paracrine signaling between specific cell types. [20,21,51] This work illustrates the ability of hiPSCs to generate functional testicular organoids for the first time. We show that testicular somatic cells and SSCs derived from hiPSCs spontaneously organize into miniature tissues that resemble the microarchitecture of native testicular tissue, triggering somatic cell maturation and spermatogenesis.…”

“…Expression of the pre-meiotic stage SSC gene STRA8 [49,50] was also noted (Figure 1F), in keeping with reports of primary SSCs grown in monolayer culture. [20,21,51] hiPSC-derived testicular organoid characterization hiPSC-derived testicular cells self-assembled into organoids when cultured overnight in AggreWell™800 microwell plates (Figure 2I), and were transferred to non-adherent plates for suspension culture for 12 days (Figure 2J). The culture medium was designed to mimic in vivo conditions through supplementation with hormones FSH, LH and testosterone, to stimulate somatic cell function and maturation, [52,53] and the Sertoli cell-secreted factors BMP4, SCF and retinoic acid, as studies have shown that these factors are required for SSC entry into differentiation.…”

“…Efforts to develop human testicular organoid systems have been significant. [19][20][21][22][23][24] However, despite success in animal testicular organoid systems, determination of the in vitro conditions necessary for human testicular organoid generation remains a challenge, compounded by the rare accessibility of human testicular tissue for research. [24] A potential solution is to engineer testicular tissues using human induced pluripotent stem cells (hiPSCs), a Nobel Prize-winning technology pioneered by Shinya Yamanaka in 2007 [25] that has since revolutionized in vitro modeling and personalized medicine.…”

Applying Single-Cell Analysis to Gonadogenesis and DSDs (Disorders/Differences of Sex Development)

“…Organoids can be derived from induced pluripotent stem cells (iPS cells) and can be used to model normal and abnormal development. For the gonad, iPS cells have been used to generate Sertoli-like cells, and also Leydig and germ cells [ 182 , 183 , 184 , 185 ]. Single-cell RNA-seq could be used to chart the differentiation of these cell types, identifying important genes activated during formation of the testis.…”

Stem cell-based therapies for fertility preservation in males: Current status and future prospects

“…Leydig cells and other interstitial cells are also involved in cellular communication within the niche[ 68 - 70 ]. This cell network responds to hormone signals and other signaling in the niche to drive spermatogenesis and testosterone production[ 7 , 71 , 72 ]. The differences in cellular interactions in the testicular microenvironments of different mammals have not yet been clarified[ 73 ], but the testicular microenvironment is essential for spermatogenesis[ 74 ].…”