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Review
. 2024 Oct 1;14(10):1251.
doi: 10.3390/life14101251.

Mechanisms of Germline Stem Cell Competition across Species

Rachel A Hodge  1 , Erika A Bach  1
Affiliations
Review

Mechanisms of Germline Stem Cell Competition across Species

Rachel A Hodge et al. Life (Basel). .

Abstract

In this review, we introduce the concept of cell competition, which occurs between heterogeneous neighboring cell populations. Cells with higher relative fitness become "winners" that outcompete cells of lower relative fitness ("losers"). We discuss the idea of super-competitors, mutant cells that expand at the expense of wild-type cells. Work on adult stem cells (ASCs) has revealed principles of neutral competition, wherein ASCs can be stochastically lost and replaced, and of biased competition, in which a winning ASC with a competitive advantage replaces its neighbors. Germline stem cells (GSCs) are ASCs that are uniquely endowed with the ability to produce gametes and, therefore, impact the next generation. Mechanisms of GSC competition have been elucidated by studies in Drosophila gonads, tunicates, and the mammalian testis. Competition between ASCs is thought to underlie various forms of cancer, including spermatocytic tumors in the human testis. Paternal age effect (PAE) disorders are caused by de novo mutations in human GSCs that increase their competitive ability and make them more likely to be inherited, leading to skeletal and craniofacial abnormalities in offspring. Given its widespread effects on human health, it is important to study GSC competition to elucidate how cells can become winners or losers.

Keywords: cell competition; germline stem cell; mosaic analysis; ovary; paternal age affect disorders; stem cell competition; testis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Clonal analysis for germline stem cell (GSC) competition-related genes in the Drosophila testis: (A) Marked GSC clones (dark grey) that are either wild-type or mutant for the gene of interest are sparsely induced in testes. Wild-type GSCs are dark blue, niche cells are green, and differentiating wild-type or mutant germ cells are light blue or light grey, respectively. In this example, 25% (1/4) of GSCs are induced to be marked as GSC clones. After time has passed, allowing the clones to proliferate, the testes are dissected and examined via microscopy. (B) If GSC mutant clones are present in the same proportion as when they were induced (25%), the gene is concluded to have no effect on competition. (C) If the number of GSC mutant clones increases relative to the number of wild-type unmarked GSCs (75% in this example), the mutants are winners, and the mutation is concluded to benefit the cell in competitive interactions. (D) If the number of GSC mutant clones decreases relative to the number of wild-type unmarked GSCs (0% in this example), the mutants are losers, and the mutation is concluded to be detrimental to the cell during competitive interactions. Created with BioRender.com.
Figure 2
Figure 2
Germline stem cell (GSC) competition models: (A) Botryllus schlosseri are tunicates that can exist as a colony of zooids (as shown), with an outer covering called a tunic (yellow). Zooids (cyan) in the same colony are connected by their shared vasculature (purple). Colonies may reproduce asexually (forming buds, green) or sexually. The terminal ends of the vasculature, called ampullae (pink), may make physical contact with ampullae from other colonies, triggering a potential fusion of the two colonies. The depicted colony is hermaphroditic, having both ovaries and testes (orange). (B) The Drosophila ovary is linearly arranged, with niche cells (green) residing at the apical tip; 2–3 GSCs (blue) are in physical contact with the niche and undergo asymmetric division to generate a pre-cystoblast (light blue), which further matures into a cystoblast. The cystoblast differentiates, which requires the presence of escort cells (gray), and undergoes multiple incomplete cell divisions until a 16-cell germline unit called a cyst is generated. Follicle stem cells (FSCs, green) generate follicle cells (light purple), necessary support cells that surround the 16-cell germline cyst. (C) The Drosophila testis is a coiled tube wrapped in a muscle sheath. Niche cells (green) reside at the tip of the tube, and the niche maintains the GSC (blue) and somatic cyst stem cell (CySC, gray) populations. GSCs undergo oriented mitosis to produce a daughter gonialblast (Gb, light blue). Gbs (light blue) are encapsulated in two cyst cells (light gray), daughters of CySCs that are necessary support cells. The germline cells continue to divide and differentiate within the cyst, becoming spermatogonia, spermatids (not shown in diagram), and finally mature sperm (not shown in diagram). (D) Cross-section of the seminiferous tubule, the site of spermatogenesis in the mammalian testis. Spermatogonial stem cells (SSCs) are sparsely distributed, with no markers to distinguish them from other spermatogonia (green). SSCs are included in the spermatogonial population. Sertoli cells (gray), the equivalent of CySCs in mammals, are necessary support cells for developing spermatogonia. They are connected by tight junctions (blue), creating the blood–testis barrier. Spermatogonia further divide and differentiate into spermatocytes (including primary and secondary) (pink), which undergo meiosis to generate haploid round spermatids (purple) and then elongating spermatids (purple) that localize to the seminiferous tubule lumen. Spermatids will differentiate further to generate mature spermatozoids (sperm, not shown in diagram). Created with BioRender.com.
Figure 3
Figure 3
Germline stem cell (GSC) competition between Botryllus schlosseri colonies. Top: Two different Botryllus colonies can come into physical contact with one another via their ampullae. Bottom: There are three possible outcomes of this interaction: (1) The two colonies have incompatible FuHc alleles. An inflammation rejection response occurs, and there is no fusion. (2) The colonies have compatible FuHc alleles, and fusion occurs successfully. GSCs move between the colonies’ shared vasculature, and neither GSC lineage has a competitive advantage over the other, so both remain present in both colonies. (3) The colonies have compatible FuHc alleles, and fusion occurs successfully. GSCs move between the colonies’ shared vasculature, and Individual A’s GSC lineage (blue) has a competitive advantage over the other. Individual B’s lineage (pink) is outcompeted, and the GSC lineage in both colonies becomes monoclonal. This is termed germ cell parasitism (gcp). Created with BioRender.com.
Figure 4
Figure 4
Germline stem cell (GSC) competition in the ovary. Mutation of bag of marbles (bam) in a female Drosophila GSC clone (orange) causes an accumulation of undifferentiated GSC-like cells (orange), which outcompete wild-type GSC neighbors (blue) for niche (green) access. Autophagy is required for bam-mutant germline cells’ competitive advantage; bam-mutant GSCs that have inhibited autophagy no longer outcompete wild-type GSCs. Escort cells are shown in gray. Created with BioRender.com.
Figure 5
Figure 5
chinmo−/− germline stem cell (GSC) clones (orange) outcompete wild-type GSC neighbors (blue) and take over the niche; arrows indicate time: (A) chinmo−/− GSC clones are sparsely induced. (B) chinmo−/− GSC clones form a moat around the testis niche (green) by secreting Perlecan (Pcan, red), resulting in the recruitment of Laminin (Lan, purple) from the nearby testis muscle sheath. (C) chinmo−/− GSCs cause the expulsion of wild-type neighbors from the niche, (D) while remaining anchored to the niche via upregulation of Dystroglycan (Dg, cyan) and βPS-integrin (βPS, gray) (see inset). (E) Over time, the entire germline becomes monoclonal, (F) resulting in biased inheritance in offspring. Created with BioRender.com.
Figure 6
Figure 6
Paternal age effect (PAE) mutations result in clonal expansion of mutant spermatogonial stem cells (SSCs) (orange). Wild-type SSCs (blue) are sparsely distributed throughout the seminiferous tubules of the testis, and they divide to produce daughter cells that further differentiate to become mature sperm. SSCs mutant for PAE-associated genes undergo clonal expansion, leading to a much higher proportion of sperm produced per SSC than wild-type SSCs, possibly as a result of increased symmetric divisions. Therefore, a single SSC with a PAE-associated mutation is more likely to produce the sperm that ultimately fertilizes an egg than a single wild-type SSC. However, because PAE mutations are rare, the associated PAE disorders remain rare in progeny. Adapted from [41]. Created with BioRender.com.
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