Figure 1.

Diagram illustrating the key roles that stem cells play throughout the schistosome life cycle. Snail stages: Eggs released in the excrements of mammalian hosts pass into the external environment and hatch into free-swimming ciliated miracidia in fresh water. Two distinct germinal cell lineages (nanos-2⁺ and nanos-2⁻ cells) have been identified in miracidia (5). The miracidium proceeds to infect a suitable snail host leading to a dramatic process of development in which the larva transforms into a mother sporocyst. Of 1662 conserved genes expressed in miracidia and sporocysts 48 hr post-transformation, 581 were shown to share similarity with planarian neoblast-enriched transcripts (5). Three sporocyst stem cell classes were designated: κ-cells (klf⁺, nanos-2⁺); φ-cells (fgfrA, B⁺); and δ-cells (nanos-2⁺ and fgfrA, B⁺) (6). In in vitro-transformed mother sporocysts, key genes upregulated in κ-cells include fgfrA/B, p53 and zfp-1, leading to the formation of δ-cells. Downregulation of nanos-2 and activation of hesl-2 in δ-cells causes the specification of φ-cells. The germinal cells in the mother sporocyst are able to undergo asexual clonal expansion to release hundreds of daughter sporocysts; these produce more daughters and infective cercariae which escape from the snail intermediate host. Intra-mammalian stages: The free-swimming cercariae penetrate the skin of the mammalian host when they contact water and these larvae transform into schistosomula which enter the host circulation. Mother sporocysts and schistosomula share 573 enriched genes including stem cell markers (e.g., nanos-2, ago2-1, and fgfrA) (6). Schistosomula stem cells are predicted to be further separated into three main populations: δ'-cells (nanos-2⁺ and fgfrs⁺), ε-cells (eled⁺) and μ-cells (ago2-1⁺ and cyclin B⁺) (7). Activation of hesl in δ-cells of the mother sporocyst may lead to δ-cells in the schistosomulum. Downregulation of nanos-2 and activation of eled in the κ-cells of mother sporocysts generates ε-cells, which subsequently develop into two subpopulations (6) (ε_α- and ε_β-cells). Supported by the differentiation of stem cells, schistosomula grow to adult worms in the definitive host and build up an extensive arrangement of sexual reproductive organs de novo. When adult S. mansoni were exposed to irradiation, 105 down-regulated genes on day 14 post-irradiation (8) were identified as delayed irradiation-sensitivity (DIS) genes that may encode potential drug/vaccine targets. Paired female worms produce and lay fertilized eggs, many of which become entrapped in tissues evoking inflammatory responses, leading to granuloma formation and hepatic fibrosis. The remainder travel to the intestine or bladder and are released from the host to ensure continuation of the life cycle. ago, argonaute; h2a, histone 2a; fgfr, fibroblast growth factor receptor; vlg, vasa-like; klf, krüppel-like factor; zfp, zinc finger protein; hesl, hes family transcription factor; astf, aschaete-scute transcription factor; bhlh, basic helix-loop-helix protein; tsp-2, tetraspanin-2.