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Regeneration, the replacement of lost or damaged tissues to restore organ function, is a widespread but poorly understood phenomenon in the Animal Kingdom. Planarian flatworms are masters of regeneration: following amputation, virtually any piece of an adult worm forms a new, fully functional individual within two weeks. This is no simple task since planaria contain a wide variety of organ systems, including a brain and nervous system, eyes, kidneys, gut, muscle and skin. Planaria owe their remarkable regenerative abilities to adult stem cells called neoblasts. Like embryonic stem cells, neoblasts replenish themselves and produce all cell types comprising the adult worm. In contrast, adult stem cells in fruit flies, zebrafish, mice and humans are normally limited to making the cell type(s) constituting their organ of residence.
Here, Davies and colleagues in the Sánchez Alvarado laboratory at the Stowers Institute for Medical Research investigate the embryonic origins of neoblasts, the wellspring of regenerative potential in S. mediterranea (Smed) flatworms. Embryogenesis, the process by which a fertilized egg develops into a juvenile animal, had not been described for this species. The authors generated a staging series, a set of unique molecular fingerprints (i.e., gene expression signatures) for embryos with distinct morphologies. In addition, they created a gene expression atlas describing embryonic tissues and formation of the major organ systems. Using these resources, Davies and colleagues identified the stage at which early embryonic cells acquire the gene expression signature of adult neoblasts. Moreover, cell transplantation experiments showed that embryonic cells start behaving like adult neoblasts as the adult gene expression signature is established. Neoblasts arise from proliferating embryonic cells as the major organ systems start to form, and their progeny are required for construction of the juvenile worm. The persistence of the neoblast population throughout life allows for continued access to embryonic developmental programs during adulthood, a unique feature of planarian flatworms that likely underlies their striking regenerative abilities.
The pioneering work on Smed embryogenesis by Davies and colleagues will be leveraged in the future to address fundamental biological questions about how stem cells are specified, maintained and regulated. Moreover, Smed are uniquely suited for formal comparisons of embryogenesis and regeneration, an endeavor not possible in many developmental model organisms because the adults simply do not regenerate. Conceptual advances from basic research using Smed may suggest reasons why most mammals have limited regenerative abilities. In addition, the genes necessary for orchestrating regenerative responses in Smed may inform therapeutic strategies to selectively manipulate developmental programs in patients suffering from degenerative diseases or traumatic injury.
Planarian neoblasts are pluripotent, adult somatic stem cells and lineage-primed progenitors required for production and maintenance of all differentiated cell types, including the germline. Neoblasts, originally defined as undifferentiated cells residing in the adult parenchyma, are frequently compared to embryonic stem cells yet their developmental origin remains obscure. We investigated the provenance of neoblasts during S. mediterranea embryogenesis, and report that neoblasts arise from an anarchic, cycling piwi-1+ population wholly responsible for production of all temporary and definitive organs during embryogenesis. Early embryonic piwi-1+ cells are molecularly and functionally distinct from neoblasts: they express unique cohorts of early embryo enriched transcripts and behave differently than neoblasts in cell transplantation assays. Neoblast lineages arise as organogenesis begins and are required for construction of all major organ systems during embryogenesis. These subpopulations are continuously generated during adulthood, where they act as agents of tissue homeostasis and regeneration.