Molecularization of Hydra
Novel computational tools and genomic resources have brought a molecular perspective on the Hydra stem cell system. A major breakthrough in research on cnidarian development came with the generation of stably transgenic Hydra by the Bosch lab using embryo injection (Wittlieb et al., 2006). This opened up a new range of experimental possibilities for studying regeneration and cellular behavior in vivo in this model organism (Siebert et al., 2008; Wittlieb et al., 2006; Khalturin et al., 2007; Gee et al., 2010; Nakamura et al., 2011; Böhm et al., 2012; Franzenburg et al., 2012) indicating the value of this approach. The successful creation of transgenic Hydra expressing GFP in all three stem cell lineages (Hemmrich et al., 2012) has greatly facilitated progress in getting insights of general relevance into stem cell biology including cellular senescence, lineage programming, the role of extrinsic signals in fate determination and tissue homeostasis, and the evolutionary origin of these cells. Loss-of-function approaches based on hairpin constructs have been successfully used to knockdown both immune (Franzenburg et al., PNAS 2012, PNAS 2013) as well as stem cell transcripts (Boehm et al., PNAS 2012).
We also provide a comparative genomics platform (http://www.compagen.org/) which provides access to a large set of genome and transcriptome sequences from basal metazoans including sponges and Cnidaria species. Since the genome organization and genome content of Cnidaria is remarkably similar to that of bilaterians, these animals offer unique insights into the content of the “genetic tool kit” present in the Cnidarian–bilaterian ancestor.
Stem cells, aging and the origin of cancer
The dynamic control of stem cell populations in response to external stimuli is critical to organismal adaptation to environmental conditions. This complexity is poorly understood. We have shown that stem cell maintenance in Hydra depends on transcription factor FoxO – which may account for the potential immortality of the animals (Boehm et al., 2012, 2013).
Stem cells in Hydra represent one of the most ancient stem cell systems in the animal kingdom and, therefore, provide informations for reconstructing the early history of stem cell control mechanisms. A major puzzle in developmental biology is why stem cells in most species have a limited proliferating potential while in Hydra they appear to proliferate continuously. Attempting to identify the underlying cellular and molecular mechanisms, that account for such species differences and that in particular are responsible for Hydra´s ability to continuously proliferate, is the basis of the research in the Bosch lab.
A hallmark of aging is stem cell senescence, the decline of functionality and number of somatic stem cells, resulting in an impaired regenerative capacity and reduced tissue function. In addition, aging is characterized by profound remodelling of the immune system and a quantitative decline of adequate immune responses, a phenomenon referred to as immune-senescence. Yet, what is causing stem cell and immune-senescence? The Bosch lab has shown that Hydra transcription factor FoxO modulates both stem cell proliferation and innate immunity, lending strong support to a role of FoxO as critical rate-of-aging regulator from Hydra to human. Constructing a model of how FoxO responds to diverse environmental factors provides a framework for how stem cell factors might contribute to aging.
Tumours have deep roots in evolution
Stem cells emerged in evolution at the point of transition to stable multicellularity. This increase in hierarchical complexity requires robust mechanisms to maintain tissue homeostasis and organism integrity, and to stably interact with the environment. Dysfunction of stem cell activity is expected to lead to cancer formation. Computational analysis of genes involved in cancer formation revealed their early emergence in metazoan evolution and predicted that all metazoans might be prone to develop tumors (Domazet-Lošo & Tautz, 2010). Recently we provided the first evidence for naturally occurring bona fide cancer in two species of Hydra (Domazet-Lošo, Klimovich et al., 2014). Histological, cellular and molecular data reveal that tumor cells originate by differentiation arrest of female-restricted germ-line progenitors. The tumor cells have migration capacity, are able to induce de novo tumor formation, and show a greatly altered transcriptome that mimics expression shifts in vertebrate cancers. Our study revisits the essential role of differentiation arrest and resistance to apoptosis in driving cancerogenesis. In sum, our findings suggest that evolutionary origin of spontaneous cancers dates back to the origin of Metazoa, and imply that the ability for tumor formation goes side by side with such evolutionary innovations as multicellularity and stem cells.
Rethinking the role of immunity
The ability of multicellular organisms to detect and respond to microorganisms is fundamental and has ancient evolutionary origins. Our work has shown that these apparently simple animals provide us with important information in understanding the evolution of epithelial-based innate immunity. The work has contributed to a paradigm shift in evolutionary immunology: components of the innate immune system with its host-specific antimicrobial peptides and a rich repertoire of pattern recognition receptors appear to have evolved in early branching metazoans because of the need to control the resident beneficial microbes rather than because of invasive pathogens. This conclusion is based on studies showing that individuals from different species differ greatly in their microbiota, that specific microbial communities are maintained over long periods of time, and that species-specific antimicrobial peptides account for different bacterial communities associated with closely related species. In sum
- The hydra immune system evolved because of the need to control resident microbiota
- Defense against invasive pathogens is secondary to the need to regulate microbiota
- Antimicrobial peptides have regulatory roles in host-microbe homeostasis and adaptations
- Developmental pathways (e.g. FoxO) interact with environmental cues such as microbes