Moving Planarian Regenerative Genes into Flies Slows Intestinal Aging, But Harms Regeneration
Various planarian species exhibit highly proficient regeneration, capable of regrowing an entire body from fragments. This exceptional degree of regeneration is only exhibited in lower animals that lack a sophisticated nervous system. Researchers have made some inroads into identifying genes that are critical to this regenerative prowess, via the usual approach of disabling genes one by one to see what breaks in each case. A full understanding of the biochemistry involved remains a work in progress, as is true for the processes of tissue regeneration more generally.
In today's open access paper researchers report on their efforts to take a few of these planarian genes and introduce them into flies, to see if this transfer improves function in the context of age-related degeneration of tissues. We might say that fly aging is dominated by intestinal dysfunction in the same way that we'd say that human aging is dominated by cardiovascular dysfunction. It appears to be the critical path to most mortality. Therefore, researchers tend to first characterize intestinal function when investigating interventions that may affect aging in this species. Indeed, in this study researchers saw a slowing of intestinal aging as a result of the introduction of planarian regeneration-associated genes. This came at a cost, however, of disruption to the normal processes of regeneration.
Experiments in moving genes between species with an eye to effects on aging are becoming more common. As this study illustrates, researchers are still in the very early stages of this sort of work, and treat this approach as more a way to learn about gene functions rather than a viable path to therapies. Cellular biochemistry is highly complex, regeneration and tissue maintenance processes are equally complex, and changes rarely produce only one effect. Turning a foreign gene into the basis for an enhancement therapy remains an aspiration.
While certain animals like planarians and hydras possess the remarkable ability to regenerate their entire body from a small fragment, other groups with more complex body structures, such as mammals and insects, exhibit a diminished regenerative potential and can only regenerate specific tissues and/or organs to a limited extent. Several cellular and molecular factors have been identified as determinants of regeneration capacity. Highly regenerative animals such as planarians and cnidarian polyps rely on pluripotent adult stem cells, called neoblasts and interstitial cells (i-cells), respectively. These stem cells migrate to the injury sites and contribute to the formation of a blastema, an undifferentiated cellular mass, enabling the restoration of amputated body structures. Some vertebrates like salamanders and fish, which do not possess adult pluripotent stem cells, can regenerate organs after injury by recruiting blastema cells through dedifferentiation and/or the activation of quiescent lineage-restricted stem cells. At the molecular level, the evolutionary conserved WNT signaling pathway promotes a wide range of regenerative events across species, including blastema formation in newts and Hydra.
In contrast to the conserved regulators of regeneration, several genes are specific to highly regenerative animal groups and species. For instance, the newt gene Prod1 regulates re-patterning during limb regeneration, and viropana family (viropana 1-5) is upregulated during lens regeneration. These species/group-specific genes might explain differences in regeneration capacity between species. Remarkably, ectopic expression of viropana 1-5 can enhance regeneration of the primordium of Drosophila eyes that maintain regenerative capacity during development. This finding raises the possibility that heterologous induction of regenerative genes may accelerate tissue regeneration, at least in developing animals, and potentially provide a cue for developing novel regenerative therapies.
Notably, given that basal metazoans such as Porifera, Ctenophore, Placozoa, and Cnidaria all exhibit robust regenerative abilities, it is conceivable that a common ancestor of all metazoans once possessed a high regenerative potential and independently lost genes related to high regenerative capacity in multiple phyla. Building upon this hypothesis, bioinformatics analysis has identified genes that are common among species with high regenerative abilities and absent in species with limited regenerative capacities. The highly regenerative species-specific JmjC domain-encoding genes (HRJDs) are a group of such genes (with typically two or three orthologs per species) characterized by their JmjC domain, yet their molecular functions remain unknown. Given their potential influence on the regenerative process, HRJDs may contribute to the high regeneration potential of highly regenerative animals. With this in mind, a question arises: what would happen if a low regenerative species, which has lost HRJDs, were to acquire them again?
Here, we express HRJDs in the fruit fly Drosophila melanogaster and evaluate their impact in vivo, especially by focusing on two epithelial tissues: developing wing discs and post-developmental adult midguts, both of which exhibit regeneration potential and can replenish damaged epithelial cells. In contrast to the predicted contribution of HRJDs in regeneration as observed in planarian, ectopic HRJD induction impedes regenerative responses and decreases organismal survival upon injury in Drosophila. Surprisingly, however, HRJD expression in the stem/progenitor population of the adult midguts extends organismal lifespan under the non-regenerative condition. Further investigations reveal that HRJDs enhance the proliferative activity of intestinal stem cells while keeping their differentiation fidelity in aged guts, ameliorating age-related decline in gut barrier functions. These findings provide evidence that genes specific to highly-regenerative animals can improve stem cell function as well as increase healthy lifespan upon heterologous expression in aging animals.