Tissue Regeneration, Eye, Stem Cells, Xenopus Development, Limb
The Tseng lab studies the injury response in animals with high regenerative ability. We focus on understanding how an animal senses that it has injured or lost body organs and how it responds to repair the damage. Understanding the conserved molecular mechanisms underlying these processes has important implications for developing regenerative therapies for damaged tissues and aging. We pursue these studies using the powerful and well-characterized vertebrate model, the South African clawed frog, Xenopus laevis. Like humans, Xenopus tadpoles display age-dependent regenerative abilities, making it a robust model for identifying the still unknown mechanisms that underlie the differences between regenerative and non-regenerative responses to injury.
Using interdisciplinary approaches (including molecular, chemical-genetic, physiological, and in vivo imaging tools), we seek to elucidate and integrate the biochemical and biophysical control of animal regeneration and repair. In the long term, our goal is to build a blueprint for organ regeneration and to apply this knowledge towards developing novel therapeutics for regenerative medicine.
1) Understanding Mechanisms that Drive Neural Regeneration and Repair
A main challenge in the regeneration field has been to identify the signaling pathways and suitable cell types needed to enable productive tissue repair. For the eye, the successful generation and maintenance of eye-specific stem cells is a key goal. Although the process of vertebrate eye development is well-characterized, the mechanisms that can induce eye stem cell proliferation following injury remain unknown. We found that Xenopus embryos successfully regrew functional eyes after excision (Kha et al., 2018). Successful eye regrowth required extended retinal progenitor cell proliferation while delaying eye formation (Kha and Tseng, 2018, and Kha et al., 2019). We have also found that eye regrowth is age dependent, providing an ideal vertebrate animal model to test strategies that can drive successful regrowth. (In contrast, other regeneration models mostly lack this feature.) This embryonic model now provides a platform to understand how developmental mechanisms are used in regeneration and to identify regeneration-specific mechanisms. Using a combination of cellular, molecular, and bioinformatics approaches, we are: 1) systematically defining mechanisms that regulate regenerative stem cell proliferation to drive eye regrowth; and 2) characterizing the stem cells that drive this process and identifying potential new stem cell markers.
2) Defining Shared Mechanisms of Regeneration
Regeneration studies have focused on different organs and animal models to identify mechanisms that are required for successful repair. Although much is now known about many of these mechanisms, it remains unclear whether there are shared mechanisms across different tissues and/or species. established a model to study vertebrate embryonic eye regrowth in Xenopus (Kha et al., 2018, Kha and Tseng, 2018, and Kha et al., 2019). By comparing eye regeneration mechanisms with those for limb regeneration, we aim to identify commonalities in repair mechanisms in different vertebrate organs. Furthermore, we are carrying out a collaboration to perform comparative studies of regenerative mechanisms between diverse species.
3) Bioelectrical Signaling as a Key Initiator of Regeneration
Increasingly, bioelectrical signaling mechanisms regulated by ion channels and transporters are recognized for their “non-excitable” roles in normal development, homeostasis, and disease. Bioelectrical signals also play essential roles in regulating appendage regeneration. Specifically, a sodium flux mediated by the voltage-gated sodium channel, NaV, is required to initiate tail regeneration in Xenopus tadpoles (Tseng et al., 2010). Inhibition of this mechanism blocks tail regeneration, whereas induction of a transient sodium current is sufficient to promote tail regrowth. Our studies indicate that Na+ ions likely act as a direct signal to initiate regeneration. We are currently using molecular and bioinformatics approaches to identify potential downstream signal transducers and characterize their roles in regeneration.
4) Using Xenopus as a Model for Rapid Assessment of Environmental Toxicology
Each year, approximately 1,000 new chemical substances enter commercial use with limited toxicity and environmental data. Xenopus has a strong history as a vertebrate model system for environmental health studies, and their responses correlate well to mammalian findings. Xenopus embryos and tadpoles are highly sensitive to the environment, and their developmental processes are well studied. Xenopus is also a highly tractable molecular model. Our initial studies have identified chemicals that disrupt normal biological processes in both frog embryos and tadpoles but which have not been implicated previously as significant toxicants (Delos Santos et al, 2016). We are also establishing assays to examine the effects of chemical toxicants on the injury response, an important biological process that is not evaluated in common toxicology protocols (Delos Santos et. al., 2016). Our goal is to establish Xenopus as a highly suitable and accessible model for the rapid determination of chemical safety and to use it for determining the molecular mechanisms of animal toxicity.