Enhancing regenerative capacities is a fundamental goal in medicine. As yet, the principles of salamander regeneration to augment mammalian healing are not directly applicable. Here we propose using lizards, more closely related to mammals yet exhibiting remarkable regenerative capabilities, as a model organism in a set of studies aimed at manipulating skeletal regeneration capacities. While both salamanders and lizards regenerate their tails, the former regenerate a near-perfect copy of the original tail, whie the latter is known as an imperfect replicate with several key anatomical differences compared to the original tail, most striking of which concerns the regenerated tail skeleton. Our recent comparative analyses of regenerated tail development have identified 3 main differences related to (1) dorsoventral patterning signals, (2) stem cell populations, and (3) segmentation signals. During skeletal regeneration, salamanders form a cartilage rod (CR) ventral to the tail axis, whereas the regenerated lizard tail lacks dorsoventral skeletal patterning and forms a cartilage tube (CT). Our initial findings suggest that the regenerated spinal cord is responsible for cartilage patterning in both salamander and lizard tails. The salamander spinal cord produces factors that both inhibit and induce cartilage formation, while the lizard spinal cord produces cartilage inductive factors only; furthermore, they differ in their neural stem cell populations. Salamander stem cells are able to differentiate into both dorsal and ventral lineages, while lizard stem cells differentiate into ventral lineages only. Once formed, the salamander CR undergoes segmentation marked by new cartilage formed at distinct regions by populations of proliferating chondrocytes and periosteal cells. These regions are not detectable in the lizard CT, which does not segment, likely due to lack of molecular proliferative signals. We hypothesize that these differences in pattern formation and regulatory networks underlie the divergent regenerative outcomes between lizards and salamanders. Based on this comparative analysis, we hypothesize the feasibility of mechanistically based intervention to shift the imperfectly regenerating lizard tail to phenocopy the perfectly regenerating salamander tail.
The Aims are: (1) Manipulate the dorsoventral signals present in regenerating salamander tails but absent in lizard tails; (2) Introduce stem cell populations found in salamander but not lizard tails; and (3) Determine and manipulate the proliferative signals in regenerating salamander tails that are absent in lizard tails. An integrated approach is proposed, incorporating transcriptomics, CRIPSR/Cas9 genome editing of lizard stem cells, molecular and cellular analyses, in vivo surgical manipulations, and delivery of cell and bioactive agents. We believe that this approach will produce the first lizard tails with skeletons exhibiting patterning and segmentation that phenocopy regenerated salamander tails. These studies will contribute towards mechanistic understanding of a vertebrate regenerative process, and may lead to improving healing in non-regenerative organisms, including humans, specifically related to skeletal development and repair.

Public Health Relevance

Lizards and salamanders both regenerate their tails, but the regenerated lizard tail lacks a skeleton with the dorsoventral patterning, the proximodistal patterning, and the segmentation characteristics of the salamander regenerate. This proposal employs an integrated approach to identify the regulatory networks underlying these differences, which will be used to guide manipulations of the regenerated lizard tail to phenocopy the more complex salamander tails. The knowledge gained here should provide important insights into approaches to improve vertebrate regenerative outcomes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Haynes, Susan R
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University of Pittsburgh
Schools of Medicine
United States
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Londono, Ricardo; Sun, Aaron X; Tuan, Rocky S et al. (2018) TISSUE REPAIR AND EPIMORPHIC REGENERATION: AN OVERVIEW. Curr Pathobiol Rep 6:61-69
Sun, Aaron X; Londono, Ricardo; Hudnall, Megan L et al. (2018) Differences in neural stem cell identity and differentiation capacity drive divergent regenerative outcomes in lizards and salamanders. Proc Natl Acad Sci U S A 115:E8256-E8265
Londono, Ricardo; Wenzhong, Wei; Wang, Bing et al. (2017) Cartilage and Muscle Cell Fate and Origins during Lizard Tail Regeneration. Front Bioeng Biotechnol 5:70
Lozito, Thomas P; Tuan, Rocky S (2017) Lizard tail regeneration as an instructive model of enhanced healing capabilities in an adult amniote. Connect Tissue Res 58:145-154
Lozito, Thomas P; Tuan, Rocky S (2016) Lizard tail skeletal regeneration combines aspects of fracture healing and blastema-based regeneration. Development 143:2946-57