Why Don’t Lizards Regenerate Perfect Tails Like Salamanders?

为什么蜥蜴不能像火蜥蜴那样再生出完美的尾巴？

• 批准号: 9256525
• 负责人: Thomas Peter Lozito
• 金额: $ 29.11万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256525
• 关键词: Amaze; Ambystoma; Anatomy; Animal Model; Animals; Area; Calcified; Cartilage; Cell Differentiation process; Cell Line; Cell Proliferation; Cell Transplantation; Cells; Characteristics; Chondrocytes; Complex; Development; Dorsal; Employee Strikes; Environment; Erinaceidae; Exhibits; Female; Genetic Engineering; Goals; Human; Immunosuppression; Individual; Intervention; Intervertebral disc structure; Knowledge; Lead; Length; Lizards; Mammals; Medicine; Molecular; Natural regeneration; Neural tube; Operative Surgical Procedures; Organism; Outcome; Patients; Pattern; Pattern Formation; Periosteal Cell; Phenocopy; Population; Process; Proliferating; Regenerative Medicine; Role; Salamander; Signal Transduction; Skeletal Development; Skeleton; Spinal Cord; Stem cells; Tail; Tissue Transplantation; Tissues; Translating; Tube; Vertebral column; asexual; base; calcification; cartilaginous; comparative; design; experience; experimental study; genome editing; healing; implantation; improved; in vivo; information model; innovation; insight; knowledge base; nerve stem cell; offspring; public health relevance; regenerative; repaired; retinal rods; skeletal; skeletal regeneration; smoothened signaling pathway; stem cell differentiation; stem cell population; tissue regeneration; transcriptomics; vertebra body

 DESCRIPTION (provided by applicant): 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.