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: 10551354
• 负责人: Thomas Peter Lozito
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 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 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551354
• 关键词: Adult; Amaze; Ambystoma; Ambystoma mexicanum; Anatomy; Apoptosis; CXCR4 Receptors; CXCR4 gene; Cartilage; Cell Lineage; Cell Survival; Cells; Characteristics; Chemotaxis; Chondrocytes; Complex; Development; Disparity; Elements; Embryo; Environment; Epiphysial cartilage; Exhibits; Funding; Generations; Goals; Homologous Transplantation; Human; Hypertrophy; Immunosuppression; Interruption; Intervention; Knowledge; Learning; Ligands; Lizards; Mammals; Medicine; Meningeal; Meninges; Molecular; Natural regeneration; Operative Surgical Procedures; Organism; Osteoblasts; Outcome; Pattern; Periosteum; Phenocopy; Physiologic Ossification; Population; Process; Regenerative Medicine; Regenerative capacity; Research Project Grants; Role; Salamander; Signal Induction; Signal Transduction; Skeletal Development; Skeleton; Source; Spinal Cord; Tail; Testing; Thyroid Hormones; Tissue Engineering; Tissues; Translating; Tube; Vertebral column; asexual; blastema; bone cell; cartilage development; cartilage regeneration; cartilaginous; cellular engineering; comparative; design; healing; improved; in vivo; innovation; insight; knock-down; migration; model organism; notochord; novel; parathyroid hormone-related protein; recruit; regenerative; skeletal; skeletal maturation; skeletal regeneration; skeletal tissue; spatiotemporal; tissue regeneration; ubiquitin-protein ligase; wound environment; wound healing

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 model organisms in a set of studies aimed at manipulating skeletal regeneration capacities. While both salamanders and lizards regenerate their tails, salamanders regenerate near-perfect copies of original tails, while regenerated lizard tails are known as an “imperfect replicates” with several key anatomical differences compared to originals. The most striking of these “imperfections” concerns the lack of dorsoventral patterning and segmentation in regenerated lizard tail skeletons. Progress made under our original proposal identified the signals regulating regenerated skeletal tissue induction and patterning, creating the first dorsoventrally-patterned regenerated lizard tails. This renewal proposal focuses on later stages of skeletal maturation that, given the proper signals, culminate in segmentation. Our recent comparative analyses indicate that regenerated skeleton segmentation is dependent upon three distinct milestones: (1) perichondrium patterning, (2) cartilage hypertrophy, and (3) periosteum formation. Both salamander and lizard regenerated tail skeletons begin as unsegmented cartilage elements. Our preliminary findings suggest a novel role for spinal cord meningeal tissues in regulating skeleton segmentation. Regenerated salamander, but not lizard, meninges contain specialized cell populations capable of recreating embryonic segmentation signals in adjacent perichondrium and initiating a signaling cascade that transforms the entire regenerated skeleton. Some of these signals induce cartilage hypertrophy in salamander cartilage before anti- ossification processes that dominate lizard skeletons have the chance to stagnate cartilage maturation. Other signals missing in lizard tails allow salamander bone cells to survive and promote periosteum development. Based on this comparative analysis, we hypothesize the feasibility of mechanistically based interventions to shift the “imperfectly” regenerating lizard tail to phenocopy the “perfectly” regenerating salamander tail. The Aims are: (1) Introduce patterning to regenerated lizard tail perichondrium by supplementing adult spinal cord meninges with embryonic segmenting cells; (2) Induce regenerated lizard cartilage hypertrophy by interrupting anti- maturation signals that result in dysregulated cartilage development; and (3) Promote periosteum formation within regenerated lizard tails by inducing bone cell survival and recruitment. An integrated approach is proposed, incorporating a unique, asexually reproducing lizard species with in vivo surgical manipulations to deliver cells and bioactive agents toward manipulating skeletal development. We believe that this approach will produce the first regenerated lizard tails with skeletons exhibiting cartilage maturation and segmentation. These studies will contribute towards mechanistic understanding of a vertebrate regenerative process, and may lead to improving skeletal healing in non-regenerative organisms, including humans.

增强再生能力是医学的一个基本目标。到目前为止，蝾螈的原则 用于增强哺乳动物愈合的再生不能直接应用。在这里，我们建议使用蜥蜴，更多 与哺乳动物密切相关，但表现出显着的再生能力，作为模式生物在一组 旨在操纵骨骼再生能力的研究。当蝾螈和蜥蜴都再生时 它们的尾巴，蝾螈再生接近原始尾巴的完美副本，而再生蜥蜴的尾巴是已知的， 作为一个“不完美的复制品”，与原件相比有几个关键的解剖学差异。中最引人注目的 这些“缺陷”涉及再生蜥蜴尾巴缺乏背腹图案和分割 骷髅在我们最初的建议下取得的进展确定了调节再生骨骼组织的信号 诱导和图案化，创造了第一个背腹图案再生蜥蜴尾巴。此续订 该提案的重点是骨骼成熟的后期阶段，给予适当的信号，最终在分割。 我们最近的比较分析表明，再生骨骼分割依赖于三个 不同的里程碑：（1）软骨膜图案，（2）软骨肥大，和（3）骨膜形成。两 蝾螈和蜥蜴再生的尾巴骨骼开始是不分节的软骨成分。我们的初步 研究结果表明脊髓脑膜组织在调节骨骼分割中的新作用。再生 蝾螈，但不是蜥蜴，脑膜含有专门的细胞群，能够重建胚胎 分割信号在相邻的软骨膜，并启动信号级联， 再生的骨骼这些信号中的一些在抗- 支配蜥蜴骨骼的骨化过程有机会阻碍软骨成熟。其他 蜥蜴尾巴上的信号缺失使得蝾螈骨细胞得以存活并促进骨膜发育。 基于这种比较分析，我们假设基于机制的干预措施的可行性， 用“不完美”再生的蜥蜴尾巴来模仿“完美”再生的蝾螈尾巴。目标是： (1)通过补充成人脊髓脊膜向再生的蜥蜴尾软骨膜引入图案化 （2）通过阻断抗- 导致软骨发育失调的成熟信号;和（3）促进骨膜形成 通过诱导骨细胞的存活和补充，采取综合办法 提出，将一种独特的，无性繁殖的蜥蜴物种与体内手术操作相结合， 提供细胞和生物活性剂来操纵骨骼发育。我们认为，这种做法将 产生第一个再生的蜥蜴尾巴，骨骼显示软骨成熟和分割。这些 研究将有助于对脊椎动物再生过程的机械理解，并可能导致 改善包括人类在内的非再生生物体的骨骼愈合。