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: 10367800
• 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/10367800
• 关键词: Adult; Amaze; Ambystoma; Ambystoma mexicanum; Anatomy; Animal Model; Apoptosis; CXCR4 Receptors; CXCR4 gene; Cartilage; Cell Lineage; Cell Survival; Cells; Characteristics; Chemotaxis; Chondrocytes; Complex; Development; Elements; Embryo; Environment; Epiphysial cartilage; Exhibits; Funding; Generations; Goals; Homologous Transplantation; Human; Hypertrophy; Immunosuppression; Interruption; Intervention; Knowledge; Lead; 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 Transduction; Skeletal Development; Skeleton; Source; Spinal Cord; Tail; Testing; Thyroid Hormones; Tissue Engineering; Tissues; Translating; Tube; Vertebral column; asexual; base; blastema; bone cell; cartilage development; cartilaginous; cellular engineering; comparative; design; healing; improved; in vivo; information model; innovation; insight; knock-down; migration; 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，蝾螈的原理 再生以增强哺乳动物的愈合并不直接适用。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，作为一组模型生物 旨在操纵骨骼再生能力的研究。虽然蝾螈和蜥蜴都会再生 蝾螈的尾巴可以再生出近乎完美的原始尾巴副本，而再生的蜥蜴尾巴是众所周知的 作为“不完美的复制品”，与原件相比有几个关键的解剖学差异。其中最引人注目的是 这些“缺陷”涉及再生蜥蜴尾部缺乏背腹图案和分割 骷髅。根据我们最初的提议取得的进展确定了调节再生骨骼组织的信号 感应和图案化，创造出第一个背腹图案化的再生蜥蜴尾巴。此次续订 该提案侧重于骨骼成熟的后期阶段，如果给予适当的信号，最终会出现分割。 我们最近的比较分析表明，再生骨架分割取决于三个 不同的里程碑：(1) 软骨膜图案化，(2) 软骨肥大，(3) 骨膜形成。两个都 蝾螈和蜥蜴再生的尾部骨骼最初是不分段的软骨元素。我们的初步 研究结果表明脊髓脑膜组织在调节骨骼分割方面具有新的作用。再生 蝾螈（但不是蜥蜴）的脑膜含有能够重建胚胎的特殊细胞群 相邻软骨膜中的分割信号并启动信号级联，从而改变整个软骨膜 再生的骨骼。这些信号中的一些信号在抗病毒之前诱导蝾螈软骨肥大。 主导蜥蜴骨骼的骨化过程有可能阻碍软骨的成熟。其他 蜥蜴尾巴中缺失的信号使蝾螈骨细胞能够存活并促进骨膜发育。 基于这种比较分析，我们假设基于机械的干预措施转变的可行性 “不完美”再生的蜥蜴尾巴来模拟“完美”再生的蝾螈尾巴。目标是： (1) 通过补充成人脊髓脑膜将图案引入再生蜥蜴尾软骨膜 与胚胎分段细胞； (2)通过中断抗-诱导再生蜥蜴软骨肥大 导致软骨发育失调的成熟信号； (3)促进骨膜形成 通过诱导骨细胞存活和募集，在再生蜥蜴尾部内进行。综合方法是 提出，将一种独特的无性繁殖蜥蜴物种与体内手术操作结合起来 输送细胞和生物活性剂来操纵骨骼发育。我们相信这种方法将 产生第一条再生蜥蜴尾巴，其骨骼表现出软骨成熟和分段。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 改善非再生生物体（包括人类）的骨骼愈合。