Why don't lizards regenerate perfect tails like salamanders?

为什么蜥蜴不能像蝾螈那样再生出完美的尾巴？

• 批准号: 10810584
• 负责人: Thomas Peter Lozito
• 金额: $ 1.86万
• 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/10810584
• 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，火蜥蜴的原理 再生以增强哺乳动物的愈合并不是直接适用的。在这里我们建议使用蜥蜴，更多 与哺乳动物关系密切但表现出显著的再生能力的，如一系列 旨在控制骨骼再生能力的研究。而火蜥蜴和蜥蜴都能再生 它们的尾巴，火蜥蜴会再生出近乎完美的原始尾巴，而再生的蜥蜴尾巴则是已知的 作为一种“不完美的复制”，与原始的相比有几个关键的解剖学差异。最引人注目的是 这些“缺陷”与再生的蜥蜴尾巴缺乏背腹图案和分割有关。 骷髅。根据我们最初的建议所取得的进展，确定了调节再生骨骼组织的信号 诱导和图案，创造了第一个背腹图案的再生蜥蜴尾巴。此次续订 该提案侧重于骨骼成熟的后期阶段，给出适当的信号，最终将其分割。 我们最近的比较分析表明，重新生成的骨架分割依赖于三个 不同的里程碑：(1)软骨膜图案化，(2)软骨肥大，(3)骨膜形成。两者都有 火蜥蜴和蜥蜴再生的尾巴骨骼开始时是不分段的软骨元素。我们的预赛 研究结果表明，脊髓脑膜组织在调节骨骼分段中扮演了一个新的角色。重新生成 蜥蜴，而不是蜥蜴，脑膜含有能够重建胚胎的特殊细胞群 分割相邻软骨膜中的信号，并启动信号级联，将整个 重新生成的骨架。这些信号中的一些信号在抗-TdR之前诱导火蜥蜴软骨肥大。 主导蜥蜴骨骼的骨化过程有可能使软骨成熟停滞。其他 蜥蜴尾巴中缺失的信号使蜥蜴骨细胞得以存活并促进骨膜发育。 在此对比分析的基础上，我们假设了机械性干预转向的可行性 “不完美”的再生蜥蜴尾巴复制了“完美”再生的蜥蜴尾巴。目标是： (1)通过补充成年脊髓脑膜在再生的蜥蜴尾部软骨膜中引入花纹 (2)通过阻断反义寡核苷酸诱导再生的蜥蜴软骨肥大。 导致软骨发育失调的成熟信号；以及(3)促进骨膜形成 在再生的蜥蜴尾巴中，通过诱导骨细胞存活和募集。一种综合的方法是 建议，将一种独特的无性繁殖蜥蜴物种与活体外科手术相结合，以 为操控骨骼发育提供细胞和生物活性物质。我们相信，这一做法将 产生第一条再生的蜥蜴尾巴，其骨骼显示出软骨成熟和分割。这些 研究将有助于从机制上理解脊椎动物的再生过程，并可能导致 改善包括人类在内的非再生有机体的骨骼愈合。