Cellular metabolism at the crossroads of skeletal regeneration

处于骨骼再生十字路口的细胞代谢

• 批准号: 10700104
• 负责人: Mimi C Sammarco
• 金额: $ 23.51万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-07 至 2023-12-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10700104
• 关键词: Affect; Aging; Amputation; Biological; Bone Regeneration; Cell Differentiation process; Cell physiology; Cells; Cellular Metabolic Process; Collagen; Complex; Data; Deposition; Digit structure; Exhibits; Gene Expression; Genes; Genetic; Glycolysis; Hepatocyte; Homeostasis; Human; Impairment; Injury; Knockout Mice; Knowledge; Link; Metabolic; Metabolism; Minerals; Modeling; Molecular; Mus; Natural regeneration; Osteoblasts; Osteogenesis; Outcome; Oxaloacetates; Oxidative Phosphorylation; Pathway interactions; Process; Proliferating; Protein Secretion; Regenerative capacity; Role; Salamander; Signal Transduction; Structure; Testing; Thick; Time; Tissues; aged; blastema; bone healing; cell type; inducible Cre; insight; limb regeneration; mineralization; mouse model; novel; osteoblast differentiation; progenitor; regenerative; repaired; respiratory; response; skeletal; skeletal regeneration; therapeutic target; transcriptomics; triple helix

Limb regeneration after injury is a sophisticated and energetically expensive process. In this process, progenitor proliferation, osteoblast differentiation and mineral deposition all require sufficient supplies of biological building blocks and ATP(1-5). However, the contribution of cell metabolism and its genetic control of skeletal regeneration is largely unknown, representing a major knowledge gap. Using the established mouse digit tip amputation model, we found that mice exhibit impaired regeneration during aging, and that this impairment is linked to increased expression of glycolysis and oxidative phosphorylation (OxPhos) genes, compared to young mice. These exciting preliminary results have led us to investigate the metabolic and genetic mechanisms that underlie skeletal regeneration. Our preliminary findings support that skeletal regeneration is metabolism-dependent and can be manipulated by exogenous metabolites and gene expression, respectively. These data suggest that administration of oxaloacetate (OAA), a pro-glycolytic and pro-respiratory metabolite, increases regenerated bone volume and thickness in a mouse model. Alternatively, modulation of collagen triple helix repeat containing 1 (Cthrc1) also alters skeletal regeneration. Cthrc1 is specifically expressed in the blastema, the dedifferentiated tissue structure central to regeneration, and Cthrc1-/- mice demonstrated impaired regeneration and dysregulated cell metabolism. Moreover, our preliminary data show that treatment with OAA increases Cthrc1 expression, reinforcing a direct link between metabolism and genetic control. We hypothesize that a finely tuned interaction between cell metabolism and genetic control synergistically regulates cell function, and that this interaction can be manipulated both exogenously (OAA) and at a gene level (Cthrc1) to modulate regenerative outcomes.

受伤后的肢体再生是一个复杂且耗能的过程。在这个过程中，祖 增殖、成骨细胞分化和矿物质沉积都需要充足的生物建筑供给 块和 ATP(1-5)。然而，细胞代谢的贡献及其对骨骼再生的遗传控制 很大程度上是未知的，代表着重大的知识差距。使用已建立的小鼠指尖截肢术 在模型中，我们发现小鼠在衰老过程中表现出再生受损，并且这种受损与 与年轻小鼠相比，糖酵解和氧化磷酸化（OxPhos）基因的表达增加。 这些令人兴奋的初步结果促使我们研究潜在的代谢和遗传机制 骨骼再生。 我们的初步研究结果支持骨骼再生依赖于新陈代谢，并且可以通过 分别是外源代谢物和基因表达。这些数据表明，管理 草酰乙酸 (OAA) 是一种促糖酵解和促呼吸代谢物，可增加再生骨量并 小鼠模型中的厚度。或者，还可以调节含有 1 (Cthrc1) 的胶原蛋白三螺旋重复序列 改变骨骼再生。 Cthrc1 在胚基（去分化的组织结构）中特异性表达 Cthrc1-/- 小鼠表现出再生受损和细胞失调 代谢。此外，我们的初步数据表明，OAA 治疗会增加 Cthrc1 表达， 加强新​​陈代谢和遗传控制之间的直接联系。我们假设精细调整的交互 细胞代谢和遗传控制之间协同调节细胞功能，这种相互作用可以 可以通过外源性（OAA）和基因水平（Cthrc1）进行操作来调节再生结果。