From ageing to space travel: Developing an organotypic model of skeletal tissue disuse for understanding degeneration in altered environments

从衰老到太空旅行：开发骨骼组织废用的器官模型，以了解改变环境中的退化

• 批准号: NC/S001859/1
• 负责人: Alexandra Iordachescu
• 金额: $ 15.51万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FS001859%2F1
• 关键词: ageing; space; travel; Developing; organotypic

The role of bone tissue in maintaining calcium balance and organ function is essential. Calcium acts as a universal currency and is essential for most physiological processes, including cellular communication, muscle contraction, blood clotting and nerve function. A substantial loss of skeletal tissue takes place in several clinical contexts, including disuse osteoporosis, ageing, spinal cord injury, immobilisation and weightlessness in microgravity, all characterised by rapid and significant loss in bone mass in the load-bearing regions, including lower limbs, spine and hip. This increases the risk in fractures and impairs the healing process, placing a significant burden on the healthcare system and the costs associated with interventions.While bone mass is known to decrease proportionally with reduced loading, the cellular processes governing it require further understanding. It is widely accepted that bone resorption is increased and bone deposition is decreased, however, there is no robust way of studying the imbalance in bone remodelling.There are well-established animal models for studying musculoskeletal disuse and bone loss, which cause a reduction in bone mass in animals either through surgical removal of glands involved in bone metabolism, immobilisation using toxins, surgical resection of nerves, tendons or the spinal cord, or a tail suspension method facilitating hindlimb unloading. Some of these processes are very detrimental for the animals and others interfere with the biochemistry of skeletal homeostasis. Moreover, the results are not entirely representative of the human conditions, as differences exist in the bone remodelling process between the two species and between strains of the same laboratory animal.The aim of this work is to produce a model that can refine and reduce the number of animals used for understanding musculoskeletal degeneration and to provide a method to study bone loss in a dish. The work will generate a physiologically-relevant model, in which specialised bone cells of human origin as well as combinations of these cell types will be cultured inside human-derived biological scaffolds. Cells will be provided with mechanical unloading using several rotary culture bioreactors that can keep cells in a constant suspension using constantly rotating vessels, thus simulating a weightless state. This platform will be used in combination with a range of active matrices derived from human tissue, such as fibrin (blood clot-like), which are degradable and pathologically representative. These will be morphologically adapted into spheroids for suspended culture and can provide a degree of support while allowing bone cells to replace them with collagenous matrix, heavily mineralise this template and bury themselves inside it, as shown by foundation work. This model will help in studying early bone loss processes which are essential for understanding disuse pathology, can provide a first-stage elimination step of cytotoxic, genotoxic and incompatible compounds leading to less harmful agents being progressed for in vivo testing, and will allow the testing of numerous promising drugs and potential therapeutics. It will also help researchers developing treatments in a wide range of skeletal conditions, not only relevant to disuse osteoporosis, but also in excessive bone research, bone cancers, inflammatory degradation and multi-systemic research.

骨组织在维持钙平衡和器官功能中的作用至关重要。钙充当通用的货币，对于大多数生理过程至关重要，包括细胞交流，肌肉收缩，血液凝结和神经功能。在几种临床环境中，骨骼组织的大量丧失发生，包括废除骨质疏松症，衰老，脊髓损伤，微重力的固定和失重性，所有这些都以承载负荷区域的骨骼质量快速而显着损失，包括下肢，脊柱，脊柱和HIP。这增加了裂缝的风险并损害了愈合过程，给医疗保健系统带来了重大负担，并与干预措施相关的成本负担。众所周知，骨骼质量会随着减少的负载而成比例地减少，但控制的细胞过程需要进一步了解。 It is widely accepted that bone resorption is increased and bone deposition is decreased, however, there is no robust way of studying the imbalance in bone remodelling.There are well-established animal models for studying musculoskeletal disuse and bone loss, which cause a reduction in bone mass in animals either through surgical removal of glands involved in bone metabolism, immobilisation using toxins, surgical resection of nerves, tendons or脊髓或尾悬架方法促进后肢卸载。这些过程中的一些对动物和其他过程非常有害，并且会干扰骨骼稳态的生物化学。此外，结果并不完全代表人类状况，因为这两种物种之间和同一实验室动物的菌株之间的骨骼重塑过程中存在差异。这项工作的目的是生产一种模型，该模型可以完善并减少用于理解肌肉骨骼骨骼变性的动物数量，并提供一种盘旋中的骨骼损失方法。这项工作将产生与生理上的相关模型，其中人类来源的专门骨细胞以及这些细胞类型的组合将在人类衍生的生物支架内培养。将使用几个旋转培养物生物反应器提供机械卸载，这些生物反应器可以使用不断旋转的容器使细胞保持恒定的悬浮液，从而模拟失重状态。该平台将与源自人体组织的一系列活性基质（例如纤维蛋白（血凝块样））结合使用，这些矩阵是可降解且具有病理学代表性的。这些将在形态学上适应悬浮培养物的球体，并可以提供一定程度的支撑，同时允许骨细胞用胶原基质代替它们，从而大量矿物质化该模板并将其埋在其中，如基础工作所示。该模型将有助于研究早期的骨质流失过程，这些过程对于理解残疾病理学至关重要，可以提供第一阶段消除的细胞毒性，遗传毒性和不兼容化合物的步骤，从而导致体内测试的有害药物较小，并允许对众多有希望的药物和潜在的治疗方法进行测试。它还将帮助研究人员在各种骨骼条件下开发治疗方法，不仅与废除骨质疏松症有关，而且在过度的骨骼研究中，骨癌，炎症性降解和多系统研究。