ISS/Collaborative Research: 3D Bone Marrow Analogs to Determine the Contribution of Mechanical Signals to Aging MSC Function in Microgravity

ISS/合作研究：利用 3D 骨髓类似物确定微重力下机械信号对 MSC 功能老化的影响

• 批准号: 2025505
• 负责人: Gunes Uzer
• 金额: $ 31.5万
• 依托单位: Boise State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-11-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2025505&HistoricalAwards=false
• 关键词: ISS; Collaborative; Research; 3D; Bone

Mechanical signals generated by exercise combat obesity and maintain a healthy musculoskeletal system. Age and reduced physical activity disrupt mechanical signaling and diminish the potency of stem cells within the bone marrow that replenish bone-building cells. Even though poor skeletal health is a major cause of injury and disability among aged individuals, the reason for reduced bone-building responsiveness to exercise in older individuals, compared to younger individuals, remains a knowledge gap. This project will quantify the mechanical forces that cells are subjected to in bone by using novel 3D printed tissue engineering constructs. Combining this technology with the aging conditions caused by microgravity in experiments to be conducted on the International Space Station will reveal the putative connections between aging and physical activity at the cellular level. Ultimately, these efforts may lead to non-pharmacologic, regenerative strategies to improve muscle and bone health in in older adults, in those who must undergo extended bedrest, and astronauts. The multidisciplinary approach taken in this bioengineering project will be an excellent platform to fascinate and engage the next generation of students and young scientists.A major technical barrier in studying the mechanical environment of mesenchymal stem cells (MSCs) that reside within bone marrow is that there are no model systems currently available that can replicate the mechanical complexity of the bone marrow compartment. To close this gap, this work will develop a 3D printed bone marrow analog system that combines an in vivo environment with the accessibility of an in vitro culture system. This will permit a systematic approach of study. To study cellular mechanical environments within these marrow analogs, the approach will include an experimental setup and a complementary and validated finite element model. These mechanoactive marrow environments will provide a novel tool for mechanobiologists to systematically study the effect of the mechanical environment on cell responses in 3D. Utilization of this novel system in this project will specifically advance mechanobiology knowledge by: (1) quantifying the mechanoresponse of old MSCs in a young bone marrow geometry and vice versa, thereby identifying the contribution of mechanical stress environment to the mechanosignaling capacity of aged MSCs. (2) establishing, for the first time, how the mechanical stress environment contributes to microgravity-simulated aging of MSCs.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

运动产生的机械信号对抗肥胖，保持健康的肌肉骨骼系统。年龄和体力活动减少会破坏机械信号，并降低骨髓中补充骨生成细胞的干细胞的效力。尽管骨骼健康状况不佳是老年人受伤和残疾的主要原因，但与年轻人相比，老年人对运动的骨生成反应性降低的原因仍然是一个知识差距。该项目将通过使用新型3D打印组织工程结构来量化细胞在骨骼中所受到的机械力。在国际空间站上进行的实验中，将这项技术与微重力造成的老化条件相结合，将揭示衰老与身体活动之间在细胞水平上的假定联系。最终，这些努力可能会导致非药理学的再生策略，以改善老年人，必须长期卧床休息的人和宇航员的肌肉和骨骼健康。在这个生物工程项目中采取的多学科方法将是一个吸引和吸引下一代学生和年轻科学家的绝佳平台。研究骨髓间充质干细胞（MSC）的力学环境的主要技术障碍是目前没有模型系统可以复制骨髓腔室的力学复杂性。为了缩小这一差距，这项工作将开发一种3D打印骨髓模拟系统，该系统将体内环境与体外培养系统的可访问性相结合。这将允许系统的研究方法。为了研究这些骨髓类似物内的细胞力学环境，该方法将包括实验装置和互补且经验证的有限元模型。这些机械活性骨髓环境将为机械生物学家提供一种新的工具，以系统地研究三维力学环境对细胞反应的影响。在该项目中利用这种新系统将通过以下方式特别推进机械生物学知识：（1）量化年轻骨髓几何结构中老年MSC的机械响应，反之亦然，从而确定机械应力环境对老年MSC机械信号传导能力的贡献。(2)首次确定了机械应力环境如何影响MSC的微重力模拟老化。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Lamin A/C Is Dispensable to Mechanical Repression of Adipogenesis.

• DOI: 10.3390/ijms22126580
• 发表时间: 2021-06-19
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Goelzer M;Dudakovic A;Olcum M;Sen B;Ozcivici E;Rubin J;van Wijnen AJ;Uzer G
• 通讯作者: Uzer G

Architectural control of mesenchymal stem cell phenotype through nuclear actin.

• DOI: 10.1080/19491034.2022.2029297
• 发表时间: 2022-12
• 期刊: Nucleus (Austin, Tex.)
• 作者: Rubin J;van Wijnen AJ;Uzer G
• 通讯作者: Uzer G