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

运动产生的机械信号对抗肥胖，并保持健康的肌肉骨骼系统。年龄和体力活动减少扰乱了机械信号，降低了骨髓中用于补充骨构建细胞的干细胞的能力。尽管骨骼健康状况不佳是老年人受伤和残疾的一个主要原因，但与年轻人相比，老年人对锻炼的建骨反应降低的原因仍然是一个知识差距。这个项目将通过使用新的3D打印组织工程结构来量化细胞在骨骼中受到的机械力。将这项技术与将在国际空间站进行的实验中的微重力引起的衰老条件相结合，将在细胞水平上揭示衰老和身体活动之间的假定联系。最终，这些努力可能导致非药理学的、再生的策略，以改善老年人、必须长时间卧床的人和宇航员的肌肉和骨骼健康。这个生物工程项目采用的多学科方法将是吸引和吸引下一代学生和年轻科学家的一个极好的平台。研究驻留在骨髓中的间充质干细胞(MSCs)的机械环境的一个主要技术障碍是，目前还没有可用的模型系统来复制骨髓室的机械复杂性。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，该系统结合了体内环境和体外培养系统的可及性。这将允许采用系统的研究方法。为了研究这些骨髓类似物中的细胞力学环境，该方法将包括一个实验装置和一个补充和验证的有限元模型。这些机械作用的骨髓环境将为机械生物学家在3D中系统地研究机械环境对细胞反应的影响提供一种新的工具。在本项目中利用这一新的系统将通过：(1)在年轻的骨髓几何结构中量化老年MSCs的力学反应，反之亦然，从而确定机械应力环境对老年MSCs机械信号能力的贡献。(2)首次确定机械应力环境如何影响MSCs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智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.