Collaborative Research: Investigating the role and interplay of microenvironment, manufacturing, and metabolism on MSC production of extracellular vesicles

间充质基质细胞(MSCs)是从骨髓和脂肪细胞中分离出来的。虽然它们不是干细胞，但它们表现出类似的分化为多种类型细胞的能力。这种能力构成了开发各种疾病治疗方法的基础。MSCs还会产生细胞外小泡(EVS)。电动汽车运输的生物活性分子可以促进细胞水平的反应。电动汽车很难重复生产。这限制了它目前的治疗潜力。当地条件的变化影响了MSC-EV的生产和功能。了解这些影响是该项目的重点。该项目还将促进来自代表性不足群体的学生参与STEM。许多挑战导致缺乏成功的MSC-EV临床翻译。MSC的异质性是一个关键问题。没有有效的关键质量属性(CQA)来预测给定批次的电动汽车将如何表现。电动汽车也没有标准化的制造方法。此外，关于扩展电动汽车制造相对于2D和3D环境的影响，存在知识差距。该项目的总体目标是了解3D结构如何影响电动汽车的生产，并确定控制这种反应的代谢途径。为了实现这些目标，项目组将：1)调查3D水凝胶微环境对电动汽车功能的影响，2)确定制造策略对电动汽车的影响，3)确定与电动汽车生产相关的代谢变化。预计已确定的机制将对不同治疗应用的MSC-EVS和其他类型细胞产生的EVS具有相关性。该项目由ENG/CBET中的细胞和生化工程计划以及BIO/MCB中的系统和合成生物学计划联合支持。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。

Mesenchymal stromal cells (MSCs) are isolated from bone marrow and fat cells. While they are not stem cells, they exhibit a similar ability to differentiate into many types of cells. That ability forms the basis for developing treatments for a variety of diseases. MSCs also generate extracellular vesicles (EVs). The EVs transport bioactive molecules that prompt cellular-level responses. It is difficult to manufacture EVs reproducibly. This limits its current therapeutic potential. Changes in local conditions impact MSC-EV production and function. Understanding those impacts is the focus of this project. The project will also promote STEM participation of students from underrepresented groups.Many challenges contribute to the lack of successful MSC-EV clinical translation. MSC heterogeneity is a key issue. There are no effective critical quality attributes (CQAs) that predict how a given batch of EVs will perform. There are also no standardized manufacturing approaches for EVs. In addition, there is a knowledge gap regarding the effects of scaling EV manufacturing with respect to 2D vs. 3D environments. The overall goals of this project are to understand how 3D structure affects EV production and to identify metabolic pathways controlling this response. To accomplish these goals, the project team will: 1) investigate the effects of 3D hydrogel microenvironments on EV function, 2) determine the effects of manufacturing strategies on EVs, and 3) define metabolic changes associated with EV production. It is anticipated that the mechanisms identified will have relevance for MSC-EVs for different therapeutic applications and for EVs generated by other cell types.This project is jointly supported by the Cellular and Biochemical Engineering Program in ENG/CBET and the Systems and Synthetic Biology Program in BIO/MCB.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.