Investigating bioengineering approaches to produce immuno-modulatory mesenchymal stromal cells and their extracellular vesicle

研究生产免疫调节间充质基质细胞及其细胞外囊泡的生物工程方法

• 批准号: 2608627
• 金额: --
• 依托单位: Aston University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2025
• 资助国家: 英国
• 起止时间: 2025 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2608627
• 关键词: Investigating; bioengineering; approaches; produce; immuno

Mesenchymal stromal cells (MSCs) are a rare population of cells found in most tissues within the body and are invaluable in the maintenance of these structures. As well as forming bone, muscle or fatty tissues, MSCs can also be immunosuppressive. They can both resolve inflammation by modulating immune cells (ImCs) and promote tissue repair through multiple mechanisms such as the release of soluble factors or lipid-bound vesicles - extracellular vesicles (EVs). Currently, MSCs are being trialed as a cell-based therapy, however, large numbers are required. EVs may reduce this cell requirement, but are themselves needed in high quantities for patient therapy, therefore expansion of MSCs is essential before transfusion of either cells or EVs. Unfortunately, MSCs spontaneously differentiate over time in laboratory culture, losing their critical naïve immunomodulatory (ImM) abilities. Moreover, the clinical demand for MSCs remains unmet as MSCs from older donors are comparatively less potent than those from younger donors. This limits the number of patients that can be currently treated with this therapy and the ability to grow functional, naïve MSCs which retain their important anti-inflammatory and tissue repair abilities remains a key goal for scientific research. Thus, there is a need to investigate new methodologies to expand MSCs in the laboratory whilst maintaining them in a naïve state for therapy.Previous observations have revealed the potential for altering the growth conditions of MSCs which affect their metabolism yet retaining their ImM and repair properties. Changes in MSC adhesion for example, affect their energy production; a key feature of how MSCs modulate their physiology. Supplementation of small molecules to MSC cell culture can also reproduce this effect and maintain the ImM functions of these cells. These represent new approaches to culturing the large number of cells required for individual patient therapy or EV collection. How these culture methods affect MSC ImM properties or EV therapeutic anti-inflammatory potential remains to be defined. Therefore using alternative growth conditions potentially allows expansion of therapeutically relevant MSC and their EVs. The delivery of molecules from EVs to cells may have the potential to control the immune system for therapeutic benefit. While actively growing cells continuously shed EVs - and EVs contain a variety of cargos including soluble factors, DNA and other proteins - EV treatment of inflammatory conditions has been demonstrated not to be associated with toxic side effects of standard drug treatments. This project will build upon initial findings, exploring the potential of novel culture systems to generate large scale cultures of functional cells for therapy. Combining polymer-based growth surfaces with expansion in bioreactors will be evaluated. MSCs will be expanded via a microcarrier-based bioreactor, initially on a small-scale to optimise culture conditions. This system allows the rapid growth of MSCs, increasing their numbers more quickly than traditional laboratory-based culture. Expanded MSC 'quality' will be evaluated by measuring growth, metabolism profiles, ImM function on ImCs, and the MSC EV's ability to modulate inflammation. Released soluble factors from MSCs within these culture systems will also be analysed. This approach may lead to a new diagnostic test to screen large scale cultures for therapy to provide patients with optimal, functional cells. Alongside this, MSC EVs collected from bioreactor expansion will be examined and characterised, with their effects on other ImCs evaluated.Overall, this project will inform on new bioprocessing and diagnostic approaches to allow the upscaling of MSC cultures to generate the required numbers of cells or EVs required for therapy. This has the potential to reveal new strategies for reversing the reduced functionality of MSCs from older donors through modulating their in-vitro growth condition

间充质基质细胞（MSC）是体内大多数组织中发现的罕见细胞群，在维持这些结构中是无价的。除了形成骨骼，肌肉或脂肪组织外，MSC还可以免疫抑制。它们既可以通过调节免疫细胞（IMC）来解决炎症，并通过多种机制（例如释放固体因子或脂质结合的蔬菜 - 细胞外蔬菜（EVS））来促进组织修复。当前，MSC正在被试用为基于细胞的治疗，但是需要大量数量。电动汽车可能会减少该细胞的需求，但本身需要大量的患者治疗，因此在输血之前，MSC的扩展是必不可少的。不幸的是，MSC在实验室文化中自发区分，失去了关键的幼稚免疫调节（IMM）能力。此外，由于老年捐助者的MSC的潜力较小，因此MSC的临床需求仍未得到满足。这限制了目前可以通过这种疗法进行治疗的患者数量以及保持功能性幼稚的MSC的能力，这些患者保留其重要的抗炎和组织修复能力仍然是科学研究的关键目标。这是有必要调查新方法以扩大实验室中的MSC，同时将其保持在幼稚的治疗状态。预览的观察结果表明，有可能改变其代谢而保留其IMM和修复特性的MSC的生长条件的潜力。例如，MSC粘附的变化会影响其能源产生； MSC如何调节其生理学的关键特征。将小分子补充为MSC细胞培养也可以再现这种作用并维持这些细胞的免疫功能。这些代表了文化的新方法，即单个患者治疗或收集EV所需的大量细胞。这些培养方法如何影响MSC IMM特性或EV疗法抗炎潜力尚待定义。因此，使用替代生长条件有可能扩大治疗相关的MSC及其电动汽车。分子从电动汽车到细胞的递送可能具有控制治疗益处的免疫系统的潜力。虽然积极生长的细胞不断脱落电动汽车 - EV含有各种cargos，包括固体因子，DNA和其他蛋白质，但已证明对炎症疾病的EV治疗与标准药物治疗的毒性副作用无关。该项目将建立在初步发现的基础上，探索新型培养系统生成用于治疗的功能细胞大规模培养的潜力。将评估基于聚合物的生长表面与生物反应器中的扩展。 MSC将通过基于微载体的生物反应器扩展，最初是在小规模上以优化培养条件的。该系统允许MSC的快速增长，比传统实验室文化更快地增加其数量。扩展的MSC“质量”将通过测量生长，代谢概况，IMC上的IMM功能以及MSC EV调节注射能力来评估。这些培养系统中从MSC中释放的可溶性因子也将进行分析。这种方法可能会导致一项新的诊断测试，以筛选大规模培养物进行治疗，从而为患者提供最佳的功能细胞。除此之外，将检查和表征从生物反应器扩展中收​​集的MSC EV，并对其对其他IMC进行评估的效果。此外，该项目将告知新的生物处理方法和诊断方法，以允许MSC培养物的升级以产生治疗所需的细胞或EVS数量。这有可能揭示新的策略，可以通过调节其体外生长状况来扭转老年捐助者的MSC功能降低