Immunoengineering Body Fat: Modelling microphages in a 3D-bioprinted human adipose tissue model

免疫工程人体脂肪：在 3D 生物打印人体脂肪组织模型中模拟微噬细胞

• 批准号: EP/X01875X/1
• 负责人: Asme Boussahel
• 金额: $ 25.76万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX01875X%2F1
• 关键词: Immunoengineering; Body; Fat; Modelling; microphages

Obesity is a rising epidemic affecting a large number of the world population and is a risk for many diseases such as diabetes, heart disease and cancers. It is characterised by the deposition of large amounts of fat tissue in the body and around the organs. This fat tissue is mainly composed of specialised cells that store energy as fat known as adipocytes and immune cells known as macrophages. Macrophages act as immune sentinels, identifying foreign bodies and pathogens and eliminating them. In the fat tissue of obese individuals however, macrophages are thought to cause chronic inflammation which is the main mechanism for developing obesity associated complications such as diabetes. There are two types of macrophages in fat tissues. Tissue resident macrophages (TRMs), which are formed in the fetus and migrate to tissues where they create self-renewing cells over an individual's life time. The second type of macrophages are bone marrow derived macrophages (BMMs), they are produced in the bone marrow in adults and are recruited into tissues in response to inflammation. To study the role of these macrophages in obesity and metabolic diseases such as diabetes, this project will develop a tissue-engineered 3D printed model of human fat tissue containing the two types of macrophage sources. To model the BMMs, we will isolate bone marrow derived cells from human blood and differentiate them to macrophages; to model the TRMs we will use human stem cells with embryonic properties that can be differentiated into macrophages following the same process as during the embryo's development; finally to model the fat tissue environment, we will isolate adipocytes from human fat tissues. These three cells will be 3D bioprinted into a biomaterial construct to allow the cells to interact together in 3D. The combination of cells and biomaterial hydrogels will enable us to tissue-engineer a model of human fat tissue with the two types of macrophages. This model could be used to study more closely the interaction of macrophages with adipocytes and how this alters in obesity and results in metabolic diseases. Once established this model system could be used to probe the effects of inflammation (e.g. by stiffening the hydrogel properties- to model increased fiber deposition by adipocytes in obese fat tissue- or introducing inflammatory chemical stimuli) to determine how this influences macrophages response to and interaction with adipocytes. This model could also be used to test drugs or identify new targets for developing treatments for obesity and type 2 diabetes.

肥胖症是一种影响全世界人群的流行病，是许多疾病（例如糖尿病，心脏病和癌症）的风险。它的特征在于体内和器官周围大量脂肪组织的沉积。该脂肪组织主要由专门的细胞组成，这些细胞将能量存储为脂肪称为脂肪细胞和免疫细胞，称为巨噬细胞。巨噬细胞充当免疫哨兵，识别出异物和病原体并消除它们。但是，在肥胖个体的脂肪组织中，巨噬细胞被认为会引起慢性炎症，这是发展肥胖相关并发症（例如糖尿病）的主要机制。脂肪组织中有两种类型的巨噬细胞。组织驻留巨噬细胞（TRM），它们在胎儿中形成并迁移到组织，在该组织中，它们会在个人的寿命上产生自我更新的细胞。第二种类型的巨噬细胞是骨髓衍生的巨噬细胞（BMM），它们是在成年人的骨髓中产生的，并因炎症而被招募到组织中。为了研究这些巨噬细胞在肥胖症和代谢疾病（例如糖尿病）中的作用，该项目将开发一种由含两种类型的巨噬细胞来源的人类脂肪组织的组织设计的3D印刷模型。为了对BMM进行建模，我们将分离从人体血液中衍生的细胞，并将其区分为巨噬细胞。为了对TRM进行建模，我们将使用具有胚胎特性的人类干细胞，可以在与胚胎发育过程中相同的过程后分化为巨噬细胞。最后，为了建模脂肪组织环境，我们将从人脂肪组织中分离脂肪细胞。这三个细胞将被3D生物打印到生物材料构建体中，以使细胞在3D中相互作用。细胞和生物材料水凝胶的组合将使我们能够组织工程师与两种类型的巨噬细胞的人脂肪组织模型。该模型可用于更仔细地研究巨噬细胞与脂肪细胞的相互作用，以及这种模型如何改变肥胖和导致代谢疾病。一旦建立，该模型系统就可以用于探测炎症的影响（例如，通过将水凝胶性能加强到建模肥胖组织中脂肪细胞的纤维沉积增加或引入炎症化学刺激的纤维沉积），以确定这如何影响巨噬细胞响应和与脂肪细胞的相互作用。该模型也可以用于测试药物或确定用于开发肥胖症和2型糖尿病治疗方法的新靶标。