Engineering the Stem Cell Microenvironment for Lymphatic Regeneration

改造干细胞微环境促进淋巴再生

• 批准号: 10276874
• 负责人: Donny Hanjaya-Putra
• 金额: $ 39.13万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10276874
• 关键词: Aging; Alzheimer' s Disease; Attenuated; Biocompatible Materials; Biological; Biology; Biomedical Engineering; Blood Vessels; Blood capillaries; Cardiovascular Diseases; Cardiovascular system; Cells; Development; Dietary Fats; Disease; Edema; Environment; Extracellular Fluid; Functional disorder; Goals; Health; Homeostasis; Human; Immune; Inflammation; Inflammatory Response; Knowledge; Link; Liquid substance; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic function; Malignant Neoplasms; Metabolic Diseases; Microfluidics; Modeling; Molecular; Morphogenesis; Muscle Cells; Natural regeneration; Obesity; Outcomes Research; Physiology; Reproducibility; Research; Source; Systems Biology; Testing; Therapeutic; Thoracic Duct; Tissues; Vascular System; Wound models; absorption; chronic wound; clinical application; clinically relevant; differentiation protocol; engineered stem cells; fluid flow; human pluripotent stem cell; innovation; interdisciplinary approach; lymphatic vasculature; lymphatic vessel; prevent; programs; public health relevance; stem cell differentiation; stem cells; therapeutic target; tissue regeneration; trafficking

ABSTRACT The lymphatic system is an integral part of the circulatory system, where extracellular fluid flows from vascular capillaries into the lymphatic vessels and is returned to the vascular system via the thoracic duct. Additionally, lymphatic vessels regulate homeostasis of tissue fluid, absorption of dietary fat, and trafficking of immune cells. Consequently, dysfunction in lymphatic vessels is associated with development of many diseases, including obesity and metabolic disease, aging and Alzheimer’s disease, chronic wound and cancer, as well as inflammation and cardiovascular diseases. Therefore, controlling lymphatic vascular formation and augmenting its function is postulated as a promising therapeutic target for preventing and treating these debilitating diseases. Unfortunately, therapeutic lymphangiogenesis has not been widely explored partly due to the unavailability of a clinically-relevant cell source and controllable matrix environment. The overall goal of the research program is to derive lymphatic endothelial cells (LECs) and lymphatic muscle cells (LMCs) from human pluripotent stem cells (hPSCs) that can be used as a clinically-relevant cell source for modeling lymphatic function and physiology, as well as therapeutic lymphangiogenesis in a synthetic and controllable matrix environment. To this end, our lab is at the forefront of developing multi-disciplinary approaches to utilize stem cells and synthetic biomaterials for basic understanding of stem cell differentiation and lymphatic vessel morphogenesis, as well as approaches in therapeutic lymphangiogenesis. We have recently established xeno-free, well-defined and controllable differentiation protocols to direct hPSCs differentiation to clinically-relevant vascular progenitor cells with high reproducibility and efficiency, as well as wide clinical applicability. Furthermore, synthetic matrices can be used to provide spatial and temporal control for these progenitor cells to undergo lymphatic vascular morphogenesis, useful for basic understanding of lymphatic vascular biology and a range of therapeutic applications. These results establish a fundamental link between vascular and lymphatic morphogenesis within synthetic matrices. We are currently focused on bridging the large knowledge gap between molecular understanding of vascular and lymphatic differentiation and morphogenesis in a developmental context. Furthermore, we are also testing the impact of lymphatic vasculature to attenuate inflammatory response, prevent edema, and eventually promote tissue regeneration in a wound healing model. Cumulatively, we are combining approaches in stem cell and bioengineering, biomaterials and microfluidics, as well as lymphatic and systems biology to develop the necessary component in therapeutic lymphangiogenesis: reliable human cell sources from hPSCs within a biologically rational synthetic and controllable matrix environment. Collectively, this research has the potential to not only advance our basic understanding of lymphatic vasculatures in health and disease, but also to revolutionize the way we manage and treat a myriad of diseases that will benefit from innovative therapeutic lymphangiogenesis.

摘要 淋巴系统是循环系统的组成部分，细胞外液体从血管流出。 毛细血管进入淋巴管，并通过胸腔导管回到血管系统。另外， 淋巴管调节组织液的动态平衡、饮食脂肪的吸收和免疫细胞的运输。 因此，淋巴管功能障碍与许多疾病的发生有关，包括 肥胖症和代谢性疾病、衰老和阿尔茨海默氏症、慢性伤口和癌症以及 炎症和心血管疾病。因此，控制淋巴管的形成和增强 它的功能被认为是预防和治疗这些衰弱疾病的一个有前途的治疗靶点。 不幸的是，治疗性淋巴管生成还没有得到广泛的探索，部分原因是没有可用的 临床相关的细胞源和可控的基质环境。研究计划的总体目标是 人多能干细胞来源的淋巴管内皮细胞和淋巴肌细胞 细胞(HPSCs)，可用作临床相关的细胞源，用于模拟淋巴功能和生理， 以及在合成和可控制的基质环境中的治疗性淋巴管生成。为此，我们的 实验室处于开发利用干细胞和合成生物材料的多学科方法的前沿 对干细胞分化和淋巴管形态发生的基本了解以及方法 在治疗性淋巴管生成方面。我们最近已经建立了无Xeno、定义明确和可控制的 HPSCs定向分化为临床相关的高分化血管祖细胞的方案 重复性和有效性，以及广泛的临床适用性。此外，还可以使用合成矩阵 为了为这些祖细胞进行淋巴管形态发生提供空间和时间控制， 有助于对淋巴管生物学和一系列治疗应用的基本了解。这些 结果在合成基质中建立了血管和淋巴形态发生之间的基本联系。 我们目前的重点是弥合分子对血管的理解之间的巨大知识鸿沟 以及发育背景下的淋巴分化和形态发生。此外，我们还在测试 淋巴管系统对减轻炎症反应，防止水肿，并最终促进 伤口愈合模型中的组织再生。总体而言，我们正在结合干细胞和 生物工程、生物材料和微流体，以及淋巴和系统生物学，以开发 治疗性淋巴管生成的必要组成部分：可靠的人类细胞来源 生物合理的合成和可控的基质环境。总体而言，这项研究有可能 不仅增进了我们对淋巴管在健康和疾病中的基本了解，而且还 彻底改变我们管理和治疗多种疾病的方式，这些疾病将从创新疗法中受益 淋巴管生成。