钙粘素改性生物材料协同hMSCs诱导hiPSCs源神经血管单元类器官构建的研究

为了构建多组织异质结构类器官，基于我们钙粘素融合蛋白基质及其调控单细胞构建肝类器官的前期基础，本项目提出研发具有细胞粘附因子和诱导因子（IF）时空有序递送功能的壳核结构复合高分子材料微球（IFMPs@Cad-Fc）调控hMSCs，协同诱导hiPSCs逐级构建神经/血管祖细胞聚集体并组装神经血管单元（NVU）类器官的仿生调控技术。研究材料微球理化特性对外源细胞黏附因子和IF可控递送及其对干细胞内源性生物信息分子表达的影响，探索IFMPs@Cad-Fc协同hMSCs仿生动态调控细胞外微环境及逐级构建NVU类器官的作用机制及其构效/量效关系，实现NVU类器官的批量制备，探索其在药筛领域的应用潜能。该研究不仅对类器官组装技术及其相关生物材料研发具有重要的研究价值，hiPSCs/hMSCs源NVU类器官模型对中枢神经系统病/生理基础研究和新药与治疗技术的研发也具有重要的理论研究意义和应用研发价值。

In order to construct multi-organism heterogeneous organoids, based on our previous researches that focused on the construction of liver organoids from single-cell sources regulated by cadherin fusion protein matrices, this project proposes to develop composite microparticles (IFMPs@Cad-Fc) with shell-core structure that capable of sequentially delivering cell-adhesion factors (Cads) and inducible factors (IFs) to regulate the cellular behaviors of hMSCs/hiPSCs, and investigate the regulation strategies on using their synergistic effects to induce the construction of hiPSCs-derived neurovascular unit (NVU) organoids from the primary neural / vascular progenitor cell aggregates step by step. The physical and chemical properties of IFMPs@Cad-Fc microparticles would be optimized to achieve the controlled delivery of Cads and IFs, and the influence on the expressions of endogenous biological information molecules of hMSCs and hiPSCs would be evaluated. Further, the dose-effect and structure-effect relationships of the synergy of IFMPs@Cad-Fc with hMSCs in regulating the extracellular microenvironment biomimetically and dynamically and driving the sequential assembly of NVU organoids. Finally, we would attempt to realize the batch preparation of NVU organoids, and explore their application potential in drug screening. The research not only has important value for the researches on organoid assembly technology and the development of related biomaterials, the NVU organoid model derived from hiPSCs / hMSCs also has a pivotal role in the basic physiological and pathological theories on central nervous system and the development of the new drugs and therapeutic technologies for cerebrovascular disease.