CAREER: Engineering instructive niches to precisely guide single stem cells

干细胞具有发育成不同类型细胞的能力。这些细胞是建立和维持正常组织所必需的。然而，受损的组织通常不会自行愈合。这个教师早期职业发展计划（CAREER）项目将开创新的方法，以了解如何通过在干细胞周围建立指导性的小生境（微环境）来精确引导干细胞再生组织，一次一个细胞。开发的方法可以与其他现有的生物制造方法相结合，通过提供具有局部定义特性的凝胶涂层细胞作为构建模块来制造新的组织。该教育计划将为来自不同背景的高中教师和学生提供参与实践研究活动的机会，这些活动整合了科学，技术，工程和数学（STEM）的多个领域。这项综合性的工作旨在促进早期接触多学科的思维和学习过程，这对解决生物系统中具有挑战性的问题至关重要。研究者的职业目标是通过展示微凝胶可以被设计为精确理解和控制单个干细胞功能的指导性线索来实现范式转变。 为了实现这一目标，这个CAREER项目基于这样一个中心前提，即构建概括单细胞周围生理相关细胞外基质特性的指导性小生境提供了一个独特的方向，这将使研究微环境如何以前所未有的分辨率调节干细胞功能成为可能。为了证实这一前提，该项目将研究如何设计三维微环境，以精确指导细胞命运决定所必需的基本过程，包括单细胞水平的细胞生长，对称性破坏，不对称分裂和分化。将采用多学科方法来进行这个项目，包括生物材料设计，液滴微流体，生物物理方法，数学建模，成像和基因工程。该研究将产生一个设计的微环境模型库，可用于以确定性方式概括和控制细胞命运决定的特定生物过程。通过本研究开发的工具，对细胞命运决定的更深入了解将有助于开发有效的干细胞治疗方法和组织再生生物制造方法。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估来支持。

Stem cells have the ability to develop into different types of cells. These cells are necessary to build and maintain normal tissues. However, damaged tissues often do not heal themselves. This Faculty Early Career Development Program (CAREER) project will pioneer new approaches to understand how stem cells can be precisely guided to regenerate tissues by building instructive niches (microenvironments) around them, one cell at a time. The approach developed can potentially be integrated with other existing biomanufacturing approaches to fabricate new tissues by providing gel-coated cells with locally defined properties as building blocks. The educational program will provide both high school teachers and students from diverse backgrounds with opportunities to be engaged in hands-on research activities that integrate multiple fields in science, technology, engineering and math (STEM). This integrated effort is designed to promote early exposure to multidisciplinary thinking and learning processes that are critical to solve challenging problems in biological systems.The investigator's career goal is to achieve a paradigm shift by showing that microgels can be designed as instructive cues to precisely understand and control single stem cell functions. Toward this goal, this CAREER project is based on the central premise that building instructive niches that recapitulate physiologically relevant extracellular matrix properties around single cells offers a unique direction that will enable investigations into how microenvironments regulate stem cell functions at an unprecedented resolution. To confirm this premise, the project will investigate how three-dimensional microenvironments can be designed to precisely direct fundamental processes that are essential for cell fate decision, including cell growth, symmetry breaking, asymmetric division and differentiation at the single cell level. Multidisciplinary approaches will be employed to pursue this project, including biomaterial design, droplet microfluidics, biophysical methods, mathematical modeling, imaging and genetic engineering. The research will yield a library of designed microenvironment models that can be used to recapitulate and control specific biological processes of cell fate decision in a deterministic manner. A greater understanding of cell fate decision enabled by the tools developed in this research will aid in endeavors to develop effective stem cell-based therapies and biomanufacturing approaches for tissue regeneration.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.