CAREER: Engineering instructive niches to precisely guide single stem cells

干细胞有能力发育成不同类型的细胞。这些细胞是构建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。这一学院早期职业发展计划(CALEAR)项目将开创新的方法，了解如何通过在干细胞周围一次一个细胞地构建具有指导性的利基环境(微环境)，精确地引导干细胞再生组织。开发的方法可以潜在地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的特性的凝胶涂层细胞作为构建块来制造新的组织。该教育项目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。这一综合努力旨在促进早期接触多学科思维和学习过程，这些过程对于解决生物系统中具有挑战性的问题至关重要。研究人员的职业目标是通过展示微凝胶可以被设计为具有指导意义的线索来精确理解和控制单个干细胞的功能，实现范式的转变。为了实现这一目标，这个职业项目的核心前提是，建立具有启发性的利基环境，概括单个细胞周围生理上相关的细胞外基质属性，提供了一个独特的方向，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来精确指导决定细胞命运的基本过程，包括细胞生长、对称性破坏、不对称分裂和单细胞水平的分化。将采用多学科方法开展这一项目，包括生物材料设计、液滴微流体、生物物理方法、数学建模、成像和遗传工程。这项研究将产生一个设计的微环境模型库，可以用来以确定性的方式概括和控制细胞命运决定的特定生物过程。通过本研究中开发的工具更好地理解细胞命运决定，将有助于努力开发有效的基于干细胞的疗法和用于组织再生的生物制造方法。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.