Engineered Sense and Response Circuits for Stem Cell-Based Tissue Regeneration and Repair

用于基于干细胞的组织再生和修复的工程传感和响应电路

• 批准号: 9327723
• 负责人: Jonathan Matthew Brunger
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327723
• 关键词: Anisotropy; Behavior; Biochemical; Biocompatible Materials; Biological Assay; Cell Death; Cell Transplants; Cell physiology; Cell-Mediated Cytolysis; Cells; Chronic Disease; Clinical Trials; Cues; Decision Making; Deposition; Detection; Disease; Engineering; Environment; Extracellular Matrix; Failure; Feedback; Fellowship; Flow Cytometry; Gene Delivery; Gene Expression; Generations; Genetic Transcription; Goals; Growth Factor; Guided Tissue Regeneration; Histologic; Homeostasis; Homing; Hydrogels; Immobilization; In Situ; Instruction; Ligands; Link; Measures; Membrane; Mentors; Mesenchymal; Methods; Molecular; Organ; Outcome; Output; Pathologic; Pattern; Pluripotent Stem Cells; Polyethylene Glycols; Process; Production; Proteins; Regenerative Medicine; Reporter; Research Proposals; Scientist; Sensory; Signal Transduction; Site; Specificity; Stem cell transplant; Stem cells; Substrate Interaction; System; T-Lymphocyte; Technology; Testing; Tissue Engineering; Tissues; Training; Transgenes; Transplantation; Work; base; biomaterial interface; body system; career; cell behavior; cell motility; cell type; combat; cytokine; empowered; experience; functional outcomes; functional restoration; genetically modified cells; immunoregulation; improved; innovation; insight; live cell microscopy; migration; notch protein; novel; programs; receptor; regenerative; repaired; response; retention rate; scaffold; stem cell differentiation; stem cell therapy; synthetic biology; therapy outcome; tissue regeneration; tissue repair; tool

ABSTRACT Regenerative medicine therapies seek to replace cells or pathological tissues with engineered substitutes, but robust methods for precisely orchestrating activities of transplanted cells do not exist. This is especially true in pathological conditions that arise from chronic diseases, in which normal homeostatic and regenerative cues are overridden by deleterious signals, leading to cell death and loss of organ function. The goal of this proposal is to develop technologies that couple highly specific interactions between stem cells and their environments with programmed cellular outputs, such as homing, differentiation, matrix synthesis, and cytokine / growth factor secretion. We have developed a synthetic receptor platform that allows cells to recognize ligands through specificity imparted by carefully selected single chain variable fragments (scFv). Upon engagement of immobilized ligand (either membrane- or substrate-tethered) by this scFv receptor, engineered cells deploy a pre-defined program that dictates the outcome of cell-cell or cell-matrix interactions. Though we have used this platform to drive various behaviors in other cell types, we have not established its utility for guiding stem cell functions that are pertinent to regenerative medicine. We hypothesize that this synthetic sensory platform can enable stem cells to autonomously implement regenerative programs, such as homing, differentiation, or matrix synthesis, in response to cell-cell and cell-biomaterial interactions. In Specific Aim 1, we will establish our ability to link specific external signals to defined changes in stem cell states, including migration, differentiation, and extracellular matrix synthesis. In Specific Aim 2, we will incorporate ligands recognized by our synthetic receptors into biomaterial scaffolds. In this way, we will produce cellular delivery vehicles and tissue engineering scaffolds that enable the cells to self-select programmed behaviors with engineered, context-dependent specificity and precision. By implementing this novel sense and response system in regenerative medicine strategies, we intend to produce stem cell therapies capable of autonomously detecting features of a microenvironment and responding with a coordinated regenerative program that restores function, even in the absence of cues normally required for cell-based repair. This fellowship will provide me with the experience and tools critical for my goal of developing into a productive, independent scientist while also contributing key insights toward stem cell-based and biomaterial-guided tissue regeneration and repair.

抽象的 再生医学疗法寻求用工程替代物替代细胞或病理组织，但是 精确协调移植细胞活动的稳健方法尚不存在。尤其是在 由慢性疾病引起的病理状况，其中正常的稳态和再生信号 被有害信号覆盖，导致细胞死亡和器官功能丧失。本提案的目标 是开发将干细胞与其环境之间高度特异性相互作用结合起来的技术 具有程序化的细胞输出，例如归巢、分化、基质合成和细胞因子/生长 因子分泌。我们开发了一个合成受体平台，可以让细胞识别配体 通过精心挑选的单链可变片段 (scFv) 赋予的特异性。订婚后 通过该 scFv 受体固定配体（膜或底物束缚），工程细胞部署 预先定义的程序，决定细胞-细胞或细胞-基质相互作用的结果。虽然我们用过这个 驱动其他细胞类型的各种行为的平台，我们尚未确定其在指导干细胞方面的效用 与再生医学相关的功能。我们假设这个合成感官平台可以 使干细胞能够自主执行再生程序，例如归巢、分化或 基质合成，响应细胞-细胞和细胞-生物材料的相互作用。在具体目标 1 中，我们将建立 我们能够将特定的外部信号与干细胞状态的定义变化联系起来，包括迁移， 分化和细胞外基质合成。在具体目标 2 中，我们将结合由 我们的合成受体进入生物材料支架。通过这种方式，我们将生产细胞运输工具并 组织工程支架使细胞能够通过工程化、 上下文相关的特异性和精确度。通过实施这种新颖的感知和响应系统 再生医学策略，我们打算生产能够自主检测的干细胞疗法 微环境的特征并通过协调的再生程序进行响应以恢复功能， 即使缺乏细胞修复通常所需的线索。这项奖学金将为我提供 经验和工具对于我发展成为一名富有成效的独立科学家的目标至关重要，同时也 为基于干细胞和生物材料引导的组织再生和修复提供重要见解。