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Decoupling Hydrogel Stiffness and Diffusivity for Hematopoietic Stem Cell Culture and Differentiation

用于造血干细胞培养和分化的水凝胶刚度和扩散率的解耦

基本信息

批准号：
10647478
负责人：
NICHOLAS A PEPPAS
金额：
$ 22.21万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10647478
关键词：
Adhesions Affect Autocrine Communication Behavior Binding Sites Biochemical Biophysics Blood Bone Marrow Budgets Categories Cell Adhesion Cell Communication Cell Culture Techniques Cell Differentiation process Cell Proliferation Cells Chemicals Crosslinker Cytokine Signaling Dependence Diffusion Disease Encapsulated Environment Extracellular Matrix Formulation Genetic Diseases Goals Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Homeostasis Human Hydrogels Immune Immune system In Vitro Integrin Binding Integrin alpha5beta1 Knowledge Libraries Long-Term Effects Malignant Neoplasms Methods Modeling Morbidity - disease rate Motivation Outcome Paracrine Communication Peptides Phenotype Physical environment Play Proliferating Property Research Role Signal Transduction System Testing Time Tissues Umbilical Cord Blood Uncertainty Variant Work arm biomaterial compatibility cell behavior cell type curative treatments cytokine design dithiol ethylene glycol graduate student hematopoietic stem cell expansion hematopoietic stem cell niche hematopoietic stem cell self-renewal improved outcome insight mechanical signal novel physical property predictive modeling response scaffold self-renewal solute stem cell survival stem-like cell success theories transplantation therapy

项目摘要

PROJECT ABSTRACT Hematopoietic stem cells (HSCs) in the bone marrow receive mechanical signals via adhesions to the extracellular matrix and chemical signals from cytokines diffusing through the extracellular matrix. These two signaling methods influence HSC survival, proliferation, and differentiation, with critical long-term effects on the immune system and the body’s ability to maintain homeostasis. While in vitro studies using synthetic hydrogels as artificial matrices have led to new insights on environmental control of HSC behavior, stiffness and solute transport are highly correlated in synthetic hydrogels, so the mechanisms behind HSC responses to these environments remain uncertain. The resulting uncertainty and limited control of hydrogel physical properties may explain why robust methods for in vitro HSC expansion have not been established. Therefore, the studies proposed here will fill a critical gap in hydrogel design capabilities and apply that new knowledge to in vitro HSC culture. First, we will create a library of forty-five unique hydrogel formulations by simultaneously manipulating three structural hydrogel synthesis parameters that our fundamental models have predicted to create robust, independent variations in stiffness and solute transport. Second, we will culture HSCs in a smaller, nine-formulation square matrix of hydrogel formulations with independently tuned stiffnesses and solute transport profiles to decouple how the two physical hydrogel properties affect HSC survival, proliferation, and differentiation. These studies will provide fundamental insight into HSC interactions with their physical environment and identify physically optimized conditions for in vitro HSC culture.

项目摘要骨髓中的造血干细胞 (HSC) 通过粘附到骨髓接收机械信号细胞外基质和细胞因子通过细胞外基质扩散的化学信号。这两个信号转导方法影响 HSC 的存活、增殖和分化，对 HSC 的生存、增殖和分化具有关键的长期影响免疫系统和身体维持体内平衡的能力。使用合成水凝胶进行体外研究因为人造基质带来了关于 HSC 行为、刚度和溶质的环境控制的新见解运输在合成水凝胶中高度相关，因此 HSC 对这些运输的反应背后的机制环境仍然不确定。由此产生的水凝胶物理的不确定性和有限的控制这些特性或许可以解释为什么尚未建立稳健的体外 HSC 扩增方法。因此，这里提出的研究将填补水凝胶设计能力的关键空白，并应用新的体外 HSC 培养知识。首先，我们将创建一个包含 45 种独特水凝胶配方的库同时操纵我们的基本模型具有的三个结构水凝胶合成参数预计会在刚度和溶质运输方面产生稳健、独立的变化。其次，我们要培养HSC 在一个较小的、九种配方的水凝胶配方方阵中，具有独立调节的刚度和溶质转运曲线可解耦两种物理水凝胶特性如何影响 HSC 存活、增殖、和差异化。这些研究将为 HSC 与其身体相互作用提供基本见解。环境并确定体外 HSC 培养的物理优化条件。