"Smart" Materials to Engineer a More Complete Stem Cell Niche

“智能”材料可构建更完整的干细胞生态位

• 批准号: 7848029
• 负责人: Adam J Engler
• 金额: $ 231.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848029
• 关键词: Acrylamides; Adult; Aging; Binding; Cell Maturation; Cell Shape; Cell Therapy; Cells; Chemicals; Cicatrix; Cues; Development; Disease; Elasticity; Engineering; Ensure; Extracellular Matrix; Gel; Growth Factor; Histocompatibility Testing; Hyaluronic Acid; Hybrids; Hydrogels; Injury; Investigation; Knowledge; Location; Medical; Myocardial Infarction; Organism; Pattern; Polymer Chemistry; Polymers; Property; Regenerative Medicine; Regulation; Scaffolding Protein; Signal Pathway; Signal Transduction; Source; Stem Cell Development; Stem cells; Stimulus; Structure; System; Therapeutic; Time; Tissue Engineering; Tissues; abstracting; base; combat; improved; mimicry; programs; public health relevance; regenerative; stem cell biology; stem cell niche; therapeutic development

DESCRIPTION (Provided by the applicant) Abstract: One of the recent paradigm shifts in stem cell biology and regenerative medicine has been the discovery that stem cells can begin to differentiate into adult tissue cells when exposed to intrinsic properties of the extracellular matrix (ECM), such as matrix structure, elasticity, and composition. ECM regulation of stem cells has also been shown to be as sensitive as well-studied soluble growth factors, and together in the body, they comprise the stem cell niche, or "microenvironment." However, these cues have typically been studied as isolated stimuli where no single cue, whether a growth factor or an ECM property, has been sufficient to generate the appropriate type of differentiated cells for a given regenerative cell therapy. Moreover, as stem cells mature in the body during development, their microenvironment is highly spatially- and temporally-controlled, yet our ability to dynamically regulate the niche as the body does has not be developed and is probably a critical requirement for developing differentiated cells from stem cells. Therefore, I propose to substantially advance the field of stem cell biology by developing a new hybrid hydrogel system using a unique combination of conventional polymer chemistries. These gels, comprised of hyaluronic acid-co-acrylamide polymer, should present spatially- and temporally-controlled matrix properties that mimic their presentation during development. When combined with spatially-patterned growth factors, these cues could more accurately recapitulate the development of a specific tissue ex vivo, which may improve the differentiated cell sources used for cell-based therapeutic applications. Public Health Relevance: Stem cells may hold the key to replacing cells and tissues lost in many devastating diseases, injuries, or by aging. Regulating how stem cells develop from immature, dividing cells to specific, non-dividing adult cells or tissues is critical to ensure proper development of therapeutic strategies to combat these medical problems. Much of our knowledge on how to direct stem cell maturation has focused on cell-secreted chemical signals, called growth factors. Recent studies have surprisingly shown that the extracellular matrix (ECM), a protein scaffold to which cells adhere, can also regulate stem cell development as well via a variety of properties that it can display, such as ECM elasticity, cell- ECM binding, cell shape, etc. Stimulation by either chemical or ECM-based cues using conventional materials, however, does not result in fully mature cells, and thus their suitability to be used to produce adult or "pre-programmed" stem cells for a clinically viable therapy is limited. Moreover, stem cells in the body are exposed to these cues to varying degrees based on their location within the organism as well as when the cues are expressed developmentally. Thus dynamic presentation of these cues also likely influences their ability to direct stem cells to become adult cells or tissues. Therefore, the investigations proposed here hypothesize that a combination of these cues, displayed at the developmentally appropriate time, place, and concentration using "smart" materials, would better recreate the microenvironment seen by cells in a given tissue. Improved mimicry could then induce more complete development of stem cells into adult cells as each signaling pathway within that cell that is required to make a specific cell or tissue type would start at the appropriate time. This form of "preprogramming" stem cells could improve their use in engineered tissues as cells could develop more naturally or in cell-based therapies as cells could possibly remodel the diseased microenvironment, such as the abnormally rigid scar formed after a heart attack.

描述（由申请人提供） 摘要：干细胞生物学和再生医学的最近范式转变之一是发现当暴露于细胞外基质（ECM）的固有性质（例如基质结构、弹性和组成）时，干细胞可以开始分化成成体组织细胞。ECM对干细胞的调节也被证明与研究充分的可溶性生长因子一样敏感，并且在体内，它们一起构成干细胞龛或“微环境”。“然而，这些线索通常被研究为孤立的刺激，其中没有单一的线索，无论是生长因子还是ECM特性，都足以为给定的再生细胞疗法产生适当类型的分化细胞。此外，随着干细胞在发育过程中在体内成熟，它们的微环境在空间和时间上受到高度控制，但我们动态调节生态位的能力还没有发展，这可能是从干细胞发育分化细胞的关键要求。因此，我建议通过开发一种新的混合水凝胶系统，使用传统聚合物化学的独特组合，大大推进干细胞生物学领域。这些凝胶，由透明质酸-共-丙烯酰胺聚合物组成，应该呈现空间和时间控制的基质性质，模拟其在发育过程中的呈现。当与空间模式化的生长因子组合时，这些线索可以更准确地再现离体特定组织的发育，这可以改善用于基于细胞的治疗应用的分化细胞来源。 公共卫生相关性：干细胞可能是替代在许多毁灭性疾病、损伤或衰老中丢失的细胞和组织的关键。调节干细胞如何从未成熟的分裂细胞发育为特定的非分裂成体细胞或组织，对于确保适当开发治疗策略以解决这些医学问题至关重要。我们对如何指导干细胞成熟的大部分知识都集中在细胞分泌的化学信号上，称为生长因子。最近的研究已经令人惊讶地表明，细胞外基质（ECM）（细胞粘附于其上的蛋白质支架）也可以通过其可以显示的各种特性（例如ECM弹性、细胞- ECM结合、细胞形状等）来调节干细胞发育。然而，使用常规材料通过化学或基于ECM的线索进行刺激不会导致完全成熟的细胞，因此它们用于产生用于临床可行治疗的成体或“预编程”干细胞的适用性受到限制。此外，身体中的干细胞根据它们在生物体中的位置以及当这些线索在发育中表达时，不同程度地暴露于这些线索。因此，这些线索的动态呈现也可能影响它们指导干细胞成为成体细胞或组织的能力。因此，这里提出的研究假设，这些线索的组合，显示在发育适当的时间，地点和浓度使用“智能”材料，将更好地重建细胞在给定组织中看到的微环境。改进的拟态可以诱导干细胞更完全地发育成成体细胞，因为细胞内产生特定细胞或组织类型所需的每个信号通路将在适当的时间启动。这种形式的“预编程”干细胞可以提高它们在工程组织中的应用，因为细胞可以更自然地发育，或者在基于细胞的治疗中，因为细胞可能重塑患病的微环境，例如心脏病发作后形成的异常坚硬的疤痕。