Biomaterials for local regulation of growth factor signaling

 产品说明： 干细胞正在成为一种强大的生物医学工具，在药物/毒素筛选、疾病建模和临床细胞治疗方面的重要应用即将出现。最近的研究通过改善干细胞的“生物制造”过程，包括细胞扩增、分化和组织形态发生，使干细胞更接近于生物医学应用。然而，对昂贵且定义不明确的生物补充剂如重组生长因子（GF）的需求仍然是一个令人望而却步的挑战。在新兴应用中，GF补充剂可以占干细胞生物制造过程成本的一半以上，而现有的过程仍然依赖于复杂的、定义不明确的GF结合基质，如Matrigel。值得注意的是，虽然目前的范例涉及用浓缩的含GF的补充剂轰击干细胞，但干细胞生物制造中的许多相关GF已经常规地由干细胞本身产生。有机会通过捕获细胞分泌的GF来改变当前的范例，从而导致成本更低且更明确的干细胞生物制造。内容：我们的初始资助期（2009年7月1日至2014年6月30日）建立了特定GF螯合的新机制，并向行业合作伙伴提供了33份手稿，8项专利申请和5项技术许可。我们发现用仿生肽工程化的生物材料可以在成体细胞培养中调节特定的GF信号传导。在下一个资助期间，我们将使用我们定义的GF螯合概念来规避干细胞生物医学应用中的关键障碍。推动下一个资助期的一个核心、挑衅性的问题是：工程生物材料能否在不提供任何GF的情况下控制GF依赖性干细胞的扩增、分化和形态发生？具体目标：具体目标1将使用生物材料来隔离细胞分泌的GF并扩增人间充质干细胞扩增和分化。Specific Aim 2将使用生物材料来局部调节人诱导多能干细胞培养物中的特定GF活性，从而增强干细胞衍生的内皮细胞的产生。具体目标3将开发生物材料，可以在体外和体内血管形态发生过程中选择性地控制旁分泌信号。创新：我们提出的研究将建立合成生物材料作为内源性，重组和旁分泌GF信号传导的定义介质。重要性：我们提出的研究将减轻目前阻碍干细胞生物医学应用的昂贵和复杂的生物补充剂的需求。由此产生的方法将是变革性的，因为GF补充剂是干细胞应用中成本增加和监管负担增加的主要驱动力。

 DESCRIPTION: Stem cells are emerging as a powerful biomedical tool, and significant applications in drug/toxin screening, disease modeling, and clinical cell therapy are on the horizon. Recent studies have pushed stem cells closer to biomedical applications by improving stem cell "biomanufacturing" processes, including cell expansion, differentiation and tissue morphogenesis. However, the need for costly and poorly defined biological supplements such as recombinant growth factors (GFs) remains a prohibitive challenge. GF supplements can represent more than half of the cost of stem cell biomanufacturing processes in emerging applications, and existing processes remain dependent on complex, poorly defined GF-binding matrices such as Matrigel. Remarkably, while the current paradigm involves bombarding stem cells with concentrated GF- containing supplements, many of the relevant GFs in stem cell biomanufacturing are already routinely produced by the stem cells themselves. There is an opportunity to shift the current paradigm by capturing cell- secreted GFs, leading to less costly and more well-defined stem cell biomanufacturing. Context: Our initial funding period (7/1/2009-6/30/2014) established new mechanisms for specific GF sequestering, and produced 33 manuscripts, 8 patent applications, and 5 technology licenses to industry partners. We discovered that biomaterials engineered with biomimetic peptides could regulate specific GF signaling in adult cell culture. During the next funding period we will use our defined GF sequestering concept to circumvent critical barriers in biomedical applications of stem cells. A central, provocative question driving the next funding period is: can engineered biomaterials control GF-dependent stem cell expansion, differentiation, and morphogenesis without delivering any GFs? Specific Aims: Specific Aim 1 will use biomaterials to sequester cell-secreted GFs and amplify human mesenchymal stem cell expansion and differentiation. Specific Aim 2 will use biomaterials to locally regulate specific GF activity in human induced pluripotent stem cell culture, and thereby enhance production of stem cell-derived endothelial cells. Specific Aim 3 will develop biomaterials that can selectively control paracrine signaling during vascular morphogenesis in vitro and in vivo. Innovation: Our proposed studies will establish synthetic biomaterials as defined mediators of endogenous, recombinant, and paracrine GF signaling. Significance: Our proposed studies will mitigate the need for expensive and complex biological supplements that currently hinder biomedical applications of stem cells. The resulting approach will be transformative, as GF supplements represent the primary driving force for increased cost and regulatory burden in stem cell applications.