Biomaterials for local regulation of growth factor signaling

 描述：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中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、分化和组织形态形成，将干细胞推向了更接近生物医学的应用。然而，对昂贵和定义不明确的生物补充剂，如重组生长因子(GFS)的需求仍然是一个令人望而却步的挑战。在新兴应用中，GF补充剂可能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、定义不佳的GF结合基质，如Matrigel。值得注意的是，虽然目前的范例包括用浓缩的含有GF的补充剂轰击干细胞，但干细胞生物制造中的许多相关GFs已经是干细胞本身常规产生的。现在有机会通过捕获细胞分泌的GFS来改变当前的范式，从而导致成本更低、定义更明确的干细胞生物制造。背景：我们最初的资助期(2014年7月1日-6月30日)为特定的GF隔离建立了新的机制，并向行业合作伙伴提供了33份手稿、8份专利申请和5份技术许可证。我们发现，仿生多肽工程生物材料可以调节成人细胞培养中的特异性生长因子信号。在下一个资助期，我们将使用我们定义的GF隔离概念来绕过干细胞在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的、具有挑衅性的问题是：工程生物材料能否在不提供任何GFS的情况下控制依赖于GF的干细胞的扩张、分化和形态形成？具体目标：特定目标1将使用生物材料隔离细胞分泌的GFS，并放大人骨髓间充质干细胞的扩增和分化。特殊目的2将使用生物材料来局部调节人类诱导的多能干细胞培养中特定的GF活性，从而提高干细胞来源的内皮细胞的产量。特定目标3将开发在体外和体内血管形态发生过程中选择性控制旁分泌信号的生物材料。创新：我们建议的研究将建立合成生物材料，作为内源性、重组和旁分泌的GF信号的明确媒介。意义：我们提议的研究将减少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增加成本和监管负担的主要驱动力。

 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.