Macrophage Polarization and Aging in the Context of Regenerative Medicine

描述（由申请人提供）：由细胞外基质（ECM）组成的生物支架材料来源于各种异种和同种异体组织和器官来源。这些材料已经广泛应用于临床前和临床组织工程以及再生医学方法的组织重建。经适当制备和利用，ECM支架已被证明可促进功能性、位点特异性宿主组织的形成。这与哺乳动物宿主对组织损伤的默认反应形成了直接对比，后者涉及炎症和疤痕。ECM支架材料能够调节默认宿主反应并促进这种“建设性”组织重塑的确切机制在很大程度上是未知的。然而，我们已经证明，那些能够促进建设性重塑的ECM支架也与植入部位内的巨噬细胞群有关。随着年龄的增长，巨噬细胞的一些生理变化已经被观察到。这些变化与无法抵抗病原体和愈合伤口有关。这些变化背后的确切机制尚不清楚，但有人认为包括局部组织微环境（即ECM组成和驻留细胞群）的改变，这些改变有助于无能巨噬细胞的行为。这项工作旨在研究来自年轻、成年和老年小鼠的巨噬细胞与来自年轻、成年和老年猪供体的ECM组成的生物支架材料相互作用后的反应（目的1）。此外，本研究旨在确定巨噬细胞-ECM支架相互作用的配体，并评估这些配体在来自年轻人和老年供体的ECM支架材料中的相对存在（目的2）。这些目标将由经验丰富的研究人员通过一系列体外研究来实现，这些研究利用了最先进的高通量方法。这些研究的完成不仅将进一步了解ECM支架调节宿主反应的机制，而且还将更好地理解随着衰老而发生的巨噬细胞生理学变化对在老龄化人群中利用再生医学策略的潜力的影响。

DESCRIPTION (provided by applicant): Biologic scaffold materials composed of extracellular matrix (ECM) have been derived from a wide variety of xenogeneic and allogeneic tissue and organ sources. These materials have been used in a similarly wide variety of pre-clinical and clinical tissue engineering and regenerative medicine approaches to tissue reconstruction. When prepared and utilized appropriately, ECM scaffolds have been shown to promote the formation of functional, site-specific host tissues. This is in direct contrast to the default mammalian host response to tissue injury, which involves inflammation and scarring. The exact mechanisms by which ECM scaffold materials are capable of modulating the default host response and promoting this type of "constructive" tissue remodeling are largely unknown. However, we have shown that those ECM scaffolds that are capable of promoting constructive remodeling are also associated with a distinct population of macrophages within the site of implantation. A number of changes in macrophage physiology have been observed to occur with advanced age. These changes have been associated with an inability to fight pathogens and to heal wounds. The exact mechanisms which underlie these changes are unclear, but have been suggested to include alterations in the local tissue microenvironment (i.e. ECM composition, and resident cell populations) which contribute to anergic macrophage behavior. The proposed work seeks to investigate the response of macrophages derived from young, adult, and aged mice following interactions with biologic scaffold materials composed of ECM derived from young, adult, and aged porcine donors (Aim 1). Further, the proposed work seeks to identify the ligands responsible for macrophage-ECM scaffold interactions and assess the relative presence of these ligands in ECM scaffold materials derived from young-adult and aged donors (Aim 2). These goals will be accomplished by experienced investigators through a set of in vitro studies which utilize state of the art high throughput methodologies. The completion of these studies will not only further the understanding of the mechanisms by which ECM scaffolds modulate the host response, but will also lead to a better understanding of the impact that the changes in macrophage physiology which occur with aging will have upon the potential to utilize regenerative medicine strategies in an aging population.