ECM Degradation and Macrophage Polarization in Endogenous Stem Cell Recruitment

描述(申请人提供)：损伤后的再生仅限于成年哺乳动物的特定组织。在大多数其他组织中，对损伤的默认反应涉及炎症和疤痕组织形成的过程(即修复)。在成年哺乳动物中，伤口的微环境在决定再生还是疤痕方面起着重要作用。在能够再生复杂组织的物种中，被招募到伤口微环境中的干细胞促进了一种称为表型再生的过程。由猪源性细胞外基质(ECM)组成的生物支架已成功地应用于100多万名人类患者，以创造促进各种软组织局部特异性、非炎性修复的创面微环境。在组织损伤后植入ECM支架会导致组织快速降解、生物活性多肽释放、局部巨噬细胞极化和内源性干细胞募集。ECM介导的干细胞体内募集的机制尚不清楚，但可能部分是由ECM降解后释放的分子介导的。极化的巨噬细胞也能够在体外募集干细胞，但它们在体内募集内源性干细胞的作用尚不清楚。本研究的总体目标是：(1)ECM降解在体内外干细胞募集中的作用；(2)ECM降解在体内和体外对巨噬细胞极化的作用；(3)ECM降解和极化巨噬细胞对体内内源性干细胞募集的相对贡献。本研究的结果进一步揭示了天然免疫系统在促进组织再生中的作用，为进一步研究细胞外基质成分、天然免疫系统和内源性干细胞之间相互作用的机制奠定了基础。

DESCRIPTION (provided by applicant): Regeneration in response to injury is limited to select tissues in adult mammals. The default response to injury in most other tissues involves the processes of inflammation and scar tissue formation (i.e., repair). The microenvironment of the wound plays an important role in determining regeneration versus scar in adult mammals. In species capable of regenerating complex tissues, stem cells recruited to the wound microenvironment promote a process known as epimorphic regeneration. Biologic scaffolds composed of porcine derived extracellular matrix (ECM) have successfully been used in over one million human patients to create a wound microenvironment that promotes site-specific, non-inflammatory repair of a variety of soft tissues. Implantation of an ECM scaffold following tissue injury results in rapid degradation, release of bioactive peptides, local macrophage polarization, and endogenous stem cell recruitment. The mechanisms underlying ECM mediated stem cell recruitment in vivo are well not understood, but may partially be mediated by molecules released following ECM degradation. Polarized macrophages are also capable of recruiting stem cells in vitro, but their contribution to endogenous stem cell recruitment in vivo is not well understood. The overall goal of the present study is to investigate: (1) role of ECM degradation in stem cell recruitment in vitro and in vivo, (2) the role of ECM degradation on macrophage polarization in vitro and in vivo, and (3) the relative contributions of ECM degradation and polarized macrophages upon endogenous stem cell recruitment in vivo. The findings of the present study further inform us on the on the role of the innate immune system in promoting tissue regeneration, and it will serve as the foundation of future studies to further investigate the mechanisms underlying interaction between extracellular matrix components, the innate immune system, and endogenous stem cells.