CONSTRUCTIVE TISSUE REMODELING BY EXTRACELLULAR MATRIX BIOSCAFFOLDS WITHIN THE AGING SKELETAL MUSCLE MICROENVIRONMENT

[摘要] Adult mammalian skeletal muscle tissue retains inherent regenerative capability in response to injury. This regenerative response is contingent upon an activated progenitor cell population and a temporal transition from pro-inflammatory M1 to immunomodulatory and constructive M2 polarized macrophages at the site of injury. Specifically, pro-inflammatory effector molecules secreted by M1 macrophages promote the expansion of skeletal muscle progenitor cells, while resolution of the inflammatory response and myogenic differentiation of skeletal muscle progenitor cells is dependent upon immunomodulatory effector molecules secreted by M2 macrophages.The decline in the regenerative capacity of skeletal muscle tissue associated with advanced age is largely a consequence of progenitor cell dysfunction. Furthermore, advanced age is accompanied with immunosenesence of the innate immune system resulting in an impaired macrophage polarization potential.Biologic scaffold materials composed of mammalian extracellular matrix (ECM) have been successfully used in both pre-clinical animal studies and in human clinical applications to promote constructive tissue remodeling in a variety of anatomic locations including skeletal muscle. The presence of ECM bioscaffolds at sites of skeletal muscle injury has been associated with a predominant M2 macrophage phenotype and downstream site-appropriate or constructive, functional tissue remodeling. The mechanisms responsible for this constructive tissue remodeling response are only partially understood.The present dissertation shows that the age of source animals from which ECM bioscaffold materials are harvested represents a determinant factor of the constructive tissue remodeling potential induced by these materials. The present work also shows that degradation products of mammalian ECM promote the constructive M2 macrophage phenotype in both young and age-impaired macrophages. Moreover, effector molecules from macrophages exposed to ECM degradation products are chemotactic and myogenic for skeletal muscle progenitor cells. The present dissertation describes a new rodent model of volumetric muscle loss (VML) and an ECM bioscaffold based approach for tissue replacement associated with modulation of macrophage phenotype and the endogenous recruitment of perivascular stem cells.

[发布机构] the University of Pittsburgh