Abstract
Soft tissue is composed of cells surrounded by an extracellular matrix that is made up of a diverse array of intricately organized proteins. These distinct components work in concert to maintain homeostasis and respond to tissue damage. During tissue repair, extracellular matrix proteins and their degradation products are known to influence physiological processes such as angiogenesis and inflammation. In this study we developed a discovery platform using a decellularized extracellular matrix biomaterial to identify new chemotrophic factors derived from the extracellular matrix. An in vitro culture of RAW.264 macrophage cells with the biomaterial ovine forestomach matrix led to the identification of a novel ~12 kDa chemotactic factor, termed ‘MayDay’, derived from the N-terminal 31–188 sequence of decorin. The recombinant MayDay protein was shown to be a chemotactic agent for mesenchymal stromal cells in vitro and in vivo. We hypothesize that the macrophage-induced cleavage of decorin, via MMP-12, leads to the release of the chemotactic molecule MayDay, that in turn recruits cells to the site of damaged tissue.
Highlights
Progenitor cells play an important role in the constructive remodeling of soft tissues following damage or disease
Studies have shown that Decellularized extracellular matrix (dECM) biomaterials have a range of biological properties and are capable of recruiting MSCs, a feature that may in part explain their clinical performance in soft tissue repair [36, 37, 45]
Ovine forestomach matrix (OFM) has previously been shown to stimulate HUVEC cell migration, proliferation and angiogenesis in vitro [25], and the current findings support the conclusion that OFM itself stimulates MSC chemotaxis, a biological property that has not previously been described. dECM biomaterials undergo proteolytic digestion once implanted and several studies have shown that chemical or enzymatic breakdown of dECM biomaterials produces novel or hidden cryptic extracellular matrix (ECM) molecules and can modify the biological properties of dECMs [46,47,48,49], including the recruitment of MSCs [40]
Summary
Progenitor cells play an important role in the constructive remodeling of soft tissues following damage or disease. A well characterized example of progenitor cell recruitment occurs through SDF-1 signaling, where SDF-1 is up-regulated at sites of tissue damage and recruits endogenous mesenchymal stem cells via the CXC chemokine receptor 4 [8]. This phenomenon has been reproduced in vitro using bone marrow-derived mesenchymal stromal cells (BM-MSCs) [4, 9,10,11,12,13] and adipose-derived mesenchymal stromal cells (AD-MSCs) [1, 11] and in an in vivo model of skeletal fracture repair [14].
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