Degradation Products of Extracellular Matrix Affect Cell Migration and Proliferation

Abstract

Biologic scaffolds composed of extracellular matrix (ECM) are utilized in numerous regenerative medicine applications to facilitate the constructive remodeling of tissues and organs. The mechanisms by which the host remodeling response occurs are not fully understood, but recent studies suggest that both constituent growth factors and biologically active degradation products derived from ECM play important roles. The objective of the present study was to determine if degradation of ECM scaffold materials in vitro by methods that are biochemically and physiologically relevant can yield products that possess chemotactic and/or mitogenic activities for fully differentiated mammalian endothelial cells and undifferentiated multipotential progenitor cells. ECM harvested from porcine urinary bladder was degraded enzymatically with pepsin/hydrochloric acid or papain. The ECM degradation products were tested for chemoattractant properties utilizing either 48-well chemotaxis filter migration microchambers or fluorescence-based filter migration assays, and were tested for mitogenic properties in cell proliferation assays. Results showed that ECM degradation products possessed chemotactic and mitogenic activities for multipotential progenitor cells and that the same degradation products inhibited both chemotaxis and proliferation of differentiated endothelial cells. These findings support the concept that degradation products of ECM bioscaffolds are important modulators of the recruitment and proliferation of appropriate cell types during the process of ECM scaffold remodeling.

Restoring Mucosal Barrier Function and Modifying Macrophage Phenotype with an Extracellular Matrix Hydrogel: Potential Therapy for Ulcerative Colitis

“…Specifically, ECM materials derived via decellularization of a variety of allogeneic or xenogeneic source tissues have been shown to induce a phenotypic transition from the proinflammatory macrophage and lymphocyte phenotype toward a regulatory, "anti-inflammatory" and healing phenotype [9,31,32,33], and to promote endogenous stem/progenitor cell activation and recruitment [11,29,34,35].…”

Epimorphic regeneration approach to tissue replacement in adult mammals

“…Because ECM scaffolds consist of various molecules such as collagen and fibronectin, proteoglycans, glycoproteins, growth factors, and cytokines (46), degradation of these ECM scaffolds releases a heterogeneous set of molecules (13,21), each with varying biologic properties in vivo. Subsets of these peptides have been found to have different bioactive properties in vitro (13,17,19,44,47,48). Although a subset of generated peptides is clearly chemotactic for stem cells, the overall contribution of these peptides to stem cell recruitment in vivo is as of yet unknown.…”

“…Although full characterization of these bioactive peptides has not been completed to date, ex vivo enzymatic, chemical, and physical methods (17)(18)(19), and in vivo physiologic methods (20), have generated a heterogeneous population of ECM peptides (13,21) with both chemotactic and mitogenic properties for a variety of stem and progenitor cells.…”

Whole-organ engineering with natural extracellular materials

“…The ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1 : FVC) taken before and 3 months after surgery, determined that the graft resulted in a reversal of airway obstruction [20]. As additional clinical studies are completed, we will continue to learn more about the instructive nature of decellularized grafts, including the preservation of angiogenic cytokines [20], as well as other chemokines preserved from previous niches that may affect morphogenesis [4,14,38,39].…”

“…As proteolytic activity degrades the ECM, cryptic binding sites are unveiled, and matrix-bound growth factors become untethered [68,71]. Cell migration occurring along a gradient, such as that which occurs during chemotaxis (chemical gradient), haptotaxis (cellular adhesion site gradients) and durotaxis (rigidity gradients), can therefore be manipulated based upon the design of the ECM [39,72]. Further studies in 3D have been able to demonstrate more physiologically relevant applications by creating matrices with natural materials that take advantage of durotaxis [73,74].…”