Extracellular Matrix Degradation Products and Low-Oxygen Conditions Enhance the Regenerative Potential of Perivascular Stem Cells

Abstract

Tissue and organ injury results in alterations of the local microenvironment, including the reduction in oxygen concentration and degradation of the extracellular matrix (ECM). The response of perivascular stem cells to these microenvironment changes are of particular interest because of their wide distribution throughout the body and their potential involvement in tissue and organ response to injury. The chemotactic, mitogenic, and phenotypic responses of this stem cell population were evaluated in response to a combination of decreased oxygen concentration and the presence of ECM degradation products. Culture in low-oxygen conditions resulted in increased proliferation and migration of the cells and increased activation of the ERK signaling pathway and associated integrins without a change in cell surface marker phenotype. The addition of ECM degradation products were additive to these processes. Reactive oxygen species within the cells were increased in association with the mitogenic and chemotactic responses. The increased proliferation and chemotactic properties of this stem cell population without any changes in phenotype and differentiation potential has important implications for both in vitro cell expansion and for in vivo behavior of these cells at the site of injury.

Multilineage stem cells in the adult

“…24 We also confirmed in vivo that human pericytes injected into the skeletal muscles of genetically dystrophic mice migrate at a remote distance from the site of injection and therefore mediate more efficient myogenesis. 20 Purified human pericytes have been used experimentally in other, different models of tissue engineering or regeneration.…”

A Murine Model of Volumetric Muscle Loss and a Regenerative Medicine Approach for Tissue Replacement

“…52 Degradation products of ECM scaffolds have been shown to include chemotactic factors for myogenic progenitor cells. 47,53,54 Thus, it is possible that a subset of the dense mononuclear cells includes progenitor cells with myogenic potential. Future studies will further investigate the spatial and temporal pattern of accumulation of various myogenic progenitor cells after implantation of an ECM scaffold at a site of volumetric muscular injury.…”

Injectable Extracellular Matrix Hydrogels as Scaffolds for Spinal Cord Injury Repair

“…As was shown previously, degradation of ECM scaffolds is essential for the constructive tissue remodeling process, by which a degradable biomaterial serves as a temporary inductive niche, which is gradually replaced by anatomically appropriate and functional tissue as opposed to scar tissue. 11,25,26 Moreover, degradation of ECM scaffolds stimulates the release of matricryptic molecules; which possess a variety of bioactive properties, such as antimicrobial activity, angiogenic effects, as well as the recruitment of endogenous stem and progenitor cells. 26 In the present study, however, despite the fact that the lesion cavity was filled with endogenous cell-populated ECM hydrogels 2 weeks after their injection, further progression in matrix degradation at later time points was not followed by full neural tissue replacement, but rather resulted in the formation of a dense network of tissue containing axons, blood vessels, and other neural tissue elements interrupted by a number of small cysts.…”