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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.

SUBMITTER: Tottey S

PROVIDER: S-EPMC3011908 | biostudies-other | 2011 Jan

REPOSITORIES: biostudies-other

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Extracellular matrix degradation products and low-oxygen conditions enhance the regenerative potential of perivascular stem cells.

Tottey Stephen S Corselli Mirko M Jeffries Eric M EM Londono Ricardo R Peault Bruno B Badylak Stephen F SF

Tissue engineering. Part A 20100906 1-2

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 evaluate ...[more]

PMID: 20653348

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Project description:Extracellular matrix (ECM)-derived bioscaffolds have been shown to elicit tissue repair through retention of bioactive signals. Given that the adventitia of large blood vessels is a richly vascularized microenvironment, we hypothesized that perivascular ECM contains bioactive signals that influence cells of blood vessel lineages. ECM bioscaffolds were derived from decellularized human and porcine aortic adventitia (hAdv and pAdv, respectively) and then shown have minimal DNA content and retain elastin and collagen proteins. Hydrogel formulations of hAdv and pAdv ECM bioscaffolds exhibited gelation kinetics similar to ECM hydrogels derived from porcine small intestinal submucosa (pSIS). hAdv and pAdv ECM hydrogels displayed thinner, less undulated, and fibrous microarchitecture reminiscent of native adventitia, with slight differences in ultrastructure visible in comparison to pSIS ECM hydrogels. Pepsin-digested pAdv and pSIS ECM bioscaffolds increased proliferation of human adventitia-derived endothelial cells and this effect was mediated in part by basic fibroblast growth factor (FGF2). Human endothelial cells cultured on Matrigel substrates formed more numerous and longer tube-like structures when supplemented with pAdv ECM bioscaffolds, and FGF2 mediated this matrix signaling. ECM bioscaffolds derived from pAdv promoted FGF2-dependent in vivo angiogenesis in the chick chorioallantoic membrane model. Using an angiogenesis-focused protein array, we detected 55 angiogenesis-related proteins, including FGF2 in hAdv, pAdv and pSIS ECMs. Interestingly, 19 of these factors were less abundant in ECMs bioscaffolds derived from aneurysmal specimens of human aorta when compared with non-aneurysmal (normal) specimens. This study reveals that Adv ECM hydrogels recapitulate matrix fiber microarchitecture of native adventitia, and retain angiogenesis-related actors and bioactive properties such as FGF2 signaling capable of influencing processes important for angiogenesis. This work supports the use of Adv ECM bioscaffolds for both discovery biology and potential translation towards microvascular regeneration in clinical applications.

Project description:Abdominal aortic aneurysms (AAA) are localized expansions of the abdominal aorta that develop due to chronic proteolytic disruption of the structural extracellular matrix (ECM) components (elastin and collagen) within the aorta wall. Major limitations in arresting or reversing AAAs lie in naturally poor and aberrant regeneration and repair of elastic matrix structures in the aorta wall. Bone marrow derived mesenchymal stem cells (BM-MSCs) have emerged as a promising regenerative tool and their therapeutic effects are also known to be effected through their paracrine secretions. Extracellular vesicles (EVs) present in these secretions have emerged as critical cellular component in facilitating many therapeutic benefits of MSCs. EV treatment is thus potentially appealing as a stem cell-inspired cell-free approach to avoid possible phenotypic plasticity of MSCs in vivo. In this study, we investigated the thus far unknown effects of BM-MSC derived EVs on vascular elastic matrix repair in the context of AAA treatment. EVs isolated from BM-MSC source were characterized and their pro-regenerative and their anti-proteolytic effects were evaluated on our established in vitro experimental conditions derived from AAA rat model. Our studies revealed the efficacy of BM-MSC derived EVs in attenuating the proteolytic activity and also in imparting elastic matrix regenerative benefits under aneurysmal environment. Interestingly, compared to cell culture conditioned media (CCM), EVs demonstrated superior regenerative and anti-proteolytic benefits in a proteolytic injury culture model of AAA. From these studies, it appears that EVs derived from BM-MSCs could be beneficial in undertaking a reparative effort in AAA induced degeneration of vascular tissue. Statement of Significance Abdominal aortic aneurysms (AAAs) are localized, rupture-prone expansions of the aorta which result from loss of wall flexibility due to enzymatic breakdown of elastic fibers. There are no established alternatives to surgery, which possess high risk for the mostly elderly patients. Our previous studies have established the elastic regenerative and reparative effect of cell culture secretions derived from adult stem cell source. In this study, we propose to isolate extracellular vesicles (exosomes) from these secretions and evaluate their regenerative benefits in AAA smooth muscle cell culture model. This simple and innovative treatment approach has the potential to arrest or reverse AAA growth to rupture, not possible so far.

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Extracellular matrix degradation products and low-oxygen conditions enhance the regenerative potential of perivascular stem cells.

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Extracellular matrix degradation products and low-oxygen conditions enhance the regenerative potential of perivascular stem cells.

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