Hypoxia Promotes Murine Bone‐Marrow‐Derived Stromal Cell Migration and Tube Formation

Abstract

Recent evidence indicates that bone-marrow-derived stromal cells (MSCs) have a histology coherent with endothelial cells that may enable them to contribute to tumor angiogenesis through yet undefined mechanisms. In this work, we investigated the angiogenic properties of murine MSCs involved in extracellular matrix degradation and in neovascularization that could take place in a hypoxic environment such as that encountered in tumor masses. MSCs were cultured in normoxia (95% air and 5% CO 2 ) or in hypoxia (1% oxygen, 5% CO 2 , and 94% nitrogen). We found that hypoxic culture conditions rapidly induced MSC migration and three-dimensional capillary-like structure formation on Matrigel. In vitro, MSC migration was induced by growth-factor-and cytokine-enriched conditioned media isolated from U-87 glioma cells as well as from MSCs cultured in hypoxic conditions, suggesting both paracrine and autocrine regulatory mechanisms. Although greater vascular endothelial growth factor levels were secreted by MSCs in hypoxic conditions, this growth factor alone could not explain their greater migration. Interestingly, matrix metalloproteinase (MMP)-2 mRNA expression and protein secretion were downregulated, while those of membrane-type (MT)1-MMP were strongly induced by hypoxia. Functional inhibition of MT1-MMP by a blocking antibody strongly suppressed MSC ability to migrate and generate capillary-like structures. Collectively, these data suggest that MSCs may have the capacity to participate in tumor angiogenesis through regulation of their angiogenic properties under an atmosphere of low oxygen that closely approximates the tumor microenvironment.

Isolation and characterization of stem cells derived from human third molar tooth germs of young adults: implications in neo-vascularization, osteo-, adipo- and neurogenesis

“…36 An in vitro tube formation assay was used to understand the role of MSCs in neurovascularization by various groups. 37 In this study, we showed that hTGSCs form tube-like structures, which might be an indication of the possible contribution of these cells to vascularization. It might be valuable to compare the responses of bone marrow-derived MSCs and hTGSCs to angiogenic factors such as the vascular endothelial growth factor.…”

Impairment of endothelial cell differentiation from bone marrow–derived mesenchymal stem cells: New insight into the pathogenesis of systemic sclerosis

“…Recent studies have shown that murine stromal cells can also differentiate into vasculatureforming cells under hypoxic conditions or when genetically transduced to express VEGF (33,34), and human bone marrow MSCs form tubular structures when cultivated in a semisolid medium. The presence of VEGF markedly enhances this behavior (34).…”

Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation

“…Several reports have suggested that hypoxia can regulate MT1-MMP at the transcriptional level in different cell systems (Ben-Yosef et al, 2002; Annabi et al, 2003;Ottino et al, 2004) . A study in renal carcinoma cells deficient in the tumor suppressor von Hippel Lindau (VHL) protein and expressing high levels of endogenous HIF-2a showed induction of MT1-MMP expression at the transcriptional level (Petrella et al, 2005).…”