Effect of Hypoxia on Gene Expression of Bone Marrow-Derived Mesenchymal Stem Cells and Mononuclear Cells

Abstract

MSC have self-renewal and multilineage differentiation potential, including differentiation into endothelial cells and vascular smooth muscle cells. Although bone marrow-derived mononuclear cells (MNC) have been applied for therapeutic angiogenesis in ischemic tissue, little information is available regarding comparison of the molecular foundation between MNC and their MSC subpopulation, as well as their response to ischemic conditions. Thus, we investigated the gene expression profiles between MSC and MNC of rat bone marrow under normoxia and hypoxia using a microarray containing 31,099 genes. In normoxia, 2,232 (7.2%) and 2,193 genes (7.1%) were preferentially expressed more than threefold in MSC and MNC, respectively, and MSC expressed a number of genes involved in development, morphogenesis, cell adhesion, and proliferation, whereas various genes highly expressed in MNC were involved in inflammatory response and chemotaxis. Under hypoxia, 135 (0.44%) and 49 (0.16%) genes were upregulated (>threefold) in MSC and MNC, respectively, and a large number of those upregulated genes were involved in glycolysis and metabolism. Focusing on genes encoding secretory proteins, the upregulated genes in MSC under hypoxia included several molecules involved in cell proliferation and survival, such as vascular endothelial growth factor-D, placenta growth factor, pre-B-cell colony-enhancing factor 1, heparin-binding epidermal growth factor-like growth factor, and matrix metalloproteinase-9, whereas the upregulated genes in MNC under hypoxia included proinflammatory cytokines such as chemokine (C-X-C motif) ligand 2 and interleukin-1␣. Our results may provide information on the differential molecular mechanisms regulating the properties of MSC and MNC under ischemic conditions.

Hypoxic and ischemic effects on gene and protein expression levels of paracrine factors by human olfactory mucosa mesenchymal-like stem cells

“…Other investigators have demonstrated an increase in VEGF gene expression and secretion by MSCs in hypoxia. 14,15 Our results generally did demonstrate an increase in VEGF after hypoxia in 20% serum supplement, while the results are the opposite in 5% serum supplement. The serum levels may influence the gene expression for VEGF, so the secretion of VEGF in hypoxia was different between the 20% serum supplement and the 5% serum supplement.…”

“…[9][10][11] There is only 3%-14% oxygen in brain. 12 Hypoxia 13 can affect the secretion of paracrine factors, 14 alter gene expression of MSCs 15,16 and enhance proliferation of MSCs. [17][18][19][20][21] The amount of serum present in the culture media also affects stem cell behavior.…”

“…In addition, hypoxia increased gene expression for trophic/growth factors in MSCs, including BDNF, GDNF and VEGF and its receptor FIK-1; erythropoietin (EPO) and its receptor EPOR; stromal derived factor-1 and its CXC chemokine receptor 4; placental growth factor; heparin-binding epidermal growth factor; MMP-9, and basic fibroblast growth factor (bFGF). 14,15,32 Hypoxia caused an increase in the secretion of transforming growth factor-β2; insulin-like growth factor (IGF) binding proteins 2, 3, 4 and 6; IGF-II and interleukin-7, 33,34 and reduced the secretion of stromal cell derived factor-1, macrophage colony stimulating factor, interleukin-1 receptor antagonist, RANTES, chemokine (C-X-C motif) ligand 1, lactate dehydrogenase and chemokine (C-X-C motif) ligand 10 by MSCs. 16,35 In short, hypoxia changes the paracrine secretions of MSCs, which would have implications for the role they play in reducing the loss of function in the brain after cerebral ischemia.…”

Enhanced fibrillin-2 expression is a general feature of wound healing and sclerosis: potential alteration of cell attachment and storage of TGF-β

“…Correlating results were shown for the fibrillin-2 gene expression level in mesenchymal stem cells cultured under normoxic and hypoxic conditions. 44 Thus, the accumulation of fibrillin-2 in wound healing and sclerosis appears to be an early event due to the contact of fibroblasts to serum or due to inflammation but is not sustained by hypoxia. The spatial expression pattern of fibrillin-2 in normal skin, wound healing and sclerotic tissue resembles the pattern found for tenascin-C, and in double-staining experiments fibrillin-2 and tenascin-C co-localized.…”

Preliminary evaluation of intravenous infusion and intrapancreatic injection of human umbilical cord blood-derived mesenchymal stem cells for the treatment of diabetic mice

“…MSCs could stimulate the production of cytokines and growth factors. The paracrine effects of these secreted factors can greatly influence the surrounding microenvironment of the MSCs and promote the survival of the surrounding cells (Dormady et al, 2001;Ohnishi et al, 2007). MSCs can "home" to the damaged area and help initiate recovery (Vija et al, 2009).…”