Angiogenic Effects Despite Limited Cell Survival of Bone Marrow-Derived Mesenchymal Stem Cells under Ischemia

Abstract

Bone marrow-derived mesenchymal stem cells (MSCs) are multipotent and secrete angiogenic factors, which could help patients with occlusive arterial diseases. We hypothesize that MSCs, in comparison to fibroblasts, survive better under hypoxic conditions in vitro and in vivo. MSCs and fibroblasts from L2G mice expressing firefly luciferase and GFP were cultured in normoxic and hypoxic conditions for 24 hours. In vitro cell viability was tested by detecting apoptosis and necrosis. MSCs released higher amounts of VEGF (281.1 +/- 62.6 pg/ml) under hypoxic conditions compared to normoxia (154.9 +/- 52.3 pg/ml, p = NS), but were less tolerant to hypoxia (45 +/- 7.9%) than fibroblasts (28.1 +/- 3.6%, p = NS). A hindlimb ischemia model was created by ligating the femoral artery of 18 FVB mice. After one week, 1 x 106 cells (MSCs, fibroblasts or saline) were injected into the limb muscles of each animal (n = 6 per group). Bioluminescence measurement to assess the viability of luciferase positive cells showed significant proliferation of MSCs on day four compared to fibroblasts (p = 0.001). Three weeks after cell delivery, the capillary to muscle fiber ratio of ischemic areas was analyzed. In the MSC group, vessel density was significantly higher than in the fibroblast or control group (0.5 +/- 0.08 and 0.3 +/- 0.03). Under hypoxia, MSCs produced more VEGF compared to normal conditions and MSC transplantation into murine ischemic limbs led to an increase in vessel density, although MSC survival was limited. This study suggests that MSC transplantation may be an effective and clinically relevant tool in the therapy of occlusive arterial diseases.

VEGF165 expressing bone marrow mesenchymal stem cells differentiate into hepatocytes under HGF and EGF induction in vitro

“…Some studies have shown that MSCs could also achieve the biological effects by secreting VEGF. VEGF secreted by MSCs has been used in gastric ulcer and oral ulcer healing (El-Menoufy et al 2010;Hayashi et al 2008), in murine ischemic limbs leading to an increase in vessel density (Hoffmann et al 2010), in inhibiting the apoptosis of lung cells (Zhen et al 2010), in facilitating neurological function (Deng et al 2010), enhancing the repair and regeneration of critical sized bone defects (Kanczler et al 2010) and improving cardiac function in failing rat hearts (Tao et al 2009). Therefore, the VEGF 165 gene is the best target gene in gene therapy for promoting angiogenesis.…”

Atorvastatin prevents mesenchymal stem cells from hypoxia and serum-free injury through activating amp-activated protein kinase

“…The stimulation of serum starvation and hypoxia could increase the secret of vasoactive substances [30]. While, eNOS is an important enzyme modulating the NO, a vasodilatation factor, especially in ischemia tissues.…”

Effect of erythropoietin on mesenchymal stem cell differentiation and secretion in vitro in an acute kidney injury microenvironment

“…However, improvement is limited. Cell apoptosis during transplantation may be one of the reasons for the poor effectiveness of the treatment (Stolzing and Scutt, 2006;Hoffmann et al, 2010). Erythropoietin (EPO) is a glycoprotein that regulates the growth and differentiation of erythroid progenitor cells.…”