Priming Mesenchymal Stem Cells with Endothelial Growth Medium Boosts Stem Cell Therapy for Systemic Arterial Hypertension

Systemic arterial hypertension (SAH), a clinical syndrome characterized by persistent elevation of arterial pressure, is often associated with abnormalities such as microvascular rarefaction, defective angiogenesis, and endothelial dysfunction. Mesenchymal stem cells (MSCs), which normally induce angiogenesis and improve endothelial function, are defective in SAH. The central aim of this study was to evaluate whether priming of MSCs with endothelial growth medium (EGM-2) increases their therapeutic effects in spontaneously hypertensive rats (SHRs). Adult female SHRs were administered an intraperitoneal injection of vehicle solutionn=10, MSCs cultured in conventional medium (DMEM plus 10% FBS,n=11), or MSCs cultured in conventional medium followed by 72 hours in EGM-2 (pMSC,n=10). Priming of the MSCs reduced the basal cell death ratein vitro. The administration of pMSCs significantly induced a prolonged reduction (10 days) in arterial pressure, a decrease in cardiac hypertrophy, an improvement in endothelium-dependent vasodilation response to acetylcholine, and an increase in skeletal muscle microvascular density compared to the vehicle and MSC groups. The transplanted cells were rarely found in the hearts and kidneys. Taken together, our findings indicate that priming of MSCs boosts stem cell therapy for the treatment of SAH.

Shear Stress Induces Differentiation of Endothelial Lineage Cells to Protect Neonatal Brain from Hypoxic-Ischemic Injury through NRP1 and VEGFR2 Signaling

Neonatal hypoxic-ischemic (HI) brain injuries disrupt the integrity of neurovascular structure and lead to lifelong neurological deficit. The devastating damage can be ameliorated by preserving the endothelial network, but the source for therapeutic cells is limited. We aim to evaluate the beneficial effect of mechanical shear stress in the differentiation of endothelial lineage cells (ELCs) from adipose-derived stem cells (ASCs) and the possible intracellular signals to protect HI injury using cell-based therapy in the neonatal rats. The ASCs expressed early endothelial markers after biochemical stimulation of endothelial growth medium. The ELCs with full endothelial characteristics were accomplished after a subsequential shear stress application for 24 hours. When comparing the therapeutic potential of ASCs and ELCs, the ELCs treatment significantly reduced the infarction area and preserved neurovascular architecture in HI injured brain. The transplanted ELCs can migrate and engraft into the brain tissue, especially in vessels, where they promoted the angiogenesis. The activation of Akt by neuropilin 1 (NRP1) and vascular endothelial growth factor receptor 2 (VEGFR2) was important for ELC migration and followingin vivotherapeutic outcomes. Therefore, the current study demonstrated importance of mechanical factor in stem cell differentiation and showed promising protection of brain from HI injury using ELCs treatment.

Effect of transplantation of pro-angiogenic monocytes to pancreatic cancer-bearing mice on resistance to chemotherapy/radiotherapy.

212 Background: Hypoxic tumors are usually resistant to conventional chemotherapy and radiotherapies, which typically target actively dividing cells. The tumor vasculatures are unorganized and lack adequate pericyte coverage, which compromises delivery of drugs to tumors. How best to normalize the aberrant tumor vasculature to maximize anticancer drug delivery comprises an area of intensive investigation. Methods: We tested out hypothesize that bone marrow (BM) cells may be able to restore appropriate vessel function in tumor vasculature using nude mice bearing pancreatic cancer xenografts and genetically engineered mice that develop pancreatic adenocarcinoma. Results: Culturing BM mononuclear cells with endothelial growth medium resulted in the early outgrowth of spindle-shaped attached monocytic cells expressing CD11b/CXCR4 with a significant vessel stabilizing activity. Intravenous administration of these cultured pro- angiogenic cells into mice bearing pancreatic cancer significantly reduced areas of hypoxia without enhancing tumor growth. The resulting vasculature structurally mimicked normal vessels with intensive pericyte coverage. Consistent with a marked reduction in gene expressions involved in drug resistance such as MDR1 and ABCG2 in monocytes-injected tumors, a combination of the transplantation and chemotherapeutic agents reduced tumor size and significantly increased areas of necrosis as compared to chemotherapy alone. Conclusions: Our findings offer an alternate approach to improve delivery and efficacy of anticancer drugs to hypoxic tumors through a remodeling of the abnormal tumor vessels. No significant financial relationships to disclose.