Environmental oxygen affects ex vivo growth and proliferation of mesenchymal progenitors by modulating mitogen-activated protein kinase and mammalian target of rapamycin signaling.

BACKGROUND AIMS: Stem and progenitor cells of hematopoietic and mesenchymal lineages reside in the bone marrow under low oxygen (O2) saturation. O2 levels used in ex vivo expansion of multipotent mesenchymal stromal cells (MSCs) affect proliferation, metabolism and differentiation. METHODS: Using cell-based assays and transcriptome and proteome data, the authors compared MSC cultures simultaneously grown under a conventional 19.95% O2 atmosphere or at 5% O2. RESULTS: In 5% O2, MSCs showed better proliferation and higher self-renewal ability, most probably sustained by enhanced signaling activity of mitogen-activated protein kinase and mammalian target of rapamycin pathways. Non-oxidative glycolysis-based energy metabolism supported growth and proliferation in 5% O2 cultures, whereas MSCs grown under 19.95% O2 also utilized oxidative phosphorylation. Cytoprotection mechanisms used by cells under 5% O2 differed from 19.95% O2  suggesting differences in the triggers of cell stress between these two O2  conditions. CONCLUSIONS: Based on the potential benefits for the growth and metabolism of MSCs, the authors propose the use of 5% O2 for MSC culture.

Pilot Study of Endovascular Delivery of Mesenchymal Stromal Cells in the Aortic Wall in a Pig Model.

Abdominal aortic aneurysms (AAAs) have a high mortality. In small-animal models, multipotent mesenchymal stromal cells (MSCs) have shown benefits in attenuating aneurysm formation. However, an optimal cell delivery strategy is lacking. The NOGA system, which targets cell injections in a less-invasive way, has been used for myocardial cell delivery. Here, we assessed the safety and feasibility of the NOGA system for endovascular delivery of MSCs to the aortic wall in an AAA pig model. We induced AAA in 9 pigs by surgery or catheter induction. MSCs were delivered using the NOGA system 6 or 8 weeks after aneurysm induction. We euthanized the pigs and harvested the aorta for histologic analysis 1, 3, and 7 days after cell delivery. During AAA creation, 1 pig died; 8 pigs completed the study without acute adverse events or complications. The cell delivery procedure was safe and feasible. We successfully injected MSCs directly into the aortic wall in a targeted manner. Histologic and immunohistochemical analyses confirmed transmural injections in the aortic wall area of interest and the presence of MSCs. Our study showed the safety and feasibility of endovascular cell delivery to the aortic wall in a pig model.