Maurizio C. Capogrossi

Acidosis Inhibits Endothelial Cell Apoptosis and Function and Induces Basic Fibroblast Growth Factor and Vascular Endothelial Growth Factor Expression

Endothelial cells are exposed to an acidotic environment in a variety of pathological and physiological conditions. However, the effect of acidosis on endothelial cell function is still largely unknown, and it was evaluated in the present study. Bovine aortic endothelial cells (BAECs) were grown in bicarbonate buffer equilibrated either with 20% CO(2) (pH 7.0, acidosis) or 5% CO(2) (pH 7.4, control). Acidosis inhibited BAEC proliferation in 10% FCS, whereas by day 7 in serum-free medium, cell number was 3-fold higher in acidotic cells than in control cells. Serum deprivation enhanced BAEC apoptosis, and apoptotic cell death was markedly inhibited by acidosis. Additionally, acidosis inhibited FCS-stimulated migration in a modified Boyden chamber assay and FCS-stimulated differentiation into capillary-like structures on reconstituted basement membrane proteins. Conditioned media from BAECs cultured for 48 hours either at pH 7.0 or pH 7.4 enhanced BAEC proliferation and migration at pH 7.4, and both effects were more marked with conditioned medium from BAECs grown in acidotic than in control conditions. Acidosis enhanced vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) mRNA expression as well as bFGF secretion, and a blocking bFGF antibody inhibited enhanced BAEC migration in response to conditioned medium from acidotic cells. These results show that acidosis protects endothelial cells from apoptosis and inhibits their proangiogenic behavior despite enhanced VEGF and bFGF mRNA expression and bFGF secretion.

When Stemness Meets Engineering: Towards “Niche” Control of Stem Cell Functions for Enhanced Cardiovascular Regeneration

The generation of bioartificial tissues using patient-derived or allogenic cells, has become a clinically relevant opportunity for translation in various branches of medicine, e.g. dermatology, ophthalmology and diabetes care. By contrast, despite the huge number of patients with cardiovascular diseases and the high economic burden, no feasible options exist to produce biomimetic engineered tissues that could be employed as definitive substitutes in cardiovascular medicine. In fact, while stem cells with cardiovascular competence have been identified and characterized, their employment has remained mainly confined to regenerative medicine, with insufficient translation into effective tissue engineering strategies. As a result, the devices presently available to replace diseased myocardium, occluded vessels and failing valves is limited to materials with tensile resistance (patches for ventricular reconstruction), autologous vessels (mammary/radial arteries and saphenous vein for aorto-coronary bypass grafts) and mechanical/bio-prosthetic valves, all of which have major limitations such as insufficient mechanical integration, post-engraftment patency reduction and calcification, respectively. Merging stem cell biology with recent bio-engineering techniques will be of great help in the production of new bio-synthetic cardiovascular medical devices. In fact, the ability to design complex biomaterial patterning in microscale or nanoscale dimensions and the ability to perform material-cell interaction analysis with a “high throughput” discovery power, can be exploited to obtain stem cell structuring in a similar fashion to natural “niche” conditions. In this way, the unique ability of stem cells to divide “asymmetrically” may be preserved, thus ensuring, at the same time, maintenance of an immature cell pool while enabling constant production of committed progenitors necessary for cellular renewal and tissue homeostasis.