Vasculogenic properties of adventitial Sca-1(+)CD45(+) progenitor cells in mice: a potential source of vasa vasorum in atherosclerosis

The cellular origins of vasa vasorum are ill-defined and may involve circulating or local progenitor cells. We previously discovered that murine aortic adventitia contains Sca-1⁺CD45⁺ progenitors that produce macrophages. Here we investigated whether they are also vasculogenic. In aortas of C57BL/6 mice, Sca-1⁺CD45⁺ cells were localised to adventitia and lacked surface expression of endothelial markers (<1% for CD31, CD144, TIE-2). In contrast, they did show expression of CD31, CD144, TIE-2 and VEGFR2 in atherosclerotic ApoE(-/-) aortas. Although Sca-1⁺CD45⁺ cells from C57BL/6 aorta did not express CD31, they formed CD31⁺ colonies in endothelial differentiation media and produced interconnecting vascular-like cords in Matrigel that contained both endothelial cells and a small population of macrophages, which were located at branch points. Transfer of aortic Sca-1⁺CD45⁺ cells generated endothelial cells and neovessels de novo in a hindlimb model of ischaemia and resulted in a 50% increase in perfusion compared to cell-free control. Similarly, their injection into the carotid adventitia of ApoE(-/-) mice produced donor-derived adventitial and peri-adventitial microvessels after atherogenic diet, suggestive of newly formed vasa vasorum. These findings show that beyond its content of macrophage progenitors, adventitial Sca-1⁺CD45⁺ cells are also vasculogenic and may be a source of vasa vasorum during atherogenesis.Deborah Toledo-Flores, Anna Williamson, Nisha Schwarz, Sanuja Fernando, Catherine Dimasi, Tyra A. Witt, Thao M. Nguyen, Amrutesh S . Puranik, Colin D. Chue, Sinny Delacroix, Daniel B. Spoon, Claudine S. Bonder, Christina A. Bursill, Belinda A. Di Bartolo, Stephen J. Nicholls, Robert D. Simari, Peter J. Psalti

Emerging roles for integrated imaging modalities in cardiovascular cell-based therapeutics: a clinical perspective

Despite preclinical promise, the progress of cell-based therapy to clinical cardiovascular practice has been slowed by several challenges and uncertainties that have been highlighted by the conflicting results of human trials. Most telling has been the revelation that current strategies fall short of achieving sufficient retention and engraftment of cells to meet the ambitious objective of myocardial regeneration. This has sparked novel research into the refinement of cell biology and delivery to overcome these shortcomings. Within this context, molecular imaging has emerged as a valuable tool for providing noninvasive surveillance of cell fate in vivo. Direct and indirect labelling of cells can be coupled with clinically relevant imaging modalities, such as radionuclide single photon emission computed tomography and positron emission tomography, and magnetic resonance imaging, to assess their short- and long-term distributions, along with their viability, proliferation and functional interaction with the host myocardium. This review details the strengths and limitations of the different cell labelling and imaging techniques and their potential application to the clinical realm. We also consider the broader, multifaceted utility of imaging throughout the cell therapy process, providing a discussion of its considerable value during cell delivery and its importance during the evaluation of cardiac outcomes in clinical studies.Peter J. Psaltis, Robert D. Simari and Martin Rodriguez-Porce

Design and testing of magnetic vascular stents for rapid endothelialization

Rapid endothelialization of cardiovascular stents by means of magnetic cell capture has the potential to enhance healing and to reduce the risk of restenosis. We designed and manufactured stents made of magnetizable 2205 duplex stainless steel (UNS S31803) to study the magnetic field strength required to capture endothelial cells labeled with superparamagnetic nanoparticles. To aid in the design, we used the finite element method to study stress and strain distributions and to ensure strain values do not exceed 30% during crimping and expansion. Stents magnetized with a permanent magnet exhibited magnetic fields in the range of 630 mG compared to 10 mG for non-magnetized stents as measured by a magnetoresistive probe. Furthermore, we observed that plastic deformation greatly reduced the magnetic field strength, but did not result in material fracture. Finally, endothelial cell capture studies revealed that approximately 310 cells/mm2 were attracted to the magnetized stents within 1-3 minutes

Magnetizable duplex steel stents enable endothelial cell capture

Emerging medical nanotechnology applications often utilize magnetic forces to guide the movement of superparamagnetic particle linked cells and drugs in order to achieve a therapeutic effect. Superparamagnetic particle labeled endothelial cells have previously been captured on the surface of prototype nickel-plated stents in proof of concept studies. Facilitated endothelialization may help improve the healing of stented arteries and reduce the risk of stent thrombosis and restenosis. Extensive evaluation of candidate materials led to the development of a magnetizable 2205 duplex stainless steel stent. Magnetic field strengths of approximately 630 mG were induced within these stents by holding them in close proximity to a 0.7 T rare earth magnet. The magnetic field strength was reliably maintained over several days, but was partially reduced upon mild mechanical shock or plastic deformation. Mechanical testing demonstrated that stents could withstand crimping and expansion necessary for vascular implantation; however, magnetic field strength was significantly reduced. When placed in an endothelial cell suspension of 1×106 cells/mL, magnetized stents captured approximately 310 cells/mm2 compared to approximately 35 cells/mm2 for non-magnetized control stents. These data provide quantitative support to the observation that low level magnetization of stents may be adequate to attract labeled, autologous, blood-derived endothelial outgrowth cells following stent placement. This, in turn, may lead to more rapid and complete healing of stented arteries with a concomitant improvement in stent performance

Magnetic Vascular Implants Promote Rapid Endothelialization

Atherosclerosis is the most prevalent and costly public health threat in the world (WHO, 2006). Treatment often involves surgical placement of a vascular graft or stent, but these interventions are susceptible to thrombosis, inflammation, and neointimal hyperplasia in vivo. We designed and tested novel, rapidly-endothelializing, magnetic vascular grafts and stents. First, endothelial outgrowth cells endocytosed superparamagnetic microspheres in culture. The cells were then seeded onto magnetic stents and grafts for in vivo experimentation. Fourteen stents were implanted into pigs, showing superior resistance to inflammation, thrombosis, and neointimal hyperplasia relative to bare metal stents. Similarly, endothelial cell coated cobalt chromium – poly(ether urethane) composite grafts were implanted into pig arteries, exhibiting improved patency at one month follow-up. These studies facilitated materials selection and design of cardiovascular implants with superior efficacy and reduced development time