Catheter Injected Bone Marrow Mesenchymal Stem Cells Induce Efficacious Occlusion of Arteriovenous Nidus in a Swine Model

Publication date: Available online 17 January 2018
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Joseph Touma, Jianping Dai, Andre Gaston, Marianne Gervais, Eric Allaire
ObjectivesArteriovenous malformations (AVMs) are complex vascular lesions. Surgical excision is the treatment of choice, but is often not achievable. Embolo-sclerotherapy alone is associated with high recurrence rates. This study tested the hypothesis that seeding hydrogel conditioned bone marrow derived mesenchymatous stem cells (BM-MSCs) in an AVM nidus model induces solid microvascular occlusion through endoluminal tissue growth.MethodsAVMs were modelled as arteriovenous microvascular nidus, using swine rete mirabile, a plexiform intracranial structure composed of arterial microvessels that extensively anastomose. A right carotid-jugular fistula was created to generate high flow in the rete, and bone marrow was aspirated. At day 14, cultured BM-MSCs marked with a red fluorochrome were incorporated into a hyaluronic acid hydrogel, and injected through a catheter into the rete mirabile, using femoral access. In specific groups microsphere embolisation immediately preceded gel injection. At day 28, the swine were euthanased and the rete mirabile harvested for qualitative and quantitative analysis of microvessel lumen occlusion.ResultsActual transfer of PKH26 labelled cells in rete was confirmed. In a first phase of the study, five swine died as a result of neurological events, prompting reductions of the injected volumes. Twenty-three animals survived until day 28. Injection of BM-MSC loaded hydrogel (n=6) significantly increased the occlusion rate compared with injection of acellular hydrogel (n=7) (10% [range, 10–12%] vs. 26% [range, 20–41%], p=.016). Injection of BM-MSC loaded hydrogel immediately after microspheres (n=6) enhanced the occlusion rate compared with embolic microspheres alone (n=6) (50% [range 46–56%] vs. 22% [range, 15–27%] p=.045). Microsphere injection resulted in vascular luminal thrombus formation. Injection of BM-MSCs induced endoluminal growth of vascular smooth muscle cells with cell proliferation and a dense collagen rich extracellular matrix.ConclusionThe luminal occlusion pattern of a microvascular AVM like structure can be changed from thrombus to solid cellular accumulation. The possibility of injecting living cells in a microvascular network, in a chronic survival model, provides new tools for research and treatment of AVMs and other microvascular diseases.



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