Therapeutic Effect of Adipose Derived Mesenchymal Stem Cell Transplantation in Reducing Restenosis in a Murine Angioplasty Model

Abstract

BackgroundPercutaneous transluminal angioplasty (PTA) is the first line of treatment for stenosis in the arteriovenous fistula (AVF) created to provide access for hemodialysis, but resenosis still occurs. Transplants of adipose-derived mesenchymal stem cells (AMSCs) labeled with green fluorescent protein (GFP) to the adventitia could reduce pro-inflammatory gene expression, possibly restoring patency in a murine model of PTA for venous stenosis.MethodsPartial nephrectomy of male C57BL/6J mice induced CKD. Placement of the AVF was 28 days later and, 14 days after that, PTA of the stenotic outflow vein was performed with delivery of either vehicle control or AMSCs (5×105) to the adventitia of the vein. Mice were euthanized 3 days later and gene expression for interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha TNF-α) analyzed, and histopathologic analysis performed on day 14 and 28. GFP (+) AMSCs were tracked after transplantation for up to 28 days and Doppler ultrasound performed weekly after AVF creation.ResultsGene and protein expression of IL-1β and TNF-α, fibrosis, proliferation, apoptosis and smooth muscle actin decreased, and the proportions of macrophage types (M2/M1) shifted in a manner consistent with less inflammation in AMSC-transplanted vessels compared to controls. After PTA, AMSC-treated vessels had significantly higher wall shear stress, average peak, and mean velocity, with increased lumen vessel area and decreased neointima/media area ratio compared to the control group. At 28 days after delivery, GFP (+) AMSC were present in the adventitia of the outflow vein.ConclusionsAMSC-treated vessels had improved vascular remodeling with decreased proinflammatory gene expression, inflammation, and fibrotic staining compared to untreated vessels.

Adventitial delivery of nanoparticles encapsulated with 1α, 25-dihydroxyvitamin D3 attenuates restenosis in a murine angioplasty model

“…Because WSS and blood flow velocity have been hypothesized as factors leading to the development of VNH associated with AVF 15 , the changes in PV and WSS after PTA were determined. A previous study from our lab showed differences in WSS after PTA compared to control vessels and in this model, increased PV and WSS are seen in vein segments with positive vascular remodeling 16 . In the present study, we extended these results by performing Doppler US to assess the hemodynamic function of the AVF.…”

“…Because fibroblast to smooth muscle differentiation can cause to VS formation in murine AVF, we assessed the presence of fibroblasts using FSP-1 staining 16 . We observed a reduction in FSP-1 staining in 1,25 NP treated vessels compared to controls.…”

Exosomes from Adipose-Derived Mesenchymal Stem Cells Overexpressing Stanniocalcin-1 Promote Reendothelialization after Carotid Endarterium Mechanical Injury

“…NLRP3 in ammasome are a group of intracellular protein complexes produced during in ammation activation, and act as innate immune signal receptor to initiate in ammatory response. IL -1β, as an important member and a major executor of NLRP3 in ammasome, is strongly expressed in the chronic in ammation and restenosis after endovascular treatment [11,18]. In the current study, the elevation of NLRP3 in ammasome (NLRP3, Caspase-1, and IL-1β) after scratching was signi cantly inhibited by exosomes from ADSCs overexpressing STC-1, suggesting that exosomes may account for reendothelialization via antiin ammation effects.…”

“…The powerful paracrine capacity of MSCs, not their differentiation potential, is the principal mechanisms of their repair action [10]. Local transplantation of adipose-derived mesenchymal stem cells around arteriovenous stula alleviates restenosis and restores patency after PTA in mice [11].…”

“…Interleukin (IL) -1β has been reported to participate in the chronic in ammation and restenosis after endovascular treatment [11,18]. As an important component of innate immunity, NLRP3 in ammasome consisting of NLRP3 receptor protein, apoptosis-associated speck-link protein containing a CARD (ASC), and Caspase-1 has recently emerged as a protein complex for inducing the release of IL-1β and IL-18 [19].…”