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ABSTRACT: Vascular rejection is characterized by intimal proliferation and perivascular inflammation. We hypothesize that recipient stem cell therapy could prevent or ameliorate the development of the obliterative lesion. We studied the kinetic expression of three cytokines (SDF-1, MCP-1, VEGF) implicated in mobilization, homing and differentiation of progenitor cells during vascular aggression. An aortic allograft mouse model was used (BALBc donor-C57BL6/j recipient). Ten mice were sacrificed at Day 0, D1, D3, D6, D9, D12, and D20. Cytokine rates were measured in blood and in graft tissue by an ELISA technique. Results showed that in the allograft, SDF-1 and VEGF tissue levels were significantly increased at D12 as compared to the isograft (SDF-1: 22.16 ng/mg vs. 5.69 ng/mg, t=3.38; VEGF: 28.3 pg/mg vs. 9.3 pg/mg, t=3.06). In allografted and isografted groups, MCP-1 tissue levels were higher at D0 as compared to the other time points, without any difference between the two groups. These results prompt us to consider cell therapy at D0 and D12 in this mouse model of aortic graft.
Acta histochemica 11/2011; 114(6):636-8. · 1.23 Impact Factor
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ABSTRACT: Transplant arteriosclerosis is characterized by intraluminal obstructive proliferation occurring in response to immune-mediated arterial wall injury. Cell therapy with vascular progenitor cells have been suggested to repair intimal lesions following endothelial injury. The aim of the current study was to assess the effects of autologous bone marrow cell direct transfer and of Fucan-mobilization bone marrow-derived progenitor cells on intimal thickening in vascular grafts.
Aortic allografts were performed in Brown Norway (BN) and Lewis (LEW) rats. Cell therapy was performed by injection of two doses of 10 million LEW bone marrow mononuclear cells to recipient LEW following aortic grafting. Fucan, a low molecular weight sulfated polysaccharide (LMWF) was used to mobilize bone marrow-derived progenitor cells. Five groups of 10 rats included: untreated isografts (BN to BN), untreated allografts, and three allografted groups, respectively, treated by fucan therapy, cell therapy, or cell and fucan therapy. Aorta were studied by morphometric analysis at 30 d.
In the absence of treatment, intimal thickening was greater in allograft than in isograft groups (299±50 versus 3.5±1.7 μm, P<0.001). Cell therapy alone, fucan therapy alone, and the combined treatment were shown to prevent intimal thickening in allografts (5.1±1.7, 6.1±2.3, 4.1±2.5, versus 299±50 μm respectively, P<0.001). In the three treated groups, the intimal lining was a single layer of endothelial cells expressing CD34 positive, endothelial nitric oxide synthase (eNOS) positive, and Ox3 specific-recipient monoclonal antibody positive.
These results provide the proof of concept of recipient syngenic bone-marrow cell therapy for the prevention of chronic vasculopathy.
Journal of Surgical Research 06/2011; 168(1):143-8. · 2.25 Impact Factor
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Dominique Guerrot,
Arnaud François,
Jean-Jacques Boffa,
Nada Boulos,
Melanie Hanoy,
Bruno Legallicier,
Aude Triquenot-Bagan,
Lucie Guyant-Marechal,
Annie Laquerriere, Caroline Freguin-Bouilland,
Pierre Ronco,
Michel Godin
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ABSTRACT: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a systemic arterial disease characterized by impairment of vascular smooth muscle cell structure and function related to NOTCH3 mutations. Pathological findings include pathognomonic granular osmiophilic material (GOM) deposition with nonspecific hyalinization within the artery wall in a variety of tissues. The main clinical presentation is iterative strokes in young adults despite the lack of cardiovascular risk factors, leading to early dementia. Although arteriosclerosis and GOM have been found in kidneys from patients with CADASIL, kidney disease has been described only once up to now, in association with immunoglobulin A nephropathy. We report the case of a 61-year-old patient with a medical history of CADASIL and recent mild hypertension. His mother also showed neuropsychiatric symptoms and end-stage renal disease of unknown cause. The patient had a chronic kidney disease defined by means of estimated glomerular filtration rate using the 4-variable Modification of Diet in Renal Disease Study equation of 58 mL/min/1.73 m(2) associated with mild proteinuria and intermittent microscopic hematuria. Renal histological analysis showed severe arteriosclerosis and mild interstitial fibrosis. Glomeruli did not show mesangial immunoglobulin A deposition or focal segmental proliferation. Electron microscopic analysis showed typical GOM deposition in the vicinity of altered vascular smooth muscle cells in interlobular and juxtaglomerular arteries. The nephroangiosclerosis-like lesions were unusually severe in contrast to the recent mild hypertension. The presence of GOM strongly suggests that renal lesions were related to the NOTCH3 mutation. Here, we describe the first case of familial occurrence of kidney disease with decreased kidney function in the absence of coexisting nephropathy in patients with CADASIL. We discuss the role of NOTCH3 mutation in the pathogenesis of nephroangiosclerosis through functional impairment of renal microcirculation or primary Notch3-related vascular disease.
American Journal of Kidney Diseases 09/2008; 52(2):340-5. · 5.43 Impact Factor
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ABSTRACT: The humoral pathway is suggested as playing a key role in transplant arteriosclerosis. The humoral immunity is demonstrated in the present study to induce direct vascular lesion.
Ten abdominal aortic grafts were performed on 4 groups of rats: Brown Norway (BN) isografts, BN to Lewis (LEW) allografts, and two BN to nude (RNU) grafted groups with and without any humoral transfer. The humoral sera were obtained by skin grafts performed in BN to LEW combination. Lewis anti-BN alloantisera was transferred in nude recipients through intraperitoneal injections. The aortic wall was histologically studied with morphometric analysis on the 21st day. Two additional BN to RNU aortic graft groups were evaluated by immunohistochemistry on days 3 (10 rats) and 10 (10 rats).
In the absence of the humoral transfer, the BN aortic wall implanted in RNU remained intact. The humoral transfer induced a marked intimal proliferation (63 +/- 4 vs 4 +/- 1.1 microm; P < .001) and an adventitial cell infiltration (5.1 +/- 0.7 vs 2.8 +/- 0.6 x 10(3) c/mm2, P < .001). The medial thickness and the medial cell density were not modified. On day 3, the remaining endothelial cells were covered by immunoglobulin G deposits. On day 10 the endothelial cells disappeared completely and intimal proliferation occurred. In an additional cardiac graft group, transplant coronary arteriopathy was evidenced in 7 of the 9 nude recipients that had undergone the humoral transfer.
The transplant arterial occlusive lesion is demonstrated here (1) to be induced by humoral antidonor immunity and (2) to be linked to an adventitial or perivascular inflammation.
The Journal of thoracic and cardiovascular surgery 04/2007; 133(3):791-7. · 3.41 Impact Factor
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ABSTRACT: Transplant arteriosclerosis is the main cause of long-term failure after cardiac transplantation. Vascular rejection is thought to be due to intimal proliferation occurring in response to arterial wall immune-mediated injury. A low molecular weight fucan (LMWF) compound, a sulfated polysaccharide, has been demonstrated to increase plasma levels of stromal cell-derived factor 1 (SDF-1) and consequently to mobilize bone marrow-derived vascular progenitor cells (BMVPC). The aim of this study was to evaluate the capacity of LMWF to prevent coronary intimal proliferation in a rat cardiac allograft model.
Heterotopic abdominal cardiac graftings were performed in Brown Norway (BN) and Lewis (LEW) rats. Animals were divided into 4 groups of 10 rats. Two groups were treated intramuscularly with LMWF (5 mg/kg/day) (one BN to BN isograft group, and one BN to LEW allograft group); and two control groups were LMWF-untreated (one BN to BN isograft group and one BN to LEW allograft group). All animals were treated by cyclosporin (15 mg/kg/day) sub-cutaneously and sacrificed at day 30. The cardiac grafts were assessed by morphometry of structural parameters and by histological and immunohistochemical analyses.
All cardiac isografts were devoid of any coronary and parenchymal lesions. In contrast, the majority of untreated allografts developed coronary intimal proliferation in close association with intimal and adventitial inflammatory CD68(+) cell infiltration. Further, the parenchyma exhibited large areas of actin(+) cells (myofibroblasts) of recipient origin colocalized with the CD68(+) infiltrating cells. Interestingly, all LMWF-treated allografts were well protected against coronary and parenchymal lesions and the coronary arteries exhibited an intimal monolayer of flat cells, which however were CD34 negative.
treatment with LMWF appeared very effective in this rat cardiac allograft model to prevent arterial and parenchymal lesions occurring in response to alloimmune injury. However this protective effect does not appear to depend on mobilization of bone marrow-derived cells.
Transplant Immunology 07/2006; 16(1):14-9. · 1.46 Impact Factor
