Contribution of Recipient-Derived Cells in Allograft Neointima Formation and the Response to Stent Implantation

Allograft coronary disease is the dominant cause of increased risk of death after cardiac transplantation. While the percutaneous insertion of stents is the most efficacious revascularization strategy for allograft coronary disease there is a high incidence of stent renarrowing. We developed a novel rabbit model of sex-mismatched allograft vascular disease as well as the response to stent implantation. In situ hybridization for the Y-chromosome was employed to detect male cells in the neointima of stented allograft, and the population of recipient derived neointimal cells was measured by quantitative polymerase chain reaction and characterized by immunohistochemistry. To demonstrate the participation of circulatory derived cells in stent neointima formation we infused ex vivo labeled peripheral blood mononuclear cells into native rabbit carotid arteries immediately after stenting. Fourteen days after stenting the neointima area was 58% greater in the stented vs. non-stented allograft segments (p = 0.02). Male cells were detected in the neointima of stented female-to-male allografts. Recipient-derived cells constituted 72.1±5.7% and 81.5±4.2% of neointimal cell population in the non-stented and stented segments, respectively and the corresponding proliferation rates were only 2.7±0.5% and 2.3±0.2%. Some of the recipient-derived neointimal cells were of endothelial lineage. The ex vivo tagged cells constituted 9.0±0.4% of the cells per high power field in the stent neointima 14 days after stenting. These experiments provide important quantitative data regarding the degree to which host-derived blood-borne cells contribute to neointima formation in allograft vasculopathy and the early response to stent implantation

Switching of magnetization by non-linear resonance studied in single nanoparticles

Magnetization reversal in magnetic particles is one of the fundamental issues in magnetic data storage. Technological improvements require the understanding of dynamical magnetization reversal processes at nanosecond time scales. New strategies are needed to overcome current limitations. For example, the problem of thermal stability of the magnetization state (superparamagnetic limit) can be pushed down to smaller particle sizes by increasing the magnetic anisotropy. High fields are then needed to reverse the magnetization that are difficult to achieve in current devices. Here we propose a new method to overcome this limitation. A constant applied field, well below the switching field, combined with a radio-frequency (RF) field pulse can reverse the magnetization of a nanoparticle. The efficiency of this method is demonstrated on a 20 nm cobalt particle by using the micro-SQUID technique. Other applications of this method might be nucleation or depinning of domain walls.Comment: 11 pages, 5 figure

Host-Derived Smooth Muscle Cells Accumulate in Cardiac Allografts: Role of Inflammation and Monocyte Chemoattractant Protein 1

Transplant arteriosclerosis is characterized by inflammation and intimal thickening caused by accumulation of smooth muscle cells (SMCs) both from donor and recipient. We assessed the relationship between clinical factors and the presence of host-derived SMCs in 124 myocardial biopsies from 26 consecutive patients who received hearts from opposite-sex donors. Clinical and demographic information was obtained from the patients' medical records. Host-derived SMCs accounted for 3.35±2.3% of cells in arterioles (range, 0.08–12.51%). As shown by linear regression analysis, an increased number of SMCs was associated with rejection grade (mean, 1.41±1.03, p = 0.034) and the number of leukocytes (19.1±12.7 per 20 high-power fields, p = 0.01). The accumulation of host-derived SMCs was associated with an increased number of leukocytes in the allografts. In vitro, monocyte chemoattractant protein 1 (MCP-1) released from leukocytes was crucial for SMC migration. After heart allotransplantion, mice treated with MCP-1-specific antibodies had significantly fewer host-derived SMCs in the grafts than mice treated with isotypic antibody controls. We conclude that the number of host-derived SMCs in human cardiac allografts is associated with the rejection grade and that MCP-1 may play pivotal role in recruiting host-derived SMCs into cardiac allografts

Targeting SDF-1/CXCR4 to inhibit tumour vasculature for treatment of glioblastomas

Local recurrence of glioblastomas is a major cause of patient mortality after definitive treatment. This review discusses the roles of the chemokine stromal cell-derived factor-1 and its receptor CXC chemokine receptor 4 (CXCR4) in affecting the sensitivity of glioblastomas to irradiation. Blocking these molecules prevents or delays tumour recurrence after irradiation by inhibiting the recruitment of CD11b+ monocytes/macrophages that participate in revascularising the tumour. We review the literature pertaining to the mechanism by which revascularisation occurs following tumour irradiation using experimental models. Areas of interest and debate in the literature include the process by which endothelial cells die after irradiation and the identity/origin of the cells that reconstitute the tumour blood vessels after injury. Understanding the processes that mediate tumour revascularisation will guide the improvement of clinical strategies for preventing recurrence of glioblastoma after irradiation

Role of progenitor cells in transplant arteriosclerosis

To date, chronic transplant dysfunction (CTD) is recognized as the major cause of transplant loss long term after transplantation. CTD has the remarkable histologic feature that the luminal areas of the intragraft arteries become obliterated as a result of occlusive neointima formation. Neointimal lesions contain predominantly vascular smooth muscle cells (VSMCs) and extracellular matrix admixed with inflammatory cells. At the luminal side, neointimal lesions are covered with a monolayer of endothelial cells (ECs). The etiology of transplant arteriosclerosis (TA) is largely unknown, and adequate prevention and treatment protocols are not available. In contrast to the largely accepted "response-to-injury" hypothesis for the development of TA that attributes an important role to graft-derived ECs and VSMCs, recent data indicate that host-derived vascular progenitor cells play a major role in the development of TA. The process leading to TA appears to be heterogeneous, and neointimal ECs and VSMCs can be recruited from different sources, possibly depending on the severity and duration of vascular damage. These data suggest a significant role of host-derived circulating EC/VSMC progenitor cells, which may be partly bone marrow derived. Circulating vascular progenitor cells are potential targets for therapeutic intervention to ameliorate TA development. Therefore, identification of mediators and cellular mechanisms that promote recruitment of vascular progenitors to sites of injury is warranted to dissect their detrimental and Possible beneficial effects in the development of TA. (c) 2005, Elsevier Inc