Objective-Intimal hyperplasia is considered to be a healing response and is a major cause of vessel narrowing after injury, where migration of vascular progenitor cells contributes to pathological events, including transplant arteriosclerosis. Approach and Results-In this study, we used a rat aortic-allograft model to identify the predominant cell types associated with transplant arteriosclerosis and to identify factors important in their recruitment into the graft. Transplantation of labeled adventitial tissues allowed us to identify the adventitia as a major source of cells migrating to the intima. RNA microarrays revealed a potential role for monocyte chemoattractant protein 1 (MCP-1), stromal cell-derived factor 1, regulated on activation, normal T cell expressed and secreted, and interferon-inducible protein 10 in the induced vasculopathy. MCP-1 induced migration of adventitial fibroblast cells. CCR2, the receptor for MCP-1, was coexpressed with CD90, CD44, NG2, or sca-1 on mesenchymal stem cells. In vivo experiments using MCP-1-deficient and CCR2-deficient mice confirmed an important role of MCP-1 in the formation of intimal hyperplasia in a mouse model of vascular injury. The aim of this study was to examine the contribution of MSCs in intimal hyperplasia and to identify relevant factors that affect their recruitment. We found that local inflammation in transplanted vessels exerts an effect on surrounding tissue and vessels that leads to phenotypic modulation of SMCs; however, those cells did not migrate to the intima and did not contribute to the intimal hyperplasia. Rather, as shown by transplantation of labeled cells, adventitial progenitor cells seemed to be a prominent source of host-derived cells in the lesion, and MCP-1 exhibits an important role in their recruitment and the pathological process of intimal hyperplasia. Conclusions-The Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results Transplantation of Allografts Leads to Structural Changes in Adjacent TissuesRejection of transplanted organs is associated with inflammation, and the production of factors that may activate cells in surrounding tissues. To determine how allografts influence the adjacent vessel tissues, we transplanted a fragment of rat isogenic (from F344 rats) or allogenic (from LEW rats) aortic graft into the abdominal aorta of F344 rats. Samples of aortic allografts and adjacent vessel segments were collected at 1, 2, 4, 8, and 12 weeks and analyzed separately; isograft samples were collected at 8 weeks.In 2-week-old allografts, immunohistochemical staining for α-smooth muscle actin was decreasing in the media, and α-smooth muscle actin positive cells had migrated to the neointima. Similar, but less prominent, changes were observed in adjacent vessels ( Figure 1A). At 1 to 2 weeks after transplantation, electron microscopy revealed distinct structural alterations in SMCs in the inner layer of the media and progressive de-endothelization of the allograft. Most of the SMCs were contracti...

ABSTRACT. Geographic atrophy is a common and untreatable form of advanced agerelated macular degeneration. The degeneration primarily affects the retinal pigment epithelium and photoreceptors of the retina and their restoration by cell transplantation seems attractive. Recently, a patient with geographic atrophy was the first human to receive cells derived from human embryonic stem cells. In this short review, the rationale, potential and obstacles for stem cellderived therapy in geographic atrophy are discussed.

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.

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