Diabetic retinopathy is a leading cause of adult vision loss and blindness. Much of the retinal damage that characterizes the disease results from retinal vascular leakage and nonperfusion. This study shows that diabetic retinal vascular leakage and nonperfusion are temporally and spatially associated with retinal leukocyte stasis (leukostasis) in the rat model of streptozotocin-induced diabetes. Retinal leukostasis increases within days of developing diabetes and correlates with the increased expression of retinal intercellular adhesion molecule-1 (ICAM-1). ICAM-1 blockade with a mAb prevents diabetic retinal leukostasis and vascular leakage by 48.5% and 85.6%, respectively. These data identify the causal role of leukocytes in the pathogenesis of diabetic retinopathy and establish the potential utility of ICAM-1 inhibition as a therapeutic strategy for the prevention of diabetic retinopathy.

Heart disease remains a leading cause of death worldwide. Owing to the limited regenerative capacity of heart tissue, cardiac regenerative therapy has emerged as an attractive approach. Direct reprogramming of human cardiac fibroblasts (HCFs) into cardiomyocytes may hold great potential for this purpose. We reported previously that induced cardiomyocyte-like cells (iCMs) can be directly generated from mouse cardiac fibroblasts in vitro and vivo by transduction of three transcription factors: Gata4, Mef2c, and Tbx5, collectively termed GMT. In the present study, we sought to determine whether human fibroblasts also could be converted to iCMs by defined factors. Our initial finding that GMT was not sufficient for cardiac induction in HCFs prompted us to screen for additional factors to promote cardiac reprogramming by analyzing multiple cardiac-specific gene induction with quantitative RT-PCR. The addition of Mesp1 and Myocd to GMT up-regulated a broader spectrum of cardiac genes in HCFs more efficiently compared with GMT alone. The HCFs and human dermal fibroblasts transduced with GMT, Mesp1, and Myocd (GMTMM) changed the cell morphology from a spindle shape to a rod-like or polygonal shape, expressed multiple cardiac-specific proteins, increased a broad range of cardiac genes and concomitantly suppressed fibroblast genes, and exhibited spontaneous Ca 2+ oscillations. Moreover, the cells matured to exhibit action potentials and contract synchronously in coculture with murine cardiomyocytes. A 5-ethynyl-2′-deoxyuridine assay revealed that the iCMs thus generated do not pass through a mitotic cell state. These findings demonstrate that human fibroblasts can be directly converted to iCMs by defined factors, which may facilitate future applications in regenerative medicine.cell fate conversion | regeneration | cardiogenesis C ardiovascular disease remains a leading cause of death worldwide, for which current therapeutic regimens remain limited. Given that adult human hearts have little regenerative capacity after injury, the demand is high for cardiac regenerative therapy. The recent discovery of induced pluripotent stem cells (iPSCs) allows the direct generation of specific cell types from differentiated somatic cells by overexpression of lineagespecific factors.Several previous studies have demonstrated that such direct lineage reprogramming can yield a diverse range of cell types, including pancreatic β cells, neurons, neural progenitors, blood progenitors, and hepatocyte-like cells (1-5). We previously reported that a minimum mixture of three cardiac-specific transcription factors-Gata4, Mef2c, and Tbx5 (GMT)-directly induced cardiomyocyte-like cells (iCMs) from mouse fibroblasts in vitro (6). Following our report, three other groups also reported generation of functional cardiomyocytes from mouse fibroblasts with various combinations of transcription factors, either with GMT plus Hand2 (GHMT) or Mef2c, Myocd, and Tbx5 or using microRNAs (7-9). Although full reprogramming into beating cardiomyocytes was not effic...