Hepatocyte growth factor (HGF) is a potent angiogenic factor. The efficacy and safety of intramuscular injection of a naked plasmid encoding human HGF gene (beperminogene perplasmid, Collategene) was investigated in patients with critical limb ischemia (CLI) in a multicenter, randomized, double-blind, placebo-controlled trial. The randomization ratio for plasmid to placebo was 2:1. Injection sites were selected in each patient limb based on angiographic findings. Placebo or plasmid was injected on days 0 and 28. Evaluation of efficacy was carried out after 12 weeks. The primary end point was the improvement of rest pain in patients without ulcers (Rutherford 4) or the reduction of ulcer size in patients with ulcer(s) (Rutherford 5).Secondary end points were ankle-brachial pressure index, amputation, and quality of life (QOL). Forty-four patients were treated, and we performed interim analysis of efficacy in 40 patients. The overall improvement rate of the primary end point was 70.4% (19/27) in HGF group and 30.8% (4/13) in placebo group, showing a significant difference (P ¼ 0.014). In Rutherford 5 patients, HGF achieved a significantly higher improvement rate (100% [11/11]) than placebo (40% [2/5]; P ¼ 0.018). HGF plasmid also improved QOL. There were no major safety problems. HGF gene therapy is safe and effective for CLI.
Although therapeutic effect of adoptive transfer of endothelial progenitor cells (EPC) has been well-substantiated, the actual engraftment is relatively low compared to a robust functional improvement of vasculopathy. Cellular mechanisms governing this action remain elusive. A recently discovered cell-cell communication via tunneling nanotube (TNT) formation is capable of transferring mitochondria and lysosomes between the cells – “organellar diakinesis”. Based on the previous demonstration of lysosomal dysfunction in endothelial cells exposed to AGE-modified collagen I, we inquired whether TNT mechanism may be involved in EPC-mediated repair of stressed endothelial cells. Here we demonstrate that EPC selectively and multiplicatively establish TNT communication with stressed endothelia. The guidance cues for the selectivity are provided by exofacially exposed phosphatidylserine moieties. Lysosomal transfer is associated with the preservation of lysosomal pH gradient, functionally reconstituting lysosomal pool of stressed cells and improving endothelial cell viability, reducing premature senescence and apoptosis. In vivo, adoptive transfer of EPC to streptozotocin-diabetic mice results in a TNT-dependent reduction of senescent endothelial cells and correction of endothelium-dependent vasorelaxation. Collectively, these data establish a selective multiplicative effect of TNT between EPC and stressed endothelia, reconstitution of the lysosomal pool, and improved viability and function of stressed endothelia.
The list of signals sent by an injured organ to systemic circulation, so-called danger signals, is growing to include multiple metabolites and secreted moieties, thus revealing a highly complex and integrated network of interlinked systemic proinflammatory and proregenerative messages. Emerging new data indicate that, apart from the well established local inflammatory response to AKI, danger signaling unleashes a cascade of precisely timed, interdependent, and intensity-gradated mediators responsible for development of the systemic inflammatory response. This fledgling realization of the importance of the systemic inflammatory response to the localized injury and inflammation is at the core of this brief overview. It has a potential to explain the additive effects of concomitant diseases or preexisting chronic conditions that can prime the systemic inflammatory response and exacerbate it out of proportion to the actual degree of acute kidney damage. Although therapies for ameliorating AKI per se remain limited, a potentially powerful strategy that could reap significant benefits in the future is to modulate the intensity of danger signals and consequently the systemic inflammatory response, while preserving its intrinsic proregenerative stimuli.
a b s t r a c tGlis3 is a member of the Gli-similar subfamily. GLIS3 mutations in humans lead to neonatal diabetes, hypothyroidism, and cystic kidney disease. We generated Glis3-deficient mice by gene-targeting. The Glis3 À/À mice had significant increases in the basal blood sugar level during the first few days after birth. The high levels of blood sugar are attributed to a decrease in the Insulin mRNA level in the pancreas that is caused by impaired islet development and the subsequent impairment of Insulinproducing cell formation. The pancreatic phenotypes indicate that the Glis3-deficient mice are a model for GLIS3 mutation and diabetes mellitus in humans.
GNRI at initiation of HD therapy could predict CVD mortality with incremental value of the predictability compared to serum albumin and body mass index in ESRD patients.
Circulating CD34-positive (CD34(+)) cells, a population that includes endothelial progenitor cells, are believed to contribute to vascular homeostasis. Here we determine the prognostic value of CD34(+) cell measurements in 216 chronic hemodialysis patients. A total of 43 cardiovascular events and 13 deaths occurred over an average 23 months follow-up in this cohort. A cutoff number for circulating CD34(+) cells was determined by receiver operating characteristic curve analysis to maximize the power of the CD34(+) cell count in predicting future cardiovascular events. Based on this, 93 patients were categorized as having low and 123 patients as having high numbers of CD34(+) cells, determined by flow cytometry at the time of enrollment. Both cumulative cardiovascular event-free survival and all-cause survival were significantly less in the group of patients with low numbers of CD34(+) cells. By multivariate analyses, a low level of circulating CD34(+) cells was an independent and significant predictor for both cardiovascular events and all-cause mortality. Our study shows that a reduced number of circulating CD34(+) cells is significantly associated with vascular risks and all-cause mortality in patients on chronic hemodialysis. These cells may be a useful biomarker.
Ratliff BB, Ghaly T, Brudnicki P, Yasuda K, Rajdev M, Bank M, Mares J, Hatzopoulos AK, Goligorsky MS. Endothelial progenitors encapsulated in bioartificial niches are insulated from systemic cytotoxicity and are angiogenesis competent.
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