BACKGROUND

Several lines of evidence have reported that serum angiotensin-converting enzyme (CD143) levels are genetically regulated by insertion/deletion (ins/del) polymorphism in intron 16 of the CD143 gene. In addition, published data on the association of ins/del polymorphism and sepsis risk yielded contradictory conclusions. Therefore, we determined to perform a meta-analysis to validate the association of much debate. Methods and major findings: Relevant literature was identified through weekly searches in databases and references of systematic reviews and the single studies incorporated in this meta-analysis. We combined ORs and its 95% CIs for several genetic models to evaluate the risk of sepsis associated with ins/del polymorphism. A total of seven studies were considered eligible for this analysis. We found significantly increased risk of sepsis in relation to the homozygote ins/ins (OR: 1.32, 95% CI: 1.04-1.68, P: 0.4201, for ins/ins vs. del/del), heterozygote del/ins (OR: 1.33, 95% CI: 1.11-1.61, P: 0.7937, for del/ins vs. del/del) and the two genotypes combined (OR: 1.33, 95% CI: 1.11-1.59, P: 0.7018, for ins/ins + del/ins vs. del/del). Subgroup analysis by age group showed a significant association in pediatric sepsis, but not in adult sepsis.

CONCLUSIONS

The statistical data suggest that the CD143 gene ins/del polymorphism may influence the risk of sepsis, especially pediatric sepsis.

Increased CD143 activity has been detected in various skin tissues, and this increase is partially caused by the intronic ID polymorphism. The genetic contribution of CD143 ID polymorphism to the progression of psoriasis, the commonest skin disease, has been extensively investigated, but reported with inconsistent results. The aim of this work was to gain new insights to shed light on the association between CD143 ID polymorphism and psoriasis risk. We systematically identified the studies examining the association of CD143 ID polymorphism with psoriasis risk. A meta-analysis combining data from all eligible studies was carried out. To evaluate the genetic association, we calculated odds ratio (OR) and its 95 % confidence intervals (CIs) for both genotypic models and allelic model. The final pooling dataset comprised ten studies. Meta-analysis of total samples did not suggest a notable association with psoriasis risk. However, subgroup analysis by ethnicity revealed a statistically significant association in East Asian samples (DD + ID vs. II: OR 0.86, 95 % CI 0.75-0.99, P heterogeneity = 0.970; DD vs. ID: OR 0.85, 95 % CI 0.73-0.99, P heterogeneity = 0.868; D vs. I: OR 0.86, 95 % CI 0.76-0.97, P heterogeneity = 0.994). This meta-analysis demonstrated that the presence of CD143 ID polymorphism may modify the risk of psoriasis in individuals with East Asian ancestry.

Despite advances to engineer transplantable hematopoietic stem and progenitor cells (HSPCs) for research and therapy, an in depth characterization of the developing human hematopoietic system is still lacking. The human embryonic liver is at the crossroad of several hematopoietic sites and harbors a complex hematopoietic hierarchy including the first, actively dividing HSPCs that will further seed the definitive hematopoietic organs. However few are known about the phenotypic and functional HSPC organization operating at these stages of development. Here, by using a combination of four endothelial and hematopoietic surface markers i.e. the endothelial-specific marker VE-cadherin, the pan-leukocyte antigen CD45, the hemato-endothelial marker CD34 and the Angiotensin-Converting Enzyme (ACE, CD143), we identified distinct HSCP subsets, among them, a population co-expressing the four markers that uniquely harbored an outstanding proliferation potential both ex vivo and in vivo. Moreover, we traced back this population to the yolk sac and AGM sites of hematopoietic emergence. Taken together, our data will help to identify human HSPC self-renewal and amplification mechanisms for future cell therapies.

Periapical granulation tissue consists of vasculature of varying sizes and types, infiltrating cells, and other stromal elements. We examined the differential expression of endothelial and stroma antigens in this tissue to determine their tissue distribution in order to obtain hints on their functions. Some of the antigens examined were present only in the endothelial lining of vasculature, including high endothelial venules (e.g. CD31 and CD105), whereas others were more widely expressed by both vascular and stromal elements (e.g. CD29, CD63, CD44, and CD151). Immunohistochemical analysis using monoclonal antibodies specific to certain tissue compartments revealed the tissue architecture more precisely and the expression of certain antigens in the tissue suggested special roles for these antigens. Tissue distribution of CD63, CD143, CD147, and CD151 in periapical granulation tissue is first reported in the present study.

Some male seasonal breeders undergo testicular growth and regression throughout the year. The objective of this study was to understand the effect of seasonality on: (i) microvasculature of cat testes; (ii) angiogenic activity in testicular tissue in vitro; and (iii) testicular endothelial cells expression throughout the year. Testicular vascular areas increased in March and April, June and July, being the highest in November and December. Testes tissue differently stimulated in vitro angiogenic activity, according to seasonality, being more evident in February, and November and December. Even though CD143 expression was higher in December, smaller peaks were present in April and July. As changes in angiogenesis may play a role on testes vascular growth and regression during the breeding and non-breeding seasons, data suggest that testicular vascularisation in cats is increased in three photoperiod windows of time, November/December, March/April and June/July. This increase in testicular vascularisation might be related to higher seasonal sexual activity in cats, which is in agreement with the fact that most queens give birth at the beginning of the year, between May and July, and in September.

Angiotensin I-converting enzyme (ACE, CD143) plays a crucial role in blood pressure regulation, vascular remodeling, and immunity. A wide spectrum of mAbs to different epitopes on the N and C domains of human ACE have been generated and used to study different aspects of ACE biology, including establishing a novel approach - conformational fingerprinting. Here we characterized a novel set of 14 mAbs, developed against human seminal fluid ACE. The epitopes for these novel mAbs were defined using recombinant ACE constructs with truncated N and C domains, species cross-reactivity, ACE mutagenesis, and competition with the previously mapped anti-ACE mAbs. Nine mAbs recognized regions on the N domain, and 5 mAbs - on the C domain of ACE. The epitopes for most of these novel mAbs partially overlap with epitopes mapped onto ACE by the previously generated mAbs, whereas mAb 8H1 recognized yet unmapped region on the C domain where three ACE mutations associated with Alzheimer's disease are localized and is a marker for ACE mutation T877M. mAb 2H4 could be considered as a specific marker for ACE in dendritic cells. This novel set of mAbs can identify even subtle changes in human ACE conformation caused by tissue-specific glycosylation of ACE or mutations, and can detect human somatic and testicular ACE in biological fluids and tissues. Furthermore, the high reactivity of these novel mAbs provides an opportunity to study changes in the pattern of ACE expression or glycosylation in different tissues, cells, and diseases, such as sarcoidosis and Alzheimer's disease. This article is protected by copyright. All rights reserved.

Keywords: ACE mutations; Alzheimer's disease; CD143; angiotensin I-converting enzyme; conformational fingerprinting; dendritic cells; glycosylation; prostate; sarcoidosis.

OBJECTIVE

To determine surface and intracellular expression of ACE antigen and Bip shaperon on leukemic dendritic cells (LDC); to study expression of ACE genes and Bip, Calnexin, calreticulin shaperons in LDC at diagnosis of acute myeloid leukemia (AML) under standard and stress cultivation.

METHODS

Expression of ACE antigens and Bip was studied with immunophenotyping and flow cytometry using monoclonal antibodies to shaperon Bip and to CD143), expression of genes of ACE and shaperons Bip, Calnexin, Calreticulin--with polymerase chain reaction (RT-PCR). Dendritic cells (DC) were obtained by culturing of a monoclonal fraction of donor peripheral blood and AML patients in the presence of 180 ng/ml calcium ionophor A23187 (Sigma) for 4 days in parallel at 37 degrees C and 33 degrees C in the atmosphere of 5% CO2. The trial included 9 patients (5 males and 4 females) aged 39-53 years (median 43 years). The control group consisted of 8 healthy donors.

RESULTS

Lowering of cultivation temperature did not increase ACE expression. Intracellular shaperon Bip rose insignificantly (1.3-fold) in DC of the controls. ACE and Bip shaperon expression on LDC membrane increased 15- and 11-fold, respectively, while the level of intracellular ACE and Bip decreased 11- and 2-fold, respectively. Expression of the genes was investigated in cultivation temperature lowering from 37 to 33 degrees C and was presented as a logarithmic scale. Changes in expression of the genes Bip, Calnexin, Calreticulin in LDc and DC of the controls were insignificant. ACE expression in LDC significantly differed from ACE gene expression in DC (p = 0.05).

CONCLUSIONS

LCD and DC of healthy donors are cells which differ by genetic and functional characteristics. Therefore, LDC may response inadequately in development of antitumor immune response. The phenomenon of ACE antigen expression normalization on cell membrane in stress open new opportunities for regulating functional activity of LDC.

The study aims to investigate the genetic association between rs4340 polymorphism at intron 16 of the angiotensin-converting enzyme (CD143) gene and pneumonia predisposition. Electronic database of PubMed, Embase, and CNKI (China National Knowledge Infrastructure) was searched for the studies addressing the association between CD143 rs4340 genotypes and pneumonia risk. The odds ratio (OR) with its 95 % confidence interval (CI) was employed to estimate the association. In total, ten case-control studies, including 1239 pneumonia cases and 2400 healthy controls, met the inclusion criteria. Our results showed a significant association between rs4340 SNP and pneumonia risk using the recessive model (OR 1.43, 95 % CI 1.20-1.70). A significantly increased risk was also indicated under the recessive model in Asian populations (OR 1.63, 95 % CI 1.16-2.30), Caucasian populations (OR 1.34, 95 % CI 1.09-1.65), community-acquired pneumonia (OR 1.42, 95 % CI 1.16-1.75) rather than nosocomial pneumonia (OR 1.47, 95 % CI 0.97-2.23). However, further studies with gene-gene and gene-environmental interactions should be considered to confirm this association.

In surgical pathology, focal nodular hyperplasia (FNH) is sometimes difficult to diagnose, and liver cirrhosis (LC) and hepatocellular adenoma (HA) are often among the differential diagnoses. Recently, we found a reduced expression of angiotensin I-converting enzyme (CD143) in FNH compared with cirrhotic and noncirrhotic liver. Intrigued by this observation, we investigated the expression pattern of CD143 in FNH, LC, and HA and its possible diagnostic value. The expression of CD143 was studied by immunohistochemistry in 20 FNHs, 13 corresponding extralesional noncirrhotic liver parenchyma, 20 patients with LC, and four HAs. Endothelial cells were identified with antibodies directed against CD31 and CD34. CD31+, CD34+, and CD143+ sinusoidal endothelial cells were found in extralesional liver, LC, HA, and FNH. However, the number of CD143+ sinusoidal endothelial cells and the intensity of immunostaining were significantly reduced in FNH compared with extralesional liver, LC, and HA. The expression of CD143 was further assessed using a numerical scoring system ranging from 0 to 6. The mean immunoreactivity score for CD143 was 2.4 +/- 1.7 for sinusoidal endothelial cells in FNH, 5.7 +/- 0.6 in extralesional liver, 4.8 +/- 1.1 in LC, and 5.8 +/- 0.5 in HA. The differences between the mean immunoreactivity scores for CD143 were highly significant. The difference between FNH and extralesional liver was confirmed on transcriptional level by fluorescence-mediated real-time RT-PCR, which also showed a significantly decreased level of CD143 mRNA in FNH. Our study provides evidence that CD143 is down-regulated in FNHs and that the phenotype of endothelial cells lining the sinusoids in FNH differs from those in non-neoplastic liver, LC, and HA. The observed variations in expression patterns for CD143 might be of diagnostic use in surgical pathology.

CD143 (angiotensin I-converting enzyme) occurs in two isoforms: a testicular form (tCD143) expressed during spermatogenesis, and a somatic form (sCD143) generally found in certain other cell types. To study these isoforms in normal and neoplastic germ cells of humans, we analyzed a broad collective of different testicular germ cell tumors (GCTs) of adults, adjacent intratubular germ cell neoplasms (IGCNs), and testicular tissues representing the regular germ cell development. Different techniques were employed on fresh frozen and formalin-fixed, paraffin-embedded tissues: CD143-mRNAs were analyzed by RT-PCR on selected cells after UV-laser-assisted cell picking and by in-situ hybridization using cRNA probes; the proteins were analyzed by semi-quantitative immunohistochemistry using monoclonal antibodies to CD143, and to PLAP/GCAP as controls. In contrast to normal germ cells bearing only tCD143 during spermiogenesis, both mRNA and protein of sCD143 were detected in neoplastic cells of all IGCNs and in the majority of seminomas. sCD143 expression also was found during testicular development, but was differently regulated in fetal germ cells and in GCTs compared with PLAP/GCAP. Thus, our findings (i) demonstrate profound changes in the expression of both CD143 isoforms during regular germ cell development and maturation, (ii) suspect sCD143 being involved in the regulation of germinal stem cell proliferation, (iii) are in agreement with the concept of an 'embryonic state' of neoplastic germ cells, (iv) indicate a close molecular relationship between IGCN and seminoma and, finally, (v) suggest sCD143 as an appropriate marker in the diagnosis of seminomas in addition to PIAP/GCAP.

Fluorescent-activated cell sorting (FACS) remains a powerful tool to enrich for blood-derived progenitor cells for the establishment of highly-proliferative endothelial colony forming cells (ECFC). Further investigation remains necessary to determine whether the retention of progenitor cell phenotypes after expansion can identify ECFC with enhanced proangiogenic and regenerative functions. This study employed FACS purification to segregate umbilical cord blood derived (UCB) ECFC using conserved pro-vascular progenitor cell markers CD34 or aldehyde dehydrogenase (ALDH) activity. ECFC FACS-purified for high versus low ALDH-activity formed single cell-derived colonies and demonstrated tubule formation in Matrigel at comparable rates. Surprisingly, FACS purification of ECFC for CD34 enriched for cells with enhanced colony forming capabilities and tubule formation within the CD34- population. CD34 expression was enriched on early ECFC populations, however steady-state expression of CD34 rapidly declined and stabilized on expanded ECFC after serial passage. CD34 expression on ECFC was shown to be cell density dependent and coincided with a loss of progenitor cell characteristics in vitro. Silica-bead surface membrane capture followed by proteomic analysis by label-free LC-MS/MS identified >100 distinctions (p<0.05) associated with the plasma membrane of CD34- vs CD34+ ECFC, including a significant enrichment of CD143 (angiotensinogen converting enzyme; ACE) on CD34+ cells. Despite an enrichment for traditional endothelial cell markers on the CD34+ ECFC in vitro, implantation of both CD34+ and CD34- ECFC within Matrigel plugs in immunodeficient NOD.SCID mice promoted the formation vessel-like structures with equivalent integration of human cells at 7-days post transplantation. Although positive selection of CD34 enriched for ECFC establishment prior to culture, FACS-purified CD34+ ECFC demonstrated reduced colony and tubule formation in vitro yet demonstrated equivalent vessel formative function in vivo compared to CD34- counterparts. The knowledge will support future studies aiming to identify ECFC subsets with enhanced vessel forming functions for applications of regenerative medicine.

Human embryonic stem cells (hESCs) offer the opportunity to create a novel source of blood cells for transfusion, transplantation and cancer immunotherapy. Identification of sequential progenitors leading to blood development, as well as a detailed understanding of the molecular mechanisms of hematopoietic lineage specification and diversification from hESCs, will be critical to advance technologies for large-scale production of blood cells and in vitro generation of hematopoietic stem cells. Multiple lines of evidence suggest that hematopoiesis, both in vivo during embryogenesis and in vitro from hESCs, is initiated from hemangioblasts; cells with the potential to generate both hematopoietic and endothelial cells. However, the phenotypic and functional properties of hemangioblasts remain largely unknown. The paper from Zambidis et al. is the first demonstration that hemangioblasts generated from hESCs express angiotensin-converting enzyme (CD143). More importantly, the current study demonstrates that the renin-angiotensin system plays a critical role in the hemangioblast fate decision to produce either blood or endothelial cells. These findings could be exploited for developing novel cellular and drug therapies for hematological and vascular diseases.

Introduction: Statins are cholesterol-lowering drugs that also have anti-inflammatory/ immunomodulatory properties, and have been suggested as an adjunct therapy for COVID-19.

Methods: To investigate the clinical impact of statins as a potential therapeutic approach in the treatment of cases infected with COVID-19, a systematic search was performed using PubMed and Google Scholar databases. To extend the search results, a set of keywords were used as follows: ("corona virus" OR "Covid-19" OR "SARS-Cov-2" OR "Severe Acute Respiratory Syndrome Coronavirus 2" OR coronavirus) AND (Statins), alongside a manual search in Google Scholar search engine.

Results: It has also been suggested that statins could influence the entry of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) into cells by altering the expression of the angiotensin-converting enzyme 2 (ACE2) and CD143 receptors. Statins may be beneficial for COVID-19 patients according to its pleiotropic effects, although, from the clinical aspect, these pleiotropic effects of statins may not be as strong as in preclinical phase on COVID-19. A retrospective study showed favorable effects for statins in SARS-CoV-2 infection.

Conclusion: Patients with SARS-CoV-2 infection have a high risk of cardiovascular and thrombotic complications and pleiotropic effects of statins may help manage the COVID-19. There is growing evidence that supports the need for trials of statin treatment in COVID-19 infection.

Keywords: Anti-inflammatory activity; COVID-19; SARS-CoV-2; Statins.