Editorial: Tissue Repair and Regenerative Mechanisms by Stem/Progenitor Cells and Their Secretome

Tissue Repair and Regenerative Mechanisms by Stem/Progenitor Cells and Their Secretome Regenerative medicine is a branch of translational research which is energizing and empowering clinical practice. A multitude of novel approaches proposed during the recent years is slowly but dramatically transforming the health care system, harnessing the power of repairing, replacing, restoring, and regenerating human organs and tissues affected by various degenerative disorders and diseases. During the twentieth century, hundreds of thousands of patients with end-stage diseases have been rescued by solid organ transplants as ultimate treatment option. In the past 3 decades, cell-based therapies have been gaining importance since they can contribute to regeneration of failing organs or damaged tissues by direct replacement of the lost cells or by facilitating the body’s natural regenerative processes by removing roadblocks. A growing armamentarium of therapeutic options, spanning from bioartificial organs and tissues, stem and progenitor cells, biomaterials, cell secretome, and extracellular vesicles have become available as medical treatments substituting the standard pharmaceutics. Examples of “classical” cellular therapies are peripheral blood stem cell or stromal cell transplantations, and more recently, allogenic hepatocyte or pancreatic islet transplants. While pancreas transplantation remains the gold standard in diabetes patients where the insulin injection fails to control symptoms, transplantation of islets of Langerhans has been recognized as a successful cell-based treatment in type 1 diabetes. The mechano-enzymatic separation of endocrine tissue from the exocrine pancreatic parenchyma required several decades to become a standardized clinical approach approved by Medical Product Agencies worldwide

SP051EXOSOMAL SHUTTLE RNA IN URINARY EXTRACELLULAR VESICLES AS BIOMARKER OF CLEAR CELL RENAL CELL CARCINOMA

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Identification and monitoring of Copy Number Variants (CNV) in monoclonal gammopathy

Monoclonal gammopathy of undetermined significance (MGUS) represents the pre-clinical stage of Multiple Myeloma (MM) with the 5% of MGUS progresses to MM. Although the progression from MGUS to MM has not been completely characterized, it is possible to monitor the DNA modifications of patients diagnosed with MGUS to detect early specific genomic abnormalities, including copy number variations (CNV). The CNVs of chromosome 1q and chromosome 13q are associated with a worse prognosis in MM.In the present study, we showed that it is possible to monitor the 1q21 gain and 13q deletion frequencies in gDNA using digital PCR. The CNV analysis of three cell lines with a well-characterized cytogenetic profile were compared with measures performed by a real-time PCR approach and with a digital PCR approach. Then, we analyzed CNVs in CD138+ plasma cells isolated from bone marrow of MGUS and MM patients.Our results show that digital PCR and targeted DNA monitoring represent a specific and accurate technique for the early detection of specific genomic abnormalities both in MM and in MGUS patients.Our results could represent a remarkable advancement in MM and MGUS diagnosis and in CNV analysis for the evaluation of the risk of progression from MGUS to MM

AQP5 is expressed in type-B intercalated cells in the collecting duct system of the rat, mouse and human kidney.

We screened human kidney-derived multipotent CD133+/CD24+ ARPCs for the possible expression of all 13 aquaporin isoforms cloned in humans. Interestingly, we found that ARPCs expressed both AQP5 mRNA and mature protein. This novel finding prompted us to investigate the presence of AQP5 in situ in kidney. We report here the novel finding that AQP5 is expressed in human, rat and mouse kidney at the apical membrane of type-B intercalated cells. AQP5 is expressed in the renal cortex and completely absent from the medulla. Immunocytochemical analysis using segment- and cell type-specific markers unambiguously indicated that AQP5 is expressed throughout the collecting system at the apical membrane of type-B intercalated cells, where it co-localizes with pendrin. No basolateral AQPs were detected in type-B intercalated cells, suggesting that AQP5 is unlikely to be involved in the net trans-epithelial water reabsorption occurring in the distal tubule. An intriguing hypothesis is that AQP5 may serve an osmosensor for the composition of the fluid coming from the thick ascending limb. Future studies will unravel the physiological role of AQP5 in the kidney

In vitro identification of new transcriptomic and miRNomic profiles associated with pulmonary fibrosis induced by high doses everolimus: Looking for new pathogenetic markers and therapeutic targets

The administration of Everolimus (EVE), a mTOR inhibitor used in transplantation and cancer, is often associated with adverse effects including pulmonary fibrosis. Although the underlying mechanism is not fully clarified, this condition could be in part caused by epithelial to mesenchymal transition (EMT) of airway cells. To improve our knowledge, primary bronchial epithelial cells (BE63/3) were treated with EVE (5 and 100 nM) for 24 h. EMT markers (α-SMA, vimentin, fibronectin) were measured by RT-PCR. Transepithelial resistance was measured by Millicell-ERS ohmmeter. mRNA and microRNA profiling were performed by Illumina and Agilent kit, respectively. Only high dose EVE increased EMT markers and reduced the transepithelial resistance of BE63/3. Bioinformatics showed 125 de-regulated genes that, according to enrichment analysis, were implicated in collagen synthesis/metabolism. Connective tissue growth factor (CTGF) was one of the higher up-regulated mRNA. Five nM EVE was ineffective on the pro-fibrotic machinery. Additionally, 3 miRNAs resulted hyper-expressed after 100 nM EVE and able to regulate 31 of the genes selected by the transcriptomic analysis (including CTGF). RT-PCR and western blot for MMP12 and CTGF validated high-throughput results. Our results revealed a complex biological network implicated in EVE-related pulmonary fibrosis and underlined new potential disease biomarkers and therapeutic targets

Complement Activation During lschemia/Reperfusion Injury Induces Pericyte-to-Myofibroblast Transdifferentiation Regulating Peritubular Capillary Lumen Reduction Through pERK Signaling

Nephrolog

A transcriptomic study of Hereditary Angioedema attacks

Background: Hereditary angioedema (HAE) caused by C1-inhibitor deficiency is a lifelong illness characterized by recurrent acute attacks of localized skin or mucosal edema. Activation of the kallikrein/bradykinin pathway at the endothelial cell level has a relevant pathogenetic role in acute HAE attacks. Moreover, other pathways are involved given the variable clinical expression of the disease in different patients. Objective: We sought to explore the involvement of other putative genes in edema formation. Methods: We performed a PBMC microarray gene expression analysis on RNA isolated from patients with HAE during an acute attack and compared them with the transcriptomic profile of the same patients in the remission phase. Results: Gene expression analysis identified 23 genes significantly modulated during acute attacks that are involved primarily in the natural killer cell signaling and leukocyte extravasation signaling pathways. Gene set enrichment analysis showed a significant activation of relevant biological processes, such as response to external stimuli and protein processing (q < 0.05), suggesting involvement of PBMCs during acute HAE attacks. Upregulation of 2 genes, those encoding adrenomedullin and cellular receptor for urokinase plasminogen activator (uPAR), which occurs during an acute attack, was confirmed in PBMCs of 20 additional patients with HAE by using real-time PCR. Finally, in vitro studies demonstrated the involvement of uPAR in the generation of bradykinin and endothelial leakage. Conclusions: Our study demonstrates the increase in levels of adrenomedullin and uPAR in PBMCs during an acute HAE attack. Activation of these genes usually involved in regulation of vascular tone and in inflammatory response might have a pathogenic role by amplifying bradykinin production and edema formation in patients with HAE

High levels of gut-homing immunoglobulin A+ B lymphocytes support the pathogenic role of intestinal mucosal hyperresponsiveness in immunoglobulin A nephropathy patients

No abstract availabl

Renal progenitor cells revert LPS-induced endothelial-to-mesenchymal transition by secreting CXCL6, SAA4, and BPIFA2 antiseptic peptides

Endothelial dysfunction is a hallmark of LPS-induced acute kidney injury (AKI). Endothelial cells (ECs) acquired a fibroblast-like phenotype and contributed to myofibroblast generation through the endothelial-to-mesenchymal transition (EndMT) process. Of note, human adult renal stem/progenitor cells (ARPCs) enhance the tubular regenerative mechanism during AKI but little is known about their effects on ECs. Following LPS exposure, ECs proliferated, decreased EC markers CD31 and vascular endothelial cadherin, and up-regulated myofibroblast markers, collagen I, and vimentin. The coculture with ARPCs normalized the EC proliferation rate and abrogated the LPS-induced EndMT. The gene expression analysis showed that most of the genes modulated in LPS-stimulated ARPCs belong to cell activation and defense response pathways. We showed that the ARPC-specific antifibrotic effect is exerted by the secretion of CXCL6, SAA4, and BPIFA2 produced after the anaphylatoxin stimulation. Next, we investigated the molecular signaling that underlies the ARPC protective mechanism and found that renal progenitors diverge from differentiated tubular cells and ECs in myeloid differentiation primary response 88-independent pathway activation. Finally, in a swine model of LPS-induced AKI, we observed that activated ARPCs secreted CXCL6, SAA4, and BPIFA2 as a defense response. These data open new perspectives on the treatment of both sepsis- and endotoxemia-induced AKI, suggesting an underestimated role of ARPCs in preventing endothelial dysfunction and novel strategies to protect the endothelial compartment and promote kidney repair.-Sallustio, F., Stasi, A., Curci, C., Divella, C., Picerno, A., Franzin, R., De Palma, G., Rutigliano, M., Lucarelli, G., Battaglia, M., Staffieri, F., Crovace, A., Pertosa, G. B., Castellano, G., Gallone, A., Gesualdo, L. Renal progenitor cells revert LPS-induced endothelial-to-mesenchymal transition by secreting CXCL6, SAA4, and BPIFA2 antiseptic peptides

Modeling the influence of alternative forest management scenarios on wood production and carbon storage: A case study in the Mediterranean region

Forest ecosystems are fundamental for the terrestrial biosphere as they deliver multiple essential ecosystem services (ES). In environmental management, understanding ES distribution and interactions and assessing the economic value of forest ES represent future challenges. In this study, we developed a spatially explicit method based on a multi-scale approach (MiMoSe-Multiscale Mapping of ecosystem services) to assess the current and future potential of a given forest area to provide ES. To do this we modified and improved the InVEST model in order to adapt input data and simulations to the context of Mediterranean forest ecosystems. Specifically, we integrated a GIS-based model, scenario model, and economic valuation to investigate two ES (wood production and carbon sequestration) and their trade-offs in a test area located in Molise region (Central Italy). Spatial information and trade-off analyses were used to assess the influence of alternative forest management scenarios on investigated services. Scenario A was designed to describe the current Business as Usual approach. Two alternative scenarios were designed to describe management approaches oriented towards nature protection (scenario B) or wood production (scenario C) and compared to scenario A. Management scenarios were simulated at the scale of forest management units over a 20-year time period. Our results show that forest management influenced ES provision and associated benefits at the regional scale. In the test area, the Total Ecosystem Services Value of the investigated ES increases 85% in scenario B and decreases 82% in scenario C, when compared to scenario A. Our study contributes to the ongoing debate about trade-offs and synergies between carbon sequestration and wood production benefits associated with socio-ecological systems. The MiMoSe approach can be replicated in other contexts with similar characteristics, thus providing a useful basis for the projection of benefits from forest ecosystems over the futureL'articolo è disponibile sul sito dell'editore www.elsevier.com/locate/envre