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Galletti M.,University of Bologna | Cantoni S.,University of Bologna | Zambelli F.,University of Bologna | Zambelli F.,Reproductive Medicine Unit | And 8 more authors.
Biochemical Pharmacology

Pulmonary Arterial Hypertension (PAH) is a rare and devasting condition characterized by elevated pulmonary vascular resistance and pulmonary artery pressure leading to right-heart failure and premature death. Pathologic alterations in proliferation, migration and survival of all cell types composing the vascular tissue play a key role in the occlusion of the vascular lumen. In the current study, we initially investigated the action of selective class I and class II HDAC inhibitors on the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) after exposure to Platelet Derived Growth Factor (PDGF). Class I HDAC inhibitors were able to counteract the hyperproliferative response to PDGF, reducing both proliferation and migration in PASMCs, while class II were ineffective. Selective silencing with siRNAs targeted against different HDACs revealed a major role of class I, and within this class, of HDAC1 in mediating PDGF-induced Akt Phosphorylation and Cyclin D1 (CycD1) expression. These results from these combinatorial approaches were further confirmed by the ability of a specific HDAC1 inhibitor to antagonize the PDGF action. The finding that HDAC1 is a major conductor of PDGF-induced patterning in PAH-PASMCs prompts the development of novel selective inhibitors of this member of class I HDACs as a potential tool to control lung vascular homeostasis in PAH. © 2014 The Authors. Source

Zaniboni A.,University of Bologna | Bernardini C.,University of Bologna | Bertocchi M.,University of Bologna | Zannoni A.,University of Bologna | And 8 more authors.
American Journal of Physiology - Cell Physiology

Recent findings suggest that progenitor and multipotent mesenchymal stromal cells (MSCs) are associated with vascular niches. Cells displaying mesenchymal properties and differentiating to whole components of a functional blood vessel, including endothelial and smooth muscle cells, can be defined as vascular stem cells (VSCs). Recently, we isolated a population of porcine aortic vascular precursor cells (pAVPCs), which have MSCand pericyte-like properties. The aim of the present work was to investigate whether pAVPCs possess VSC-like properties and assess their differentiation potential toward endothelial and smooth muscle lineages. pAVPCs, maintained in a specific pericyte growth medium, were cultured in high-glucose DMEM + 10% FBS (long-term medium, LTM) or in human endothelial serum-free medium + 5% FBS and 50 ng/ml of hVEGF (endothelial differentiation medium, EDM). After 21 days of culture in LTM, pAVPCs showed an elongated fibroblast-like morphology, and they seem to organize in cord-like structures. qPCR analysis of smooth muscle markers [α-smooth muscle actin (α-SMA), calponin, and smooth muscle myosin (SMM) heavy chain] showed a significant increment of the transcripts, and immunofluorescence analysis confirmed the presence of α-SMA and SMM proteins. After 21 days of culture in EDM, pAVPCs displayed an endothelial cell-like morphology and revealed the upregulation of the expression of endothelial markers (CD31, vascular endothelialcadherin, von Willebrand factor, and endothelial nitric oxide synthase) showing the CD31-typical pattern. In conclusion, pAVPCs could be defined as a VSC-like population considering that, if they are maintained in a specific pericyte medium, they express MSC markers, and they have, in addition to the classical mesenchymal trilineage differentiation potential, the capacity to differentiate in vitro toward the smooth muscle and the endothelial cell phenotypes. © 2015 the American Physiological Society. Source

Biava P.M.,Scientific Institute of Research and Care Multimedica | Canaider S.,University of Bologna | Canaider S.,Italian National Institute of Biosystems and Biostructures | Facchin F.,University of Bologna | And 9 more authors.
Current Pharmaceutical Biotechnology

In spite of the growing body of evidence on the biology of the Zebrafish embryo and stem cells, including the use of Stem Cell Differentiation Stage Factors (SCDSFs) taken from Zebrafish embryo to impact cancer cell dynamics, comparatively little is known about the possibility to use these factors to modulate the homeostasis of normal human stem cells or to modulate the behavior of cells involved in different pathological conditions. In the present review we recall in a synthetic way the most important researches about the use of SCDSFs in reprogramming cancer cells and in modulating the high speed of multiplication of keratinocytes which is characteristic of some pathological diseases like psoriasis. Moreover we add here the results about the capability of SCDSFs in modulating the homeostasis of human adiposederived stem cells (hASCs) isolated from a fat tissue obtained with a novel-non enzymatic method and device. In addition we report the data not yet published about a first protein analysis of the SCDSFs and about their role in a pathological condition like neurodegeneration. © 2015 Bentham Science Publishers. Source

Rinaldi S.,Rinaldi Fontani Institute | Maioli M.,University of Sassari | Maioli M.,Stem Wave Institute for Tissue Healing SWITH | Maioli M.,University of Bologna | And 9 more authors.
Scientific Reports

Decline in the gene expression of senescence repressor Bmi1, and telomerase, together with telomere shortening, underlay senescence of stem cells cultured for multiple passages. Here, we investigated whether the impairment of senescence preventing mechanisms can be efficiently counteracted by exposure of human adipose-derived stem cells to radio electric asymmetrically conveyed fields by an innovative technology, named Radio Electric Asymmetric Conveyer (REAC). Due to REAC exposure, the number of stem cells positively stained for senescence associated b-galactosidase was significantly reduced along multiple culturing passages. After a 90-day culture, REAC-treated cells exhibited significantly higher transcription of Bmi1 and enhanced expression of other stem cell pluripotency genes and related proteins, compared to unexposed cells. Transcription of the catalytic telomerase subunit (TERT) was also increased in REAC-treated cells at all passages. Moreover, while telomere shortening occurred at early passages in both REAC-treated and untreated cells, a significant rescue of telomere length could be observed at late passages only in REAC-exposed cells. Thus, REAC-asymmetrically conveyed radio electric fields acted on a gene and protein expression program of both telomerase-independent and telomerase-dependent patterning to optimize stem cell ability to cope with senescence progression. Source

Maioli M.,University of Sassari | Maioli M.,Italian National Institute of Biosystems and Biostructures | Maioli M.,Rinaldi Fontani Institute | Rinaldi S.,Rinaldi Fontani Institute | And 15 more authors.
Cell Transplantation

Human adipose-derived stem cells (hASCs) have been recently proposed as a suitable tool for regenerative therapies for their simple isolation procedure and high proliferative capability in culture. Although hASCs can be committed into different lineages in vitro, the differentiation is a low-yield and often incomplete process. We have recently developed a novel nonenzymatic method and device, named Lipogems, to obtain a fat tissue derivative highly enriched in pericytes/mesenchymal stem cells by mild mechanical forces from human lipoaspirates. When compared to enzymatically dissociated cells, Lipogems-derived hASCs exhibited enhanced transcription of vasculogenic genes in response to provasculogenic molecules, suggesting that these cells may be amenable for further optimization of their multipotency. Here we exposed Lipogems-derived hASCs to a radioelectric asymmetric conveyer (REAC), an innovative device asymmetrically conveying radioelectric fields, affording both enhanced differentiating profiles in mouse embryonic stem cells and efficient direct multilineage reprogramming in human skin fibroblasts. We show that specific REAC exposure remarkably enhanced the transcription of prodynorphin, GATA-4, Nkx-2.5, VEGF, HGF, vWF, neurogenin-1, and myoD, indicating the commitment toward cardiac, vascular, neuronal, and skeletal muscle lineages, as inferred by the overexpression of a program of targeted marker proteins. REAC exposure also finely tuned the expression of stemness-related genes, including NANOG, SOX-2, and OCT-4. Noteworthy, the REAC-induced responses were fashioned at a significantly higher extent in Lipogems-derived than in enzymatically dissociated hASCs. Therefore, REAC-mediated interplay between radioelectric asymmetrically conveyed fields and Lipogemsderived hASCs appears to involve the generation of an ideal “milieu” to optimize multipotency expression from human adult stem cells in view of potential improvement of future cell therapy efforts. © 2014 Cognizant Comm. Corp. Source

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