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Murray I.R.,University of Edinburgh | Murray I.R.,Queens Medical Research Institute | Murray I.R.,University of California at Los Angeles | West C.C.,University of Edinburgh | And 13 more authors.
Cellular and Molecular Life Sciences | Year: 2014

Mesenchymal stem/stromal cells (MSCs) can regenerate tissues by direct differentiation or indirectly by stimulating angiogenesis, limiting inflammation, and recruiting tissue-specific progenitor cells. MSCs emerge and multiply in long-term cultures of total cells from the bone marrow or multiple other organs. Such a derivation in vitro is simple and convenient, hence popular, but has long precluded understanding of the native identity, tissue distribution, frequency, and natural role of MSCs, which have been defined and validated exclusively in terms of surface marker expression and developmental potential in culture into bone, cartilage, and fat. Such simple, widely accepted criteria uniformly typify MSCs, even though some differences in potential exist, depending on tissue sources. Combined immunohistochemistry, flow cytometry, and cell culture have allowed tracking the artifactual cultured mesenchymal stem/stromal cells back to perivascular anatomical regions. Presently, both pericytes enveloping microvessels and adventitial cells surrounding larger arteries and veins have been described as possible MSC forerunners. While such a vascular association would explain why MSCs have been isolated from virtually all tissues tested, the origin of the MSCs grown from umbilical cord blood remains unknown. In fact, most aspects of the biology of perivascular MSCs are still obscure, from the emergence of these cells in the embryo to the molecular control of their activity in adult tissues. Such dark areas have not compromised intents to use these cells in clinical settings though, in which purified perivascular cells already exhibit decisive advantages over conventional MSCs, including purity, thorough characterization and, principally, total independence from in vitro culture. A growing body of experimental data is currently paving the way to the medical usage of autologous sorted perivascular cells for indications in which MSCs have been previously contemplated or actually used, such as bone regeneration and cardiovascular tissue repair. © 2013 Springer.


Corselli M.,University of California at Los Angeles | Corselli M.,Broad Stem Cell Research Center | Chin C.J.,University of California at Los Angeles | Parekh C.,Childrens Hospital Los Angeles | And 14 more authors.
Blood | Year: 2013

Hematopoietic stem and progenitor cells (HSPCs) emerge and develop adjacent to blood vessel walls in the yolk sac, aorta-gonad-mesonephros region, embryonic liver, and fetal bone marrow. In adult mouse bone marrow, perivascular cells shape a "niche" for HSPCs. Mesenchymal stem/stromal cells (MSCs), which support hematopoiesis in culture, are themselves derived in part from perivascular cells. In order to define their direct role in hematopoiesis, we tested the ability of purified human CD146+ perivascular cells, as compared with unfractionated MSCs and CD146- cells, to sustain human HSPCs in coculture. CD146+ perivascular cells support the long-term persistence, through cell-to-cell contact and at least partly via Notch activation, of human myelolymphoid HSPCs able to engraft primary and secondary immunodeficient mice. Conversely, unfractionated MSCs and CD146- cells induce differentiation and compromise ex vivo maintenance of HSPCs. Moreover, CD146+ perivascular cells express, natively and in culture, molecular markers of the vascular hematopoietic niche. Unexpectedly, this dramatic, previously undocumented ability to support hematopoietic stem cells is present in CD146+ perivascular cells extracted from the nonhematopoietic adipose tissue. © 2013 by The American Society of Hematology.


Corselli M.,Childrens Hospital of Pittsburgh | Corselli M.,University of California at Los Angeles | Corselli M.,Erasmus Medical Center | Chen C.-W.,Childrens Hospital of Pittsburgh | And 5 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2010

Independent studies by numerous investigators have shown that it is possible to harvest multipotent progenitor cells from diverse dissociated and cultured fetal, perinatal, and principally adult developed tissues. Despite the increasingly recognized medical value of these progenitor cells, the archetype of which remains the mesenchymal stem cell, this indirect extraction method has precluded the understanding of their native identity, tissue distribution, and frequency. Consistent with other researchers, we have hypothesized that blood vessels in virtually all organs harbor ubiquitous stem cells. We have identified, marked, and sorted to homogeneity by flow cytometry endothelial and perivascular cells in a large selection of human fetal, perinatal, and adult organs. Perivascular cells, including pericytes in the smallest blood vessels and adventitial cells around larger ones, natively express mesenchymal stem cell markers and produce in culture a long-lasting progeny of multilineage mesodermal progenitor cells. Herein, we review results from our and other laboratories that suggest a perivascular origin for mesenchymal stem cells and other adult progenitor cells. Recent experiments illustrate the therapeutic potential of human pericytes to regenerate skeletal muscle and promote functional recovery in the diseased heart and kidney. © 2010 American Heart Association, Inc.


Pierro M.,Cardiovascular Research Center and Pulmonary Research Group | Pierro M.,University of Milan | Ionescu L.,Cardiovascular Research Center and Pulmonary Research Group | Montemurro T.,Cell Factory | And 10 more authors.
Thorax | Year: 2013

Background: Bronchopulmonary dysplasia (BPD) remains a main complication of extreme prematurity and currently lacks efficient treatment. Rat bone marrow-derived mesenchymal stem cells (MSC) prevent lung injury in an oxygen-induced model of BPD. Human cord is an advantageous source of stem cells that is especially appealing for the treatment of neonatal diseases. The therapeutic benefit after established lung injury and long-term safety of cord-derived stem cells is unknown. Methods: Human cord-derived perivascular cells (PCs) or cord blood-derived MSCs were delivered prophylactically or after established alveolar injury into the airways of newborn rats exposed to hyperoxia, a well-established BPD model. Results: Rat pups exposed to hyperoxia showed the characteristic arrest in alveolar growth with air space enlargement and loss of lung capillaries. PCs and MSCs partially prevented and rescued lung function and structure. Despite therapeutic benefit, cell engraftment was low, suggesting that PCs and MSCs act via a paracrine effect. Accordingly, cell free-derived conditioned media from PCs and MSCs also exerted therapeutic benefit when used either prophylactically or therapeutically. Finally, long-term (6 months) assessment of stem cell or conditioned media therapy showed no adverse lung effects of either strategy, with persistent improvement in exercise capacity and lung structure. Conclusions: Human umbilical cord-derived PCs and MSCs exert short- and long-term therapeutic benefit without adverse lung effects in this experimental model and offer new therapeutic options for lung diseases characterised by alveolar damage.


Castellani M.,Fondazione IRCCS Ca Granda | Colombo A.,L Sacco Hospital | Giordano R.,Cell Factory | Pusineri E.,Clinical Cardiology Unit | And 8 more authors.
Journal of Nuclear Medicine | Year: 2010

Over the last decade, the effects of stem cell therapy on cardiac repair after acute myocardial infarction (AMI) have been investigated with different imaging techniques. We evaluated a new imaging approach using 13N-ammonia and 18F-FDG PET for a combined analysis of cardiac perfusion, metabolism, and function in patients treated with intracoronary injection of endothelial progenitors or with conventional therapy for AMI. Methods: A total of 15 patients were randomly assigned to 3 groups based on different treatments (group A: bone marrow-derived stem cells; group B: peripheral blood-derived stem cells; group C: standard therapy alone). The number of scarred and viable segments, along with the infarct size and the extent of the viable area, were determined on a 9-segment 13N- ammonia/18F-FDG PET polar map. Myocardial blood flow (MBF) was calculated for each segment on the ammonia polar map, whereas a global evaluation of left ventricular function was obtained by estimating left ventricular ejection fraction (LVEF) and end-diastolic volume, both derived from electrocardiography-gated 18F-FDG images. Both intragroup and intergroup comparative analyses of the mean values of each parameter were performed at baseline and 3, 6, and 12 mo after AMI. During follow-up, major cardiac events were also registered. Results: A significant decrease (P < 0.05) in the number of scarred segments and infarct size was observed in group A, along with an increase in MBF (P < 0.05) and a mild improvement in cardiac function. Lack of infarct size shrinkage in group B was associated with a marked impairment of MBF (P = 0.01) and cardiac dysfunction. Ambiguous changes in infarct size, MBF, and LVEF were found in group C. No differences in number of viable segments or in extent of viable area were found among the groups. At clinical follow-up, no major cardiac events occurred in group A patients, whereas 2 patients of group B experienced in-stent occlusion and one patient of group C received a transplant for heart failure. Conclusion: Our data suggest that a single nuclear imaging technique accurately analyzes changes in myocardial perfusion and metabolism occurring after stem cell transplantation. Copyright © 2010 by the Society of Nuclear Medicine, Inc.


PubMed | Nuclear Medicine Unit, Bone Marrow Transplantation Center, University of Würzburg, University of Milan and 5 more.
Type: Journal Article | Journal: Journal of translational medicine | Year: 2016

The trophic, anti-apoptotic and regenerative effects of bone marrow mesenchymal stromal cells (MSC) may reduce neuronal cell loss in neurodegenerative disorders.We used MSC as a novel candidate therapeutic tool in a pilot phase-I study for patients affected by progressive supranuclear palsy (PSP), a rare, severe and no-option form of Parkinsonism. Five patients received the cells by infusion into the cerebral arteries. Effects were assessed using the best available motor function rating scales (UPDRS, Hoehn and Yahr, PSP rating scale), as well as neuropsychological assessments, gait analysis and brain imaging before and after cell administration.One year after cell infusion, all treated patients were alive, except one, who died 9months after the infusion for reasons not related to cell administration or to disease progression (accidental fall). In all treated patients motor function rating scales remained stable for at least six-months during the one-year follow-up.We have demonstrated for the first time that MSC administration is feasible in subjects with PSP. In these patients, in whom deterioration of motor function is invariably rapid, we recorded clinical stabilization for at least 6months. These encouraging results pave the way to the next randomized, placebo-controlled phase-II study that will definitively provide information on the efficacy of this innovative approach. Trial registration ClinicalTrials.gov NCT01824121.


PubMed | Cell Factory, University of Parma and University of Milan
Type: Journal Article | Journal: Biochemical and biophysical research communications | Year: 2016

Hydroquinone (HQ) is an important benzene-derived metabolite associated with acute myelogenous leukemia risk. Although altered DNA methylation has been reported in both benzene-exposed human subjects and HQ-exposed cultured cells, the inventory of benzene metabolite effects on the epigenome is only starting to be established. In this study, we used a monocytic leukemia cell line (THP-1) and hematopoietic stem cells (HSCs) from cord blood to investigate the effects of HQ treatment on the expression of the three most important families of retrotransposons in the human genome: LINE-1, Alu and Endogenous retroviruses (HERVs), that are normally subjected to tight epigenetic silencing. We found a clear tendency towards increased retrotransposon expression in response to HQ exposure, more pronounced in the case of LINE-1 and HERV. Such a partial loss of silencing, however, was generally not associated with HQ-induced DNA hypomethylation. On the other hand, retroelement derepression was also observed in the same cells in response to the hypomethylating agent decitabine. These observations suggest the existence of different types of epigenetic switches operating at human retroelements, and point to retroelement activation in response to benzene-derived metabolites as a novel factor deserving attention in benzene carcinogenesis studies.


PubMed | University of Genoa, Polytechnic of Milan, Renal Research Laboratory, Irccs Instituto Of Ricerche Farmacologiche Mario Negri and 2 more.
Type: | Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences | Year: 2016

Proteinuria is a common symptom of glomerular diseases and is due to leakage of proteins from the glomerular filtration barrier, a three-layer structure composed by two post-mitotic highly specialized and interdependent cell populations, i.e. glomerular endothelial cells and podocytes, and the basement membrane in between. Despite enormous progresses made in the last years, pathogenesis of proteinuria remains to be completely uncovered. Studies in the field could largely benefit from an in vitro model of the glomerular filter, but such a system has proved difficult to realize. Here we describe a method to obtain and utilize a three-dimensional podocyte-endothelial co-culture which can be largely adopted by the scientific community because it does not rely on special instruments nor on the synthesis of devoted biomaterials. The device is composed by a porous membrane coated on both sides with type IV collagen. Adhesion of podocytes on the upper side of the membrane has to be preceded by VEGF-induced maturation of endothelial cells on the lower side. The co-culture can be assembled with podocyte cell lines as well as with primary podocytes, extending the use to cells derived from transgenic mice. An albumin permeability assay has been extensively validated and applied as functional readout, enabling rapid drug testing. Additionally, the bottom of the well can be populated with a third cell type, which multiplies the possibilities of analyzing more complex glomerular intercellular signaling events. In conclusion, the ease of assembly and versatility of use are the major advantages of this three-dimensional model of the glomerular filtration barrier over existing methods. The possibility to run a functional test that reliably measures albumin permeability makes the device a valid companion in several research applications ranging from drug screening to intercellular signaling studies.


One of the most serious complications of diabetes, heart arrhythmias, is now on its way to be prevented and combated. Researchers from the Federal University of Rio de Janeiro (UFRJ) in partnership with investigators from University of Bonn, Universidad del Pais Vasco, Universidad de La Plata, FIOCRUZ and UNICAMP, show how the disease affects the heart and how the process can be reversed with two promising drugs. The findings have just been published in the October issue of the journal Nature Communications (EMBARGO DATE: 24th November 2016). Heart problems are responsible for 65% of the deaths related to diabetes. The most common disorder in these cases is ventricular tachycardia (a dysregulation in the heart rhythm). This work, coordinated by Prof. Emiliano Medei, from the Institute of Biophysics Carlos Chagas Filho and CENABIO at UFRJ, confirms that the increase in blood glucose causes a specific inflammation, which directly affects the heart. To investigate this process, researchers caused diabetes in wild-type mice and mutant animals unable to produce a specific type of inflammation related to production of IL-1-beta substance. Both had similar increases in blood glucose, but only those typically inflamed- the wild-type mice -- had altered heart rate. Furthermore, mutants which do not produce IL-1 beta suffered much less from arrhythmias even when under effect of caffeine or dobutamine, drugs that promote ventricular tachycardia. The researchers found a large amount of circulating IL-1-beta and especially in the hearts of common diabetic mice. They also observed that IL-1-beta alone altered heart function when given to healthy rat hearts (without diabetes), or human heart cells. The good news is that the group also tested successfully two drugs that specifically inhibit this inflammatory process: MCC-950 and anakinra. The first blocks IL1-beta production, while the latter prevents it from having active effects in the body cells and is already being used to treat some autoimune diseases, such as rheumatoid arthritis. The team managed to even reverse the cardiac alterations in diabetic mice. "It is noteworthy that inflammation is an important tool to fight infections, which usually ends when the 'intruder' is removed. In the case of diabetes, there is no infection. Persistent hyperglycemia stimulates the immune system to produce a constant inflammation, with great production of IL-1-beta -- "we found inflammation to be the link between arrhythmias and diabetes", explains Medei. "I believe that the new therapeutic tools that we propose in this study are very promising to treat the heart disease caused by diabetes" he says. The present work was funded by FAPERJ, CENABIO/IDOR, CNPq, CAPES, Deutsche Forschungsgemeinschaft, Stem Cell Factory II co-founded by the European Union, German federal state North Rhine-Westphalia and FONCYT (Argentina).


News Article | November 8, 2016
Site: globenewswire.com

Patent granted to Cell Factory in Europe confirms great potential with its exclusive extracellular vesicles in broad therapeutic applications like Crohn's disease and Type 1 Diabetes Consolidated results Esperite N.V. (Euronext: ESP, "Esperite" or "the Group") announces that cumulative consolidated revenue increased by 2% compared to the same period last year. The Group was able to increase the gross margin percentage by 1 percent point from 55% to 56%. Consolidated EBITDA improved by 20% for the Group but remains negative. Stem Cell Cumulative Stem-Cell segment revenue decreased by 12% compared to the same period in 2015. In absolute numbers the gross margin was equal to Q3 2015. The gross margin percentages increased from 60% for Q3-2015 to 66% for Q3-2016. As a result of the announced cost saving measures, EBITDA was around breakeven in Q3-2016 compared to a considerable negative amount for the same period last year. Genoma The market is changing fast in favor to a more regulated price structure including the reimbursements of the genetic tests by both the public and private health care systems. To further expand its sales, Genoma is contracting with local partners for the installation of new Genoma laboratories in several countries. Genoma expects significant development on its markets. Cumulative Genoma revenue more than doubled compared to Q3-2015. Gross margin percentage also more than doubled. EBITDA is negative due to the ramp up phase and is relatively stable for the first 3 quarters in 2016. The broad international patent on MSC-derived extracellular vesicles (including exosomes) has been granted in Europe. The patent covers use of extracellular vesicles (EVs) in treatment of acute and chronic inflammatory and autoimmune diseases. Esperite's R&D business unit The Cell Factory is leading an international consortium focused on clinical translation of the EVs-based drugs in treatment of drug-resistant epilepsy and Crohn's disease. Esperite's goal, with Cell Factory, is to become a leader in development and production of extracellular vesicles drugs in treatment of different indications i.e. graft versus host disease (GvHD) after solid organ and cell transplantations, arthritis, multiple sclerosis, cystic fibrosis, stroke, traumatic brain and spinal cord injury, newborn encephalopathy, and type 1 diabetes among others. EVs including exosomes are nanometre-size, natural biological particles secreted by different types of cells in vivo and in vitro. They contain proteins, growth factors, mRNA and other molecules responsible for the therapeutic effect of MSCs. In addition, EVs have several advantages over allogenic MSCs e.g.: up to 10-times lower production costs, no risk of uncontrolled proliferation and differentiation, lower risk of immune response and easy and safe delivery into different tissues and organs in vivo. High stability allows for easy transport and storage of the "ready-to-use" products. Currently Esperite is looking for partners to support the developments and clinical translations of the extracellular vesicle therapeutics. Patent infringement case Genoma strongly believes that Genoma's prenatal genetic test does not infringe the patents as claimed by Illumina and this alleged infringement is unfounded. No date has currently been set for the proceedings of the claim lodged by Illumina. ESPERITE Group (www.esperite.com), listed at Euronext Amsterdam and Paris (ticker: ESP), established in 2000, is the leading international company in regenerative and predictive medicine, operational in almost 40 countries with a network of 6'000 clinics worldwide. ESPERITE serves clients in its state-of-the-art lab facilities in Switzerland, Belgium, Germany, Dubai, South Africa and Portugal. CryoSave (www.cryo-save.com) is Esperite's leading international stem cell processing and cryo-conservation company and the largest family stem cell bank in Europe, which offers umbilical cord blood and cord tissue storage to parents. The family stem cell bank, CryoSave stores 300'000 samples from umbilical cord blood and cord tissue. Genoma (www.genoma.com) is Esperite's portfolio which comprises innovative tests based on sequencing and genomics: Tranquility, a non-invasive prenatal test (NIPT) and Serenity, a breast cancer screening test. Esperite is already working on the development of some other exclusive technologies in collaboration with the market leaders in this field. Cell Factory (www.cell-factory.com) is Esperite's know how R&D division, at the heart of the value chain, between stem cells collection & storage and the existing and future treatments in the regenerative medicine. Esperite, mainly focused on autologous treatments, will play a key role in research for the development of new medical treatments, in partnership with medical research centers, public universities and private partners. To learn more about the ESPERITE Group, or to book an interview with CEO Mr. Frédéric Amar:   - ir@esperite.com or visit the website at www.esperite.com.

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