Fundacion Inbiomed

Donostia / San Sebastián, Spain

Fundacion Inbiomed

Donostia / San Sebastián, Spain

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Arminan A.,Fundacion para la Investigacion Hospital Universitario La Fe | Arminan A.,Research Center Principe Felipe | Gandia C.,Fundacion para la Investigacion Hospital Universitario La Fe | Gandia C.,Research Center Principe Felipe | And 12 more authors.
Journal of the American College of Cardiology | Year: 2010

Objectives: The purpose of this study was to compare the ability of human CD34+ hematopoietic stem cells and bone marrow mesenchymal stem cells (MSC) to treat myocardial infarction (MI) in a model of permanent left descendent coronary artery (LDA) ligation in nude rats. Background: Transplantation of human CD34+ cells and MSC has been proved to be effective in treating MI, but no comparative studies have been performed to elucidate which treatment prevents left ventricular (LV) remodelling more efficiently. Methods: Human bone marrow MSC or freshly isolated CD34+ cells from umbilical cord blood were injected intramyocardially in infarcted nude rats. Cardiac function was analyzed by echocardiography. Ventricular remodelling was evaluated by tissue histology and electron microscopy, and neo-formed vessels were quantified by immunohistochemistry. Chronic local inflammatory infiltrates were evaluated in LV wall by hematoxylin-eosin staining. Apoptosis of infarcted tissue was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Results: Both cell types induced an improvement in LV cardiac function and increased tissue cell proliferation in myocardial tissue and neoangiogenesis. However, MSC were more effective for the reduction of infarct size and prevention of ventricular remodelling. Scar tissue was 17.48 ± 1.29% in the CD34 group and 10.36 ± 1.07% in the MSC group (p < 0.001 in MSC vs. CD34). Moreover, unlike MSC, CD34+-treated animals showed local inflammatory infiltrates in LV wall that persisted 4 weeks after transplantation. Conclusions: Mesenchymal stem cells might be more effective than CD34+ cells for the healing of the infarct. This study contributes to elucidate the mechanisms by which these cell types operate in the course of MI treatment. © 2010 American College of Cardiology Foundation.


Corominas-Faja B.,Catalan Institute of Nanoscience and Nanotechnology | Corominas-Faja B.,Girona Biomedical Research Institute IDIBGI | Cuyas E.,Catalan Institute of Nanoscience and Nanotechnology | Cuyas E.,Girona Biomedical Research Institute IDIBGI | And 6 more authors.
Oncotarget | Year: 2014

Cancer stem cells (CSC) may take advantage of the Warburg effect-induced siphoning of metabolic intermediates into de novo fatty acid biosynthesis to increase self-renewal growth. We examined the anti-CSC effects of the antifungal polyketide soraphen A, a specific inhibitor of the first committed step of lipid biosynthesis catalyzed by acetyl-CoA carboxylase (ACACA). The mammosphere formation capability of MCF-7 cells was reduced following treatment with soraphen A in a dose-dependent manner. MCF-7 cells engineered to overexpress the oncogene HER2 (MCF-7/HER2 cells) were 5-fold more sensitive than MCF-7 parental cells to soraphen A-induced reductions in mammosphere-forming efficiency. Soraphen A treatment notably decreased aldehyde dehydrogenase (ALDH)-positive CSC-like cells and impeded the HER2's ability to increase the ALDH+-stem cell population. The following results confirmed that soraphen A-induced suppression of CSC populations occurred through ACACA-driven lipogenesis: a.) exogenous supplementation with supraphysiological concentrations of oleic acid fully rescued mammosphere formation in the presence of soraphen A and b.) mammosphere cultures of MCF-7 cells with stably silenced expression of the cytosolic isoform ACACA1, which specifically participates in de novo lipogenesis, were mostly refractory to soraphen A treatment. Our findings reveal for the first time that ACACA may constitute a previously unrecognized target for novel anti-breast CSC therapies.


PubMed | Fundacion Inbiomed, StemTek Therapeutics and Catalan Institute of Nanoscience and Nanotechnology
Type: Journal Article | Journal: Oncotarget | Year: 2014

Cancer stem cells (CSC) may take advantage of the Warburg effect-induced siphoning of metabolic intermediates into de novo fatty acid biosynthesis to increase self-renewal growth. We examined the anti-CSC effects of the antifungal polyketide soraphen A, a specific inhibitor of the first committed step of lipid biosynthesis catalyzed by acetyl-CoA carboxylase (ACACA). The mammosphere formation capability of MCF-7 cells was reduced following treatment with soraphen A in a dose-dependent manner. MCF-7 cells engineered to overexpress the oncogene HER2 (MCF-7/HER2 cells) were 5-fold more sensitive than MCF-7 parental cells to soraphen A-induced reductions in mammosphere-forming efficiency. Soraphen A treatment notably decreased aldehyde dehydrogenase (ALDH)-positive CSC-like cells and impeded the HER2s ability to increase the ALDH+-stem cell population. The following results confirmed that soraphen A-induced suppression of CSC populations occurred throughACACA-driven lipogenesis: a.) exogenous supplementation with supraphysiological concentrations of oleic acid fully rescued mammosphere formation in the presence of soraphen A and b.) mammosphere cultures of MCF-7 cells with stably silenced expression of the cytosolic isoform ACACA1, which specifically participates in de novo lipogenesis, were mostly refractory to soraphen A treatment. Our findings reveal for the first time that ACACA may constitute a previously unrecognized target for novel anti-breast CSC therapies.


Monfort A.,Fundacion Inbiomed | Soriano-Navarro M.,CIBER ISCIII | Garcia-Verdugo J.M.,CIBER ISCIII | Izeta A.,Fundacion Inbiomed | Izeta A.,Hospital Donostia
Journal of Tissue Engineering and Regenerative Medicine | Year: 2013

Full thickness wounds require a dermal component to achieve functional permanent skin restoration. Currently available tissue-engineered skin substitutes lack a subcutaneous fat layer that would functionally contribute some of the mechanical and thermoregulatory properties of normal skin. To generate a trilayer engineered skin equivalent, we included bone marrow mesenchymal (BM-MSC) or adipose tissue-derived (ASC) stromal cells in a human plasma hydrogel exposed to adipogenic clues for three weeks. Approximately half of the cells differentiated under these conditions into mature adipocytes that survived for two years in culture with minimal medium change. In vitro generation of bona fide fully differentiated adipocytes was assessed by leptin secretion and ultrastructurally demonstrated through semithin to ultrathin sectioning and lipid staining with osmium tetroxide. Furthermore, presence of BM-MSCs or ASCs within the subcutaneous layer contributed to the epidermal differentiation program, with more proliferating basal cells depositing basal membrane proteins and differentiating into mature keratinocytes that were able to generate a pluristratified epithelium. In conclusion, we engineered a fully differentiated human skin trilayer that could present multiple applications such as use for in vitro drug absorption tests and regenerative therapies. © 2012 John Wiley & Sons, Ltd.


Li L.,CIC Nanogune | Munoz-Culla M.,Biodonostia Health Research Institute | Carmona U.,CIC Nanogune | Lopez M.P.,Fundacion Inbiomed | And 7 more authors.
Biomaterials | Year: 2016

We demonstrate a straightforward method to encapsulate siRNA into naturally available and unmodified human apoferritin. The encapsulation into apoferritin is independent of the sequence of the siRNA and provides superior protection for those sensitive molecules. High efficiency in transfection can be achieved in human tumorigenic cells, human primary mesenchymal stem cells (hMSC) and peripheral blood mononuclear cells (PBMCs). In contrast to Lipofectamine, highly effective gene silencing can be achieved with ferritin as the delivery agent in both tumor cells and PBMCs at low siRNA concentrations (10 nM). As an endogenous delivery agent, apoferritin does not induce immune activation of T- and B-cells in human PBMCs. Apoferritin shows intrinsic anti-inflammatory effects and apoferritin-mediated delivery shows a preference for immune-activated T- and B-cells, a natural selectivity which may turn useful for drug delivery in case of infections or inflammatory diseases. © 2016 Elsevier Ltd.


Rodriguez R.,University of Granada | Garcia-Castro J.,Institute Salud Carlos III | Trigueros C.,Fundacion Inbiomed | Garcia Arranz M.,Hospital Universitario La Paz | Menendez P.,University of Granada
Advances in Experimental Medicine and Biology | Year: 2012

The recognition of the therapeutic potential of Multipotent Mesenchymal Stromal Cells (MSCs) is one of the most exciting recent advances in cell therapy. In just ten years, since the description of the multilineage potential of MSCs by Pittenger et al in 1999 until now, MSCs are being used in more than 150 clinical trials as therapeutic agents. The potential of these cells for cell-based therapies relies on several key properties: (1) their capacity to differentiate into several cell lineages; (2) their lack of immunogenicity and their immunomodulatory properties; (3) their ex vivo expansion potential; (4) their ability to secrete soluble factors which regulate crucial biological functions such as proliferation and differentiation over a broad spectrum of target cells; and (5) their ability to home to damaged tissues and tumor sites. Based on these properties MSCs are being exploited worldwide for a wide range of potential clinical applications including cell replacement strategies, treatment of graft-versus-host disease, autoimmune diseases and rejection after solid organ transplantation as well as their use as vehicles to deliver anti-cancer therapies. Importantly, the low inherent immunogenicity of MSCs means that they could be used not only for autologous but also for allogeneic cell therapies. In addition, increasing evidence has revealed a complex relationship between MSCs and cancer. Thus, solid evidence has placed MSCs transformed with specific mutations as the most likely cell of origin for certain sarcomas, and MSCs have been reported to both, inhibit or promote tumor growth depending on yet undefined conditions. Here we will thoroughly discuss the different potential clinical applications of MSC as well as the role of MSCs on sarcomagenesis and the control of tumor growth. © 2012 Landes Bioscience and Springer Science+Business Media.


Carrero R.,Fundacion para la Investigacion Hospital Universitario La Fe | Cerrada I.,Fundacion para la Investigacion Hospital Universitario La Fe | Cerrada I.,CEU Cardenal Herrera University | Lledo E.,CEU Cardenal Herrera University | And 10 more authors.
Stem Cell Reviews and Reports | Year: 2012

Mesenchymal stem cells are often transplanted into inflammatory environments where they are able to survive and modulate host immune responses through a poorly understood mechanism. In this paper we analyzed the responses of MSC to IL-1β: a representative inflammatory mediator. Microarray analysis of MSC treated with IL-1β revealed that this cytokine activateds a set of genes related to biological processes such as cell survival, cell migration, cell adhesion, chemokine production, induction of angiogenesis and modulation of the immune response. Further more detailed analysis by real-time PCR and functional assays revealed that IL-1β mainly increaseds the production of chemokines such as CCL5, CCL20, CXCL1, CXCL3, CXCL5, CXCL6, CXCL10, CXCL11 and CX3CL1, interleukins IL-6, IL-8, IL23A, IL32, Toll-like receptors TLR2, TLR4, CLDN1, metalloproteins MMP1 and MMP3, growth factors CSF2 and TNF-α, together with adhesion molecules ICAM1 and ICAM4. Functional analysis of MSC proliferation, migration and adhesion to extracellular matrix components revealed that IL-1β did not affect proliferation but also served to induce the secretion of trophic factors and adhesion to ECM components such as collagen and laminin. IL-1β treatment enhanced the ability of MSC to recruit monocytes and granulocytes in vitro. Blockade of NF-κβ transcription factor activation with IκB kinase beta (IKKβ) shRNA impaired MSC migration, adhesion and leucocyte recruitment, induced by IL-1β demonstrating that NF-κB pathway is an important downstream regulator of these responses. These findings are relevant to understanding the biological responses of MSC to inflammatory environments. © 2012 The Author(s).


O'Prey J.,Beatson Institute for Cancer Research | Crighton D.,Beatson Institute for Cancer Research | Martin A.G.,Fundacion Inbiomed | Vousden K.H.,Beatson Institute for Cancer Research | And 2 more authors.
Cell Cycle | Year: 2010

The intricate regulation of cell survival and cell death is critical for the existence of both normal and transformed cells. Two factors central to these processes are p53 and NFκB, with both factors having ascribed roles in both promoting and repressing cell death. Not surprisingly, a number of studies have previously reported interplay between p53 and NFκB. The mechanistic basis behind these observations, however, is currently incomplete. We report here further insights into this interplay using a system where blockade of NFκB inhibits cell death from p53, but at the same time sensitizes cells to death by TNFα. We found in agreement with a recent report showing that NFκB is required for the efficient activation of the BH3-only protein Noxa by the p53 family member p73, that p53's ability to induce Noxa is also impeded by inhibition of NFκB. In contrast to the regulation by p73, however, blockade of NFκB downstream of p53 decreases Noxa protein levels without effects on Noxa mRNA. Our further analysis of the effects of NFκB inhibition on p53 target gene expression revealed that while most target genes analysed where unaffected by blockade of NFκB, the p53-mediated induction of the pro-apoptotic gene p53AIp1 was significantly dependent on NFκB. these studies therefore add further insight into the complex relationship of p53 and NFκB. In addition, since both Noxa and p53AIp1 have been shown to be important components of p53-mediated cell death responses, these findings may also indicate critical points where NFκB plays a pro-apoptotic role downstream of p53. © 2010 Landes Bioscience.


Cerrada I.,Fundacion Para la Investigacion Hospital la Fe | Cerrada I.,CEU Cardenal Herrera University | Ruiz-Sauri A.,University of Valencia | Carrero R.,Fundacion Para la Investigacion Hospital la Fe | And 6 more authors.
Stem Cells and Development | Year: 2013

Mesenchymal stem cells (MSC) are effective in treating myocardial infarction (MI) and previous reports demonstrated that hypoxia improves MSC self-renewal and therapeutics. Considering that hypoxia-inducible factor-1 alpha (HIF-1α) is a master regulator of the adaptative response to hypoxia, we hypothesized that HIF-1α overexpression in MSC could mimic some of the mechanisms triggered by hypoxia and increase their therapeutic potential without hypoxia stimulation. Transduction of MSC with HIF-1α lentivirus vectors (MSC-HIF) resulted in increased cell adhesion and migration, and activation of target genes coding for paracrine factors. When MSC-HIF were intramyocardially injected in infarcted nude rats, significant improvement was found (after treatment of infarcted rats with MSC-HIF) in terms of cardiac function, angiogenesis, cardiomyocyte proliferation, and reduction of fibrotic tissue with no induction of cardiac hypertrophy. This finding provides evidences for a crucial role of HIF-1α on MSC biology and suggests the stabilization of HIF-1α as a novel strategy for cellular therapies. © 2013, Mary Ann Liebert, Inc.


PubMed | CIC Nanogune, Fundacion Inbiomed and Biodonostia Health Research Institute
Type: | Journal: Biomaterials | Year: 2016

We demonstrate a straightforward method to encapsulate siRNA into naturally available and unmodified human apoferritin. The encapsulation into apoferritin is independent of the sequence of the siRNA and provides superior protection for those sensitive molecules. High efficiency in transfection can be achieved in human tumorigenic cells, human primary mesenchymal stem cells (hMSC) and peripheral blood mononuclear cells (PBMCs). In contrast to Lipofectamine, highly effective gene silencing can be achieved with ferritin as the delivery agent in both tumor cells and PBMCs at low siRNA concentrations (10nM). As an endogenous delivery agent, apoferritin does not induce immune activation of T- and B-cells in human PBMCs. Apoferritin shows intrinsic anti-inflammatory effects and apoferritin-mediated delivery shows a preference for immune-activated T- and B-cells, a natural selectivity which may turn useful for drug delivery in case of infections or inflammatory diseases.

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