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4. Topical Administration of a Marine Oil Rich in Pro-Resolving Lipid Mediators Accelerates Wound Healing in Diabetic db/db Mice through Angiogenesis and Macrophage Polarization

Author

Ontoria-Oviedo I, Amaro-Prellezo E, Castellano D, Venegas-Venegas E, Gonzalez-Santos F, Ruiz-Sauri A, Pelacho B, Prosper F, del Caz M, and Sepulveda P

Subjects
pro-resolving lipid mediators, angiogenesis, SPMs, macrophage polarization, wound healing, omega-3, diabetic ulcer
Abstract

Impaired wound healing in patients with type 2 diabetes (DM2) is characterized by chronic inflammation, which delays wound closure. Specialized pro-resolving lipid mediators (SPMs) are bioactive molecules produced from essential polyunsaturated fatty acids (PUFAs), principally omega-3 docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). SPMs are potent regulators of inflammation and have been used to suppress chronic inflammation in peripheral artery disease, non-alcoholic fatty liver disease, and central nervous system syndromes. LIPINOVA(R) is a commercially available safe-grade nutritional supplement made from a fractionated marine lipid concentrate derived from anchovy and sardine oil that is rich in SPMs and EPA, as well as DHA precursors. Here, we assessed the effect of LIPINOVA(R) in wound dressing applications. LIPINOVA(R) showed biocompatibility with keratinocytes and fibroblasts, reduced the abundance of pro-inflammatory macrophages (M phi 1), and promoted in vitro wound closure. Daily application of the marine oil to open wounds made by punch biopsy in db/db mice promoted wound closure by accelerating the resolution of inflammation, inducing neoangiogenesis and M phi 1/M phi 2 macrophage polarization. In conclusion, LIPINOVA(R) displays pro-resolutive properties and could be exploited as a therapeutic agent for the treatment of diabetic ulcers.

Published
2022

5. Targeted delivery controlled release of hepatic growth factor and insulin-like growth factor-1 improves left ventricular repair in a porcine model of myocardial ischemia reperfusion injury

Author

Wu, M, primary, Claus, P, additional, De Buck, S, additional, Veltman, D, additional, Gillijns, H, additional, Holemans, P, additional, Pokreisz, P, additional, Caluwe, E, additional, Estefania, E, additional, Cohen, S, additional, Prosper, F, additional, Pelacho, B, additional, and Janssens, S, additional

Published
2021
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6. Development of cellularized and functionalized collagen scaffolds for the treatment of myocardial infarction

Author

Pérez-Estenaga, I. (Iñigo) and Pelacho, B. (Beatriz)

Subjects
Ciencias de la vida::Citología, biología celular [Materias Investigacion], Ciencias de la vida::Inmunología [Materias Investigacion], Ciencias de la Salud::Microbiología y biología molecular [Materias Investigacion]
Abstract

Cardiovascular diseases (CVD) are the leading cause of death in the developed countries. According to the las report of the European Society of Cardiology, CVD remain the most common cause of death within Europe, accounting for 2.2 million deaths in females and 1.9 million deaths in males. These equate to 47% and 39% of all deaths in females and males, respectively, and almost half of them are caused by Myocardial Infarction (MI). In the last 20 years, in order to overcome the limitations of the conventional treatments, cell therapy, has emerged as a promising therapeutic option for the treatment of MI. In this thesis we have employed Adipose Derived Mesenchymal Stem Cells (ADSC) seeded in a collagen scaffold fabricated under GMP-conditions, to treat the infarcted heart in preclinical MI animal models. First, we assessed the patch safety in rodent models, proving a safe profile of the system, established by tumorigenicity, toxicity and biodistribution studies. Secondly, the collagen scaffold was cellularized with allogeneic ADSC and its immunological effect was analysed both in vitro and in vivo, showing no alloreactive response by the immune cells towards the allogeneic patch. Moreover in vitro, in a human context, the cellularized patch elicited a potent immunomodulatory effect towards lymphocytes by inhibiting their proliferation, phenotypical activation and pro-inflammatory cytokine production. Finally, the functionalization of the collagen membrane with the angiogenic factor SDF-1 was achieved, by the creation of a bilayer collagen scaffold, which confirmed to be biocompatible in vivo and exerted a therapeutic effect when tested in a rat MI model in the shape of cardiac function recovery.

Published
2021

9. Delivery of cardiovascular progenitors with biomimetic microcarriers reduces adverse ventricular remodeling in a rat model of chronic myocardial infarction

Author

Garbayo, E., primary, Ruiz-Villalba, A., additional, Hernandez, S.C., additional, Saludas, L., additional, Abizanda, G., additional, Pelacho, B., additional, Roncal, C., additional, Sanchez, B., additional, Palacios, I., additional, Prósper, F., additional, and Blanco-Prieto, M.J., additional

Published
2021
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12. Nanoparticles loaded with hepatic growth factor and insulin-like growth factor-1 improve left ventricular repair in a porcine model of myocardial Ischemia reperfusion injury

Author

Wu, M, primary, Claus, P, additional, De Buck, S, additional, Veltman, D, additional, Gillijns, H, additional, Holemans, P, additional, Pokreisz, P, additional, Caluwe, E, additional, Colino, E, additional, Cohen, S, additional, Prosper, F, additional, Pelacho, B, additional, and Janssens, S, additional

Published
2020
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13. Antibodies in pemphigus vulgaris

Author

Ivars, M., primary, España, A., additional, Alzuguren, P., additional, Pelacho, B., additional, Lasarte, J.J., additional, and López‐Zabalza, M.J., additional

Published
2020
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14. 寻常型天疱疮抗体

Author

Ivars, M., primary, España, A., additional, Alzuguren, P., additional, Pelacho, B., additional, Lasarte, J.J., additional, and López‐Zabalza, M.J., additional

Published
2020
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16. Analysis of AAV9 biodistribution, transduction efficiency and AAV-miR-935 cardio-specific overexpression in a murine model of myocardial infarction

Author

García-Olloqui, P. (Paula) and Pelacho, B. (Beatriz)

Subjects
Ciencias de la vida::Citología, biología celular [Materias Investigacion], Ciencias de la Salud::Microbiología y biología molecular [Materias Investigacion], Cultivo celular, Ciencias de la Salud [Materias Investigacion], Patología cardiovascular
Abstract

Myocardial infarction (MI) leads to an irreversible loss of cardiac myocytes, which compromises cardiac function. The cellular and molecular mechanisms involved in the ischemic event remain under study, being the cardiac exosomes transfer of non-coding RNAs a key process in this pathology. In this context, a comparative analysis of the exosomal compartment of human cardiac progenitor cells (CPC) was performed in comparison with human bone marrow-mesenchymal stem cells (MSC) and human dermal fibroblasts (HDF). A total of 481 differentially expressed microRNAs (miR) were found, being miR-935 the most differentially expressed in CPC. Analysis of miR-935 in vitro overexpression promoted a positive trend to increment cardiomyocyte survival, in response to oxidative stress. Furthermore, when miR-935 regulation was analyzed in a mouse model of MI disease, miR downregulation was shown five days post-infarct in different cardiac subpopulations. In order to study the role of miR-935 in MI and to achieve an optimal miR-935 overexpression in our mouse model, we developed a robust viral-based method for cardiac-specific miR overexpression. Cardiotropic Serotype 9-Adeno-Associated Virus (AAV9) were used for this purpose and their biodistribution was first determined in mice. Ubiquitous EF1α or the cardiac-specific TnT promoters were combined with Luciferase (Luc) or GFP reporters and administered by intramyocardial or intravenous injection, either in healthy or myocardial-infarcted mice. High transgene expression levels were found in the heart, but not in the liver, of mice receiving AAV-TnT, which was significantly higher after intramyocardial injection regardless of ischemia-induction. On the contrary, high hepatic transgene expression levels were detected with the EF1α-promoter, independently of the administration route and heart damage. Luc expression increased with both promoters in a time-dependent manner, reaching a peak by day 3-7 that was stable for at least 60 days. Moreover, tissue-specific GFP expression was found in cardiomyocytes with the TnT-vector, while minimal cardiac expression was detected with the ubiquitous one. Interestingly, we found that MI greatly increased the transcriptional activity of AAV genomes. Thus, we found AAV9-TnT as a robust and stable vector for cardiac-specific delivery after intramyocardial injection. Finally, the therapeutic potential of this vector in combination with miR-935 was evaluated in a mouse model of myocardial ischemia. Intramyocardial injection of AAV9-TnT-miR935 vector did not significantly improve heart function 60 days post-infarct. However, a slight positive trend in the ejection fraction and a decreased adverse cardiac remodeling are observed, suggesting miR-935 putative cardioprotective role.

Published
2019

18. Electrospun poly(hydroxybutyrate) scaffolds promote engraftment of human skin equivalents via macrophage M2 polarization and angiogenesis

Author

Castellano, D, Sanchis, A, Blanes, M, Pérez del Caz, MD, Ruiz-Sauri, A, Pelacho, B, and Ontoria-Oviedo, I

Subjects
skin equivalents, technology, industry, and agriculture, human skin xenograft, poly(hydroxybutyrate), electrospinning
Abstract

Human dermo-epidermal skin equivalents (DE) comprising in vitro expanded autologous keratinocytes and fibroblasts are a good option for massive burn treatment. However, the lengthy expansion time required to obtain sufficient surface to cover an extensive burn together with the challenging surgical procedure limits their clinical use. The integration of DE and biodegradable scaffolds has been proposed in an effort to enhance their mechanical properties. Here, it is shown that poly(hydroxybutyrate) electrospun scaffolds (PHB) present good biocompatibility both in vitro and in vivo and are superior to poly-epsilon-caprolactone electrospun scaffolds as a substrate for skin reconstruction. Implantation of PHB scaffolds in healthy rats polarized macrophages to an M2-type that promoted constructive in vivo remodelling. Moreover, implantation of DE-PHB composites in a NOD/SCID mouse xenograft model resulted in engraftment accompanied by an increase in angiogenesis that favoured the survival of the human graft. Thus, PHB scaffolds are an attractive substrate for further exploration in skin reconstruction procedures, probably due in part to their greater angiogenic and M2 macrophage polarization properties. Copyright (c) 2017 John Wiley & Sons, Ltd.

Published
2018

20. The involvement of ADAM10 in acantholysis in mucocutaneous pemphigus vulgaris depends on the autoantibody profile of each patient.

Author

Ivars, M., España, A., Alzuguren, P., Pelacho, B., Lasarte, J.J., and López‐Zabalza, M.J.

Subjects
EPIDERMAL growth factor receptors, DESMOGLEINS, EPIDERMAL growth factor
Abstract

Summary: Background: Acantholysis in pemphigus vulgaris (PV) may be triggered by desmoglein (Dsg) and non‐Dsg autoantibodies. The autoantibody profile of each patient results in distinct intracellular signalling patterns. Objectives: Based on our previous findings, we aimed to elucidate whether PV acantholysis in a mouse model may be mediated by activation of a disintegrin and metalloproteinase 10 (ADAM10). Methods: We used three PV‐IgG fractions from different patients containing high or low levels of anti‐Dsg1 and anti‐Dsg3 antibodies, and the presence or not of anti‐desmocollin (Dsc) antibodies, using a passive transfer mouse model of PV. Results: Although all of the PV‐IgG fractions produced suprabasal acantholysis, only those containing anti‐Dsg1/3, but not anti‐Dsc2/3 antibodies, induced ADAM10 activation in a Src‐dependent way, and an increase in the epidermal growth factor (EGF) receptor ligands EGF and betacellulin (BTC). In contrast, the presence of anti‐Dsc2/3 antibodies, in addition to anti‐Dsg1/3, triggered earlier and ADAM10‐independent epidermal detachment, with no increase in EGF and BTC, which was associated with an earlier and more intense acantholysis. Conclusions: All PV‐IgG fractions produced suprabasal acantholysis, but our results reveal that depending on the levels of anti‐Dsg antibodies or the presence of non‐Dsg antibodies, such as anti‐Dsc, more severe cell–cell epidermal detachment will occur at different times, and in an ADAM10‐dependent manner or not. Acantholysis in these different groups of patients with PV may be a consequence of the activation of specific intracellular mechanisms downstream of Autoantibodies binding to Dsg or non‐Dsg proteins, and therefore more specific therapeutic approaches in PV should be used. What's already known about this topic? Suprabasal acantholysis in pemphigus vulgaris (PV) may be triggered by both desmoglein (Dsg) and non‐Dsg autoantibodies.The autoantibody profile of each patient is associated with a distinct intracellular signalling pattern. What does this study add? In patients with PV with anti‐Dsg3 and anti‐Dsg1, but not anti‐desmocollin (Dsc)3 antibodies, ADAM10 activation is induced in an Src‐dependent way, together with an increase in the epidermal growth factor receptor (EGFR) ligands EGF and betacellulin.The presence of anti‐Dsc3 antibodies triggers an earlier and ADAM10‐independent acantholysis, without increasing EGFR ligands, and is associated with more severe epidermal detachment.Lower levels of anti‐Dsc3 antibodies are associated with less severe acantholysis. What is the translational message? In some patients with PV, the severity and the timing for cell–cell detachment seem to depend on the level of anti‐Dsg1/3 antibodies, although other as yet uncharacterized antibodies may also participate.These patients with PV would exhibit inhibition of acantholysis by Src, ADAM10, EGF and EGFR inhibitors.In other patients, the presence of non‐Dsg antibodies, such as anti‐Dsc2/3, would produce an earlier and more severe ADAM10‐independent suprabasal acantholysis. Plain language summary available online [ABSTRACT FROM AUTHOR]

Published
2020
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21. P5676Safety and immunomodulatory action of epicardial patches combined with allogeneic adipose-derived mesenchymal stem cells in a rodent and porcine model of myocardial infarction

Author

Pelacho, B, primary, Lopez-Diaz De Cerio, A, additional, Inoges, S, additional, Perez-Astenaga, I, additional, Gavira, J J, additional, Abizanda, G, additional, Andreu, E, additional, Crisostomo, V, additional, Bermejo, J, additional, Huss, A, additional, Gil, A G, additional, Koblizek, T, additional, Quintana, L L, additional, Fernandez-Aviles, F, additional, and Prosper, F, additional

Published
2018
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22. Global position paper on cardiovascular regenerative medicine

Author

Fernández-Avilés, F. (Francisco), Sanz-Ruiz, R. (Ricardo), Climent, A.M. (Andreu M.), Badimon, L. (Lina), Bolli, R. (Roberto), Charron, D. (Dominique), Fuster, V. (Valentin), Janssens, S. (Stefan), Kastrup, J. (Jens), Kim, H.-S. (Hyo-Soo), Lüscher, T.F., Martin, J.F. (John F.), Menasche, P. (Philippe), Simari, P. (Patricio), Stone, G.W. (Gregg), Terzic, A. (Andre), Willerson, J.T. (James), Wu, J.C. (Joseph C.), Joseph, C.W. (C. Wu), Broughton, K. (Kathleen), DiFede, D.L. (Darcy L.), Dimmeler, S. (Stefanie), Madonna, R. (Rosalinda), Penn, M.S. (Marc S.), Sussman, M.A. (Mark A.), Sluijter, J.P.G., Woller, K.C. (Kai C.), Balkan, W. (Wayne), Chamuleau, S.A.J. (Steven), Fernández-Santos, M.E. (Maria Eugenia), Goliasch, G. (Georg), Gyöngyösi, M. (Mariann), Hare, J.M. (Joshua M.), Tompkins, B.A. (Bryon A.), Winkler, J. (Johannes), Bayés-Genis, A. (Antoni), Henry, T.D. (Timothy), Taylor, D.A. (Doris), Lerman, A. (Amir), Pelacho, B. (Beatriz), Prosper, F. (Felipe), Perin, E.C. (Emerson ), Pompilio, G. (Giulio), Gersh, B.J. (Bernard), Bartúnek, J. (Jozef), Duckers, E. (Eric), Ferdinandy, P. (Péter), Losordo, D.W. (Douglas W.), Čanchez, P.L. (Pedro L.), Sherman, W. (Warren), Wojakowski, W. (Wojtek), Zeiher, A.M. (Andreas), Roncalli, J. (Jérôme), Mathur, A. (Anthony), Crea, F. (Filippo), D'Amario, D. (Domenico), Povsic, T.J. (Thomas J.), Traverse, J.H. (Jay), Ylä-Herttuala, S. (Seppo), Fernández-Avilés, F. (Francisco), Sanz-Ruiz, R. (Ricardo), Climent, A.M. (Andreu M.), Badimon, L. (Lina), Bolli, R. (Roberto), Charron, D. (Dominique), Fuster, V. (Valentin), Janssens, S. (Stefan), Kastrup, J. (Jens), Kim, H.-S. (Hyo-Soo), Lüscher, T.F., Martin, J.F. (John F.), Menasche, P. (Philippe), Simari, P. (Patricio), Stone, G.W. (Gregg), Terzic, A. (Andre), Willerson, J.T. (James), Wu, J.C. (Joseph C.), Joseph, C.W. (C. Wu), Broughton, K. (Kathleen), DiFede, D.L. (Darcy L.), Dimmeler, S. (Stefanie), Madonna, R. (Rosalinda), Penn, M.S. (Marc S.), Sussman, M.A. (Mark A.), Sluijter, J.P.G., Woller, K.C. (Kai C.), Balkan, W. (Wayne), Chamuleau, S.A.J. (Steven), Fernández-Santos, M.E. (Maria Eugenia), Goliasch, G. (Georg), Gyöngyösi, M. (Mariann), Hare, J.M. (Joshua M.), Tompkins, B.A. (Bryon A.), Winkler, J. (Johannes), Bayés-Genis, A. (Antoni), Henry, T.D. (Timothy), Taylor, D.A. (Doris), Lerman, A. (Amir), Pelacho, B. (Beatriz), Prosper, F. (Felipe), Perin, E.C. (Emerson ), Pompilio, G. (Giulio), Gersh, B.J. (Bernard), Bartúnek, J. (Jozef), Duckers, E. (Eric), Ferdinandy, P. (Péter), Losordo, D.W. (Douglas W.), Čanchez, P.L. (Pedro L.), Sherman, W. (Warren), Wojakowski, W. (Wojtek), Zeiher, A.M. (Andreas), Roncalli, J. (Jérôme), Mathur, A. (Anthony), Crea, F. (Filippo), D'Amario, D. (Domenico), Povsic, T.J. (Thomas J.), Traverse, J.H. (Jay), and Ylä-Herttuala, S. (Seppo)

Published
2017
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23. Global position paper on cardiovascular regenerative medicine

Author

Fernandez-Aviles, F, Sanz-Ruiz, R, Climent, AM, Badimon, L, Bolli, R, Charron, D, Fuster, V, Janssens, S, Kastrup, J, Kim, HS, Luscher, TF, Martin, JF, Menasche, P, Simari, RD, Stone, GW, Terzic, A, Willerson, JT, Wu, JC, Broughton, K, DiFede, DL, Dimmeler, S, Madonna, R, Penn, MS, Sussman, MA, Sluijter, JPG, Wollert, KC, Balkan, W, Chamuleau, S, Fernandez-Santos, ME, Goliasch, G, Gyongyosi, M, Hare, JM, Tompkins, BA, Winkler, J, Bayes-Genis, A, Henry, TD, Taylor, DA, Lerman, A, Pelacho, B, Prosper, F, Perin, EC, Pompilio, G, Gersh, B, Bartunek, J, Duckers, Eric, Ferdinandy, P, Losordo, DW, Sanchez, PL, Sherman, W, Wojakowski, W, Zeiher, A, Roncalli, J, Mathur, A, Crea, F, D'Amario, D, Povsic, TJ, Traverse, J, Yla-Herttuala, S, Fernandez-Aviles, F, Sanz-Ruiz, R, Climent, AM, Badimon, L, Bolli, R, Charron, D, Fuster, V, Janssens, S, Kastrup, J, Kim, HS, Luscher, TF, Martin, JF, Menasche, P, Simari, RD, Stone, GW, Terzic, A, Willerson, JT, Wu, JC, Broughton, K, DiFede, DL, Dimmeler, S, Madonna, R, Penn, MS, Sussman, MA, Sluijter, JPG, Wollert, KC, Balkan, W, Chamuleau, S, Fernandez-Santos, ME, Goliasch, G, Gyongyosi, M, Hare, JM, Tompkins, BA, Winkler, J, Bayes-Genis, A, Henry, TD, Taylor, DA, Lerman, A, Pelacho, B, Prosper, F, Perin, EC, Pompilio, G, Gersh, B, Bartunek, J, Duckers, Eric, Ferdinandy, P, Losordo, DW, Sanchez, PL, Sherman, W, Wojakowski, W, Zeiher, A, Roncalli, J, Mathur, A, Crea, F, D'Amario, D, Povsic, TJ, Traverse, J, and Yla-Herttuala, S

Published
2017

24. Analysis of the regenerative potential of the induced pluripotent stem cells in a model of acute myocardial infarction in mice

Author

Iglesias-García, O. (Olalla), Pelacho, B. (Beatriz), and Prosper, F. (Felipe)

Subjects
Ciencias de la Vida [Materias Investigacion], Biología molecular, Biología celular, Cultivo celular
Abstract

Principal limitation for generating cardiomyocytes from stem cells is that differentiated cells generally present electrophysiological immature and heterogeneous phenotype, which may hamper their in vitro and in vivo application. The purpose of this study was to examine the effect of NRG-1b and DMSO in the in vitro generation of mature working-type cardiomyocytes from induced pluripotent stem (iPS) cells and to determine their contribution to the cardiac tissue regeneration after acute myocardial infarction (AMI). iPS cells were derived from α-MHC-GFP mice fibroblasts and were in vitro differentiated towards cardiomyocytes by DMSO and/or NRG-1b treatment. iPS cardiac specification and maturation was analyzed by Q-RT-PCR, immunofluorescence, electronic microscopy and patch-clamp techniques. The iPS-derived cardiomyocytes (n=15) or culture-medium as control (n=13) were injected into the peri-infarct region of mice hearts following coronary artery ligation. Echocardiography and histology assessments were performed from 1-8 weeks post-transplantation. iPS cells showed early and robust in vitro cardiogenesis with cardiac gene and protein expression in all cases. Electrophysiological studies demonstrated a more mature ventricular-like cardiac phenotype when cells were treated with NRG-1b and DMSO than with DMSO-treatment alone. In vivo studies in the AMI mouse model demonstrated that iPS-derived CMs preserved cardiac function and induced a positive heart tissue remodeling. Moreover, iPS-CMs engrafted and electromechanically couple into the heart tissue. The combination of NRG-1b and DMSO induced iPS cells differentiation towards mature ventricular-like cardiac cells which, when transplanted in a model of AMI, contributed to preserve the cardiac function and tissue viability.

Published
2015

25. Substrate Stiffness and Composition Specifically Direct Differentiation of Induced Pluripotent Stem Cells

Author

Macrí-Pellizzeri L, Pelacho B, Sancho A, Iglesias-García O, Simón-Yarza AM, Soriano-Navarro M, González-Granero S, García-Verdugo JM, De-Juan-Pardo EM, and Prosper F

Abstract

Substrate stiffness, biochemical composition, and matrix topography deeply influence cell behavior, guiding motility, proliferation, and differentiation responses. The aim of this work was to determine the effect that the stiffness and protein composition of the underlying substrate has on the differentiation of induced pluripotent stem (iPS) cells and the potential synergy with specific soluble cues. With that purpose, murine iPS-derived embryoid bodies (iPS-EBs) were seeded on fibronectin- or collagen I-coated polyacrylamide (pAA) gels of tunable stiffness (0.6, 14, and 50 kPa) in the presence of basal medium; tissue culture polystyrene plates were employed as control. Specification of iPS cells toward the three germ layers was analyzed, detecting an increase of tissue-specific gene markers in the pAA matrices. Interestingly, soft matrix (0.6 kPa) coated with fibronectin favored differentiation toward cardiac and neural lineages and, in the case of neural differentiation, the effect was potentiated by the addition of specific soluble factors. The generation of mature astrocytes, neural cells, and cardiomyocytes was further proven by immunofluorescence and transmission electron microscopy. In summary, this work emphasizes the importance of using biomimetic matrices to accomplish a more specific and mature differentiation of stem cells for future therapeutic applications.

Published
2015

26. Hematopoietic reconstitution by multipotent adult progenitor cells: Precursors to long-term hematopoietic stem cells

Author

Serafini, M, Dylla, S, Oki, M, Heremans, Y, Tolar, J, Jiang, Y, Buckley, S, Pelacho, B, Burns, T, Frommer, S, Rossi, D, Bryder, D, Panoskaltsis-Mortari, A, O'Shaughnessy, M, Nelson-Holte, M, Fine, G, Weissman, I, Blazar, B, Verfaillie, C, Serafini M, Dylla SJ, Oki M, Heremans Y, Tolar J, Jiang YH, Buckley SM, Pelacho B, Burns TC, Frommer S, Rossi DJ, Bryder D, Panoskaltsis-Mortari A, O'Shaughnessy MJ, Nelson-Holte M, Fine GC, Weissman IL, Blazar BR, Verfaillie CM, Serafini, M, Dylla, S, Oki, M, Heremans, Y, Tolar, J, Jiang, Y, Buckley, S, Pelacho, B, Burns, T, Frommer, S, Rossi, D, Bryder, D, Panoskaltsis-Mortari, A, O'Shaughnessy, M, Nelson-Holte, M, Fine, G, Weissman, I, Blazar, B, Verfaillie, C, Serafini M, Dylla SJ, Oki M, Heremans Y, Tolar J, Jiang YH, Buckley SM, Pelacho B, Burns TC, Frommer S, Rossi DJ, Bryder D, Panoskaltsis-Mortari A, O'Shaughnessy MJ, Nelson-Holte M, Fine GC, Weissman IL, Blazar BR, and Verfaillie CM

Abstract

For decades, in vitro expansion of transplantable hematopoietic stem cells (HSCs) has been an elusive goal. Here, we demonstrate that multipotent adult progenitor cells (MAPCs), isolated from green fluorescent protein (GFP)-transgenic mice and expanded in vitro for >40-80 population doublings, are capable of multilineage hematopoietic engraftment of immunodeficient mice. Among MAPC-derived GFP+CD45.2+ cells in the bone marrow of engrafted mice, HSCs were present that could radioprotect and reconstitute multilineage hematopoiesis in secondary and tertiary recipients, as well as myeloid and lymphoid hematopoietic progenitor subsets and functional GFP + MAPC-derived lymphocytes that were functional. Although hematopoietic contribution by MAPCs was comparable to control KTLS HSCs, approximately 103-fold more MAPCs were required for efficient engraftment. Because GFP+ host-derived CD45.1+ cells were not observed, fusion is not likely to account for the generation of HSCs by MAPCs. JEM

Published
2007

27. Aplicación terapéutica de la bioingeniería mediante la combinación de células madre y matrices extracelulares en un modelo de infarto de miocardio en rata

Author

Araña, M. (Miriam), Prosper, F. (Felipe), and Pelacho, B. (Beatriz)

Subjects
Corazón, Ciencias de la vida [Materias Investigacion], Rata Sprague‐Dawley, Infartos de miocardio, Células madres
Abstract

Los objetivos del presente trabajo han sido los siguientes: 1. Aislar y caracterizar la población de células madre derivadas del tejido adiposo (ADSC), a partir de grasa de rata Sprague‐Dawley. 2. Caracterizar el comportamiento biológico y mecánico de distintos tipos de membranas de colágeno y determinar su biocompatibilidad in vivo. 3. Analizar de forma comparativa, el potencial terapéutico de las ADSC en el corazón, al ser trasplantadas como parche celular (mediante su previa adhesión a una membrana de colágeno) o inyectadas sin soporte, en un modelo de infarto crónico de miocardio en rata. 4. Determinar los mecanismos implicados en la posible acción terapéutica de las membranas celularizadas con ADSC.

Published
2014

28. Vascular endothelial growth factor-delivery systems for cardiac repair: An overview

Author

Simon-Yarza, T. (Teresa), Formiga, F.R. (Fabio R.), Tamayo, E. (Esther), Pelacho, B. (Beatriz), Prosper, F. (Felipe), and Blanco-Prieto, M.J. (María José)

Subjects
Protein delivery, Tissue engineering, Angiogenesis, Cardiovascular disease, VEGF
Abstract

Since the discovery of the Vascular Endothelial Growth Factor (VEGF) and its leading role in the angiogenic process, this has been seen as a promising molecule for promoting neovascularization in the infarcted heart. However, even though several clinical trials were initiated, no therapeutic effects were observed, due in part to the short half life of this factor when administered directly to the tissue. In this context, drug delivery systems appear to offer a promising strategy to overcome limitations in clinical trials of VEGF. The aim of this paper is to review the principal drug delivery systems that have been developed to administer VEGF in cardiovascular disease. Studies published in the last 5 years are reviewed and the main features of these systems are explained. The tissue engineering concept is introduced as a therapeutic alternative that holds promise for the near future.

Published
2012

29. Growth factor loaded-microparticles as a tool for cardiac repair

Author

Rocha, F. (Fabio), Pelacho, B. (Beatriz), and Blanco-Prieto, M.J. (María José)

Subjects
Farmacia [Materias Investigacion]
Abstract

The clinical trials performed in patients with myocardial infarction and based on the intravascular injection of growth factors have failed, owing, among other reasons, to protein instability after injection. The hypothesis of this research is that a local controlled release of the growth factors by using a polymeric delivery system could protect the growth factors from degradation and stimulate cardiac repair. To test this, the following specific objectives were proposed: 1. Design, development and physico-chemical characterization of PLGA microparticles intended for intramyocardial administration. In vivo compatibility assessment of the developed microparticles with the cardiac tissue. 2. Development of VEGF165 loaded PLGA microparticles, in vitro characterization and assessment of the potential benefit of the VEGF165-microparticles in an acute rat myocardial ischemia– reperfusion model. 3. Development of FGF-1 and NRG-1 into PLGA microparticles, in vitro characterization and evaluation of the therapeutic potential of FGF-1 and/or NRG-1 cytokines delivered from PLGA microparticles in a rat myocardial infarction model.

Published
2011

30. Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration

Author

Formiga, F.R. (Fabio R.), Pelacho, B. (Beatriz), Garbayo, E. (Elisa), Imbuluzqueta, I. (Izaskun), Diaz-Herraez, P. (Paula), Abizanda, G. (Gloria), Gavira, J.J. (Juan José), Simon-Yarza, T. (Teresa), Albiasu, E. (Edurne), Tamayo, E. (Esther), Prosper, F. (Felipe), Blanco-Prieto, M.J. (María José), Formiga, F.R. (Fabio R.), Pelacho, B. (Beatriz), Garbayo, E. (Elisa), Imbuluzqueta, I. (Izaskun), Diaz-Herraez, P. (Paula), Abizanda, G. (Gloria), Gavira, J.J. (Juan José), Simon-Yarza, T. (Teresa), Albiasu, E. (Edurne), Tamayo, E. (Esther), Prosper, F. (Felipe), and Blanco-Prieto, M.J. (María José)

Abstract

Acidic fibroblast growth factor (FGF1) and neuregulin-1 (NRG1) are growth factors involved in cardiac development and regeneration. Microparticles (MPs) mediate cytokine sustained release, and can be utilized to overcome issues related to the limited therapeutic protein stability during systemic administration. We sought to examine whether the administration of microparticles (MPs) containing FGF1 and NRG1 could promote cardiac regeneration in a myocardial infarction (MI) rat model. We investigated the possible underlying mechanisms contributing to the beneficial effects of this therapy, especially those linked to endogenous regeneration. FGF1- and NRG1-loaded MPs were prepared using a multiple emulsion solvent evaporation technique. Seventy-three female Sprague-Dawley rats underwent permanent left anterior descending coronary artery occlusion, and MPs were intramyocardially injected in the peri-infarcted zone four days later. Cardiac function, heart tissue remodeling, revascularization, apoptosis, cardiomyocyte proliferation, and stem cell homing were evaluated one week and three months after treatment. MPs were shown to efficiently encapsulate FGF1 and NRG1, releasing the bioactive proteins in a sustained manner. Three months after treatment, a statistically significant improvement in cardiac function was detected in rats treated with growth factor-loaded MPs (FGF1, NRG1, or FGF1/NRG1). The therapy led to inhibition of cardiac remodeling with smaller infarct size, a lower fibrosis degree and induction of tissue revascularization. Cardiomyocyte proliferation and progenitor cell recruitment was detected. Our data support the therapeutic benefit of NRG1 and FGF1 when combined with protein delivery systems for cardiac regeneration. This approach could be scaled up for use in pre-clinical and clinical studies.

Published
2014

31. New strategies for echocardiographic evaluation of left ventricular function in a mouse model of long-term myocardial infarction

Author

Benavides, C. (Carolina), Corbacho, D. (David), Iglesias, O. (Olalla), Pelacho, B. (Beatriz), Albiasu, E. (Edurne), Castaño, S. (Sara), Muñoz-Barrutia, A. (Arrate), Prosper, F. (Felipe), Ortiz-de-Solorzano, C. (Carlos), Benavides, C. (Carolina), Corbacho, D. (David), Iglesias, O. (Olalla), Pelacho, B. (Beatriz), Albiasu, E. (Edurne), Castaño, S. (Sara), Muñoz-Barrutia, A. (Arrate), Prosper, F. (Felipe), and Ortiz-de-Solorzano, C. (Carlos)

Abstract

In summary, we have performed a complete characterization of LV post-infarction remodeling in a DBA/2J mouse model of MI, using parameters adapted to the particular characteristics of the model In the future, this well characterized model will be used in both investigative and pharmacological studies that require accurate quantitative monitoring of cardiac recovery after myocardial infarction.

Published
2014

32. Can bone marrow-derived multipotent adult progenitor cells regenerate infarcted myocardium?

Author

Agbulut, O. (Onnik), Mazo, M. (Manuel), Bressolle, C. (C.), Gutierrez-Perez, M. (María), Azarnoush, K. (K.), Sabbah, L. (Laurent), Niederlander, N. (Nicholas), Abizanda, G. (Gloria), Andreu, E.J. (Enrique José), Pelacho, B. (Beatriz), Gavira, J.J. (Juan José), Perez-Ilzarbe, M. (Maitane), Peyrard, S. (Séverine), Bruneval, P. (P.), Samuel, J.L. (Jane Lyse), Soriano, M. (Mario), Garcia-Verdugo, J.M. (José Manuel), Hagege, A.A. (A. A.), Prosper, F. (Felipe), and Menasche, P. (Philippe)

Published
2006

33. In vivo blockade of pemphigus vulgaris acantholysis by inhibition of intracellular signal transduction cascades

Author

Lopez Moratalla, N., Rubenstein, D.S., Diaz, L.A., Pelacho, B., Sanchez-Carpintero, I., Espana, A., and Lopez-Zabalza, M.J.

Subjects
integumentary system
Abstract

BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune disease characterized by mucocutaneous intraepithelial blisters and pathogenic autoantibodies against desmoglein 3. The mechanism of blister formation in pemphigus has not been defined; however, in vitro data suggest a role for activation of intracellular signalling cascades. OBJECTIVES: To investigate the contribution of these signalling pathways to the mechanism of PV IgG-induced acantholysis in vivo. METHODS: We used the passive transfer mouse model. Mice were injected with IgG fractions of sera from a patient with PV, with or without pretreatment with inhibitors of proteins that mediate intracellular signalling cascades. RESULTS: Inhibitors of tyrosine kinases, phospholipase C, calmodulin and the serine/threonine kinase protein kinase C prevented PV IgG-induced acantholysis in vivo. CONCLUSIONS: These observations strongly support the role of intracellular signalling cascades in the molecular mechanism of PV IgG-induced acantholysis.

Published
2004
Full Text
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34. Poster Session 1: Thursday 8 December 2011, 08:30-12:30 * Location: Poster Area

Author

Vijayan, S., primary, Khanji, M., additional, Ionescu, A., additional, Vijayan, S., additional, Podoleanu, C., additional, Frigy, A., additional, Ugri, A., additional, Varga, A., additional, Podoleanu, D., additional, Incze, A., additional, Carasca, E., additional, Dobreanu, D., additional, Mjolstad, O., additional, Dalen, H., additional, Graven, T., additional, Kleinau, J., additional, Hagen, B., additional, Fu, H., additional, Liu, T., additional, Li, J., additional, Liu, C., additional, Zhou, C., additional, Li, G., additional, Bordese, R., additional, Capriolo, M., additional, Brero, D., additional, Salvetti, I., additional, Cannillo, M., additional, Antolini, M., additional, Grosso Marra, W., additional, Frea, S., additional, Morello, M., additional, Gaita, F., additional, Maffessanti, F., additional, Caiani, E., additional, Muraru, D., additional, Tuveri, F., additional, Dal Bianco, L., additional, Badano, L., additional, Majid, A., additional, Soesanto, A., additional, Ario Suryo Kuncoro, B., additional, Sukmawan, R., additional, Ganesja, M. H., additional, Benedek, T., additional, Chitu, M., additional, Beata, J., additional, Suciu, Z., additional, Kovacs, I., additional, Bucur, O., additional, Benedek, I., additional, Hrynkiewicz-Szymanska, A., additional, Szymanski, F., additional, Karpinski, G., additional, Filipiak, K., additional, Radunovic, Z., additional, Lande Wekre, L., additional, Steine, K., additional, Bech-Hanssen, O., additional, Rundqvist, B., additional, Lindgren, F., additional, Selimovic, N., additional, Jedrzychowska-Baraniak, J., additional, Jozwa, R., additional, Larysz, B., additional, Kasprzak, J., additional, Ripp, T., additional, Mordovin, V., additional, Ripp, E., additional, Ciobanu, A., additional, Dulgheru, R., additional, Dragoi, R., additional, Magda, S., additional, Florescu, M., additional, Mihaila, S., additional, Rimbas, R., additional, Cinteza, M., additional, Vinereanu, D., additional, Benavides-Vallve, C., additional, Pelacho, B., additional, Iglesias, O., additional, Castano, S., additional, Munoz-Barrutia, A., additional, Prosper, F., additional, Ortiz De Solorzano, C., additional, Manouras, A., additional, Sahlen, A., additional, Winter, R., additional, Vardas, P., additional, Brodin, L., additional, Sarvari, S. I., additional, Haugaa, K. H., additional, Zahid, W., additional, Bendz, B., additional, Aaberge, L., additional, Edvardsen, T., additional, Di Bella, G., additional, Pedri, S., additional, Donato, R., additional, Madaffari, A., additional, Zito, C., additional, Stapf, D., additional, Schreckenberg, M., additional, Carerj, S., additional, Yoshikawa, H., additional, Suzuki, M., additional, Kusunose, Y., additional, Hashimoto, G., additional, Otsuka, T., additional, Nakamura, M., additional, Sugi, K., additional, Grapsa, J., additional, Dawson, D., additional, Gin-Sing, W., additional, Howard, L., additional, Gibbs, J., additional, Nihoyannopoulos, P., additional, Smith, B., additional, Coulter, T., additional, Rendon, A., additional, Gorissen, W., additional, Shiran, A., additional, Asmer, I., additional, Adawi, S., additional, Ganaeem, M., additional, Shehadeh, J., additional, Cameli, M., additional, Lisi, M., additional, Righini, F., additional, Maccherini, M., additional, Sani, G., additional, Galderisi, M., additional, Mondillo, S., additional, Kalimanovska-Ostric, D., additional, Nastasovic, T., additional, Jovanovic, I., additional, Milakovic, B., additional, Dostanic, M., additional, Stosic, M., additional, Sasic, I., additional, Sveen, K., additional, Nerdrum, T., additional, Hanssen, K., additional, Dahl-Jorgensen, K., additional, Holte, E., additional, Vegsundvaag, J., additional, Hole, T., additional, Hegbom, K., additional, Wiseth, R., additional, Ikonomidis, I., additional, Lekakis, J., additional, Tritakis, V., additional, Papadakis, I., additional, Kadoglou, N., additional, Tzortzis, S., additional, Trivilou, P., additional, Koukoulis, C., additional, Paraskevaidis, I., additional, Anastasiou-Nana, M., additional, Smedsrud, M. K., additional, Sarvari, S., additional, Gjesdal, O., additional, Beraldo, M., additional, Solda', E., additional, Cucchini, U., additional, Peluso, D., additional, Tuveri, M., additional, Al Mamary, A., additional, Iliceto, S., additional, Dores, H., additional, Abecasis, J., additional, Carvalho, M., additional, Santos, M., additional, Andrade, M., additional, Ribeiras, R., additional, Reis, C., additional, Horta, E., additional, Gouveia, R., additional, Mendes, M., additional, Zaliaduonyte-Peksiene, D., additional, Mizariene, V., additional, Cesnaite, G., additional, Tamuleviciute, E., additional, Jurkevicius, R., additional, Vaskelyte, J., additional, Zaliunas, R., additional, Smarz, K., additional, Zaborska, B., additional, Jaxa-Chamiec, T., additional, Maciejewski, P., additional, Budaj, A., additional, Trifunovic, D., additional, Sobic-Saranovic, D., additional, Stankovic, S., additional, Ostojic, M., additional, Vujisic-Tesic, B., additional, Petrovic, M., additional, Nedeljkovic, I., additional, Banovic, M., additional, Tesic, M., additional, Petrovic, I., additional, Peovska, I., additional, Srbinovska, E., additional, Maksimovic, J., additional, Andova, V., additional, Arnaudova, F., additional, Hristova, E., additional, Otljanska, M., additional, Vavlukis, M., additional, Jovanova, S., additional, Tamborini, G., additional, Fusini, L., additional, Gripari, P., additional, Muratori, M., additional, Pontone, G., additional, Andreini, D., additional, Bertella, E., additional, Ghulam Ali, S., additional, Bartorelli, A., additional, Pepi, M., additional, Cusma-Piccione, M., additional, Salvia, J., additional, Antonini-Canterin, F., additional, Lentini, S., additional, Donato, D., additional, Miceli, M., additional, Oreto, G., additional, Sachner, R., additional, Rubinshtein, R., additional, Shnapp, M., additional, Gaspar, T., additional, Marchese, A., additional, Deste, W., additional, Sanfilippo, A., additional, Aruta, P., additional, Patane, M., additional, Millan, G., additional, Ussia, G., additional, Tamburino, C., additional, Kujacic, V., additional, Obradovic, S., additional, Crkvenac, Z., additional, Bernard, A., additional, Piquemal, M., additional, Muller, G., additional, Arbeille, P., additional, Charbonnier, B., additional, Broyd, C., additional, Davies, J., additional, Mikhail, G., additional, Mayet, J., additional, Francis, D., additional, Rosca, M., additional, Magne, J., additional, Szymanski, C., additional, Popescu, B., additional, Ginghina, C., additional, Pierard, L., additional, Lancellotti, P., additional, Gonzalez-Mansilla, A., additional, Solis, J., additional, Angulo, R., additional, Perez-David, E., additional, Madrid, G., additional, Garcia-Robles, J., additional, Yotti, R., additional, Prieto, R., additional, Bermejo, J., additional, Fernandez-Aviles, F., additional, Ishikawa, Y., additional, Ishida, T., additional, Osaki, T., additional, Matsuyama, M., additional, Yamashita, H., additional, Ozaki, S., additional, Stevanella, M., additional, Votta, E., additional, Veronesi, F., additional, Alamanni, F., additional, Redaelli, A., additional, Park, S. D., additional, Lee, J., additional, Shin, S., additional, Woo, S., additional, Kim, D., additional, Park, K., additional, Kwan, J., additional, Tsang, W., additional, Chandra, S., additional, Weinert, L., additional, Gayat, E., additional, Djelassi, M., additional, Balbach, T., additional, Mor-Avi, V., additional, Lang, R., additional, De Meester, P., additional, Van De Bruaene, A., additional, Delcroix, M., additional, Budts, W., additional, Abid, L., additional, Frikha, Z., additional, Makni, K., additional, Rekik, H., additional, Znazen, A., additional, Mourad, H., additional, Kammoun, S., additional, Sargento, L., additional, Satendra, M., additional, Sousa, C., additional, Lopes, S., additional, Longo, S., additional, Lousada, N., additional, Palma Reis, R., additional, Fouad, D., additional, Shams Eldeen, R., additional, Beladan, C., additional, Calin, A., additional, Voinea, F., additional, Enache, R., additional, Jurcut, R., additional, Coman, I., additional, Ghionea, M., additional, Djordjevic-Dikic, A., additional, Petrovic, O., additional, Boricic, M., additional, Giga, V., additional, Pisciella, L., additional, Lanzillo, C., additional, Minati, M., additional, Caselli, S., additional, Di Roma, M., additional, Fratini, S., additional, Romano, S., additional, Calo', L., additional, Lioy, E., additional, Penco, M., additional, Finocchiaro, G., additional, Pinamonti, B., additional, Merlo, M., additional, Barbati, G., additional, Sinagra, G., additional, Dilenarda, A., additional, Comenale Pinto, S., additional, Ancona, R., additional, Caso, P., additional, Cavallaro, C., additional, Vecchione, F., additional, D'onofrio, A., additional, Fero', M., additional, Calabro', R., additional, Gustafsson, S., additional, Ihse, E., additional, Henein, M., additional, Westermark, P., additional, Suhr, O., additional, Lindqvist, P., additional, Oliva Sandoval, M., additional, Gonzalez Carrillo, M., additional, Garcia Navarro, M., additional, Garcia-Molina Saez, E., additional, Sabater Molina, M., additional, Saura Espin, D., additional, Lacunza Ruiz, J., additional, Gimeno Blanes, J., additional, De La Morena Valenzuela, G., additional, Valdes Chavarri, M., additional, Prinz, C., additional, Faber, L., additional, Horstkotte, D., additional, Hoetz, H., additional, Voigt, J., additional, Gandara, F., additional, Correia, M., additional, Rosario, I., additional, Fonseca, C., additional, Arroja, I., additional, Aleixo, A., additional, Martins, A., additional, Radulescu, L., additional, Dan Radulescu, D., additional, Parv Andreea, P., additional, Duncea Caius, D., additional, Ciuleanu T, C., additional, Mitrea Paulina, M., additional, Cali Quaglia, F., additional, Ribezzo, M., additional, Boffini, M., additional, Rinaldi, M., additional, Maceira Gonzalez, A. M., additional, Cosin-Sales, J., additional, Dalli, E., additional, Diago, J., additional, Aguilar, J., additional, Ruvira, J., additional, Goncalves, S., additional, Gomes, A., additional, Pinto, F., additional, Tsai, W.-C., additional, Liu, Y.-W., additional, Shih, J.-Y., additional, Huang, Y.-Y., additional, Chen, J.-Y., additional, Tsai, L.-M., additional, Chen, J.-H., additional, Ribeiro, S., additional, Doroteia, D., additional, Santos, L., additional, David, C., additional, Vinhas De Sousa, G., additional, Almeida, A., additional, Iwase, M., additional, Itou, Y., additional, Yasukochi, S., additional, Shiino, K., additional, Inuzuka, H., additional, Sugimoto, K., additional, Ozaki, Y., additional, Gieszczyk-Strozik, K., additional, Sikora-Puz, A., additional, Mizia, M., additional, Lasota, B., additional, Chmiel, A., additional, Lis-Swiety, A., additional, Michna, J., additional, Brzezinska-Wcislo, L., additional, Mizia-Stec, K., additional, Gasior, Z., additional, Luijendijk, P., additional, De Bruin-Bon, H., additional, Zwiers, C., additional, Vriend, J., additional, Van Den Brink, R., additional, Mulder, B., additional, Bouma, B., additional, Brigido, S., additional, Gianfagna, P., additional, Proclemer, A., additional, Plicht, B., additional, Kahlert, P., additional, Kaelsch, H., additional, Buck, T., additional, Erbel, R., additional, Konorza, T., additional, Yoon, H., additional, Kim, K., additional, Ahn, Y., additional, Jeong, M., additional, Cho, J., additional, Park, J., additional, Kang, J., additional, Rha, W., additional, Jansen Klomp, W. W., additional, Brandon Bravo Bruinsma, G., additional, Van 'T Hof, A., additional, Spanjersberg, S., additional, Nierich, A., additional, Bombardini, T., additional, Gherardi, S., additional, Picano, E., additional, Ciarka, A., additional, Herbots, L., additional, Eroglu, E., additional, Van Cleemput, J., additional, Droogne, W., additional, Jasityte, R., additional, Meyns, B., additional, D'hooge, J., additional, Vanhaecke, J., additional, Al Barjas, M., additional, Iskreva, R., additional, Morris, R., additional, Davar, J., additional, Zhao, Y., additional, Holmgren, A., additional, Morner, S., additional, Stepanovic, J., additional, Beleslin, B., additional, Nedeljkovic, M., additional, Mazic, S., additional, Stojanov, V., additional, Piatkowski, R., additional, Kochanowski, J., additional, Scislo, P., additional, Grabowski, M., additional, Marchel, M., additional, Roik, M., additional, Kosior, D., additional, Opolski, G., additional, Tomaszewski, A., additional, Kutarski, A., additional, Tomaszewski, M., additional, Eibel, S., additional, Hasheminejad, E., additional, Mukherjee, C., additional, Tschernich, H., additional, Ender, J., additional, Delithanasis, I., additional, Celutkiene, J., additional, Kenny, C., additional, Monaghan, M., additional, Van Den Oord, S., additional, Ten Kate, G., additional, Akkus, Z., additional, Renaud, G., additional, Sijbrands, E., additional, Ten Cate, F., additional, De Jong, N., additional, Bosch, J., additional, Van Der Steen, A., additional, Schinkel, A., additional, Lisowska, A., additional, Knapp, M., additional, Tycinska, A., additional, Sawicki, R., additional, Kralisz, P., additional, Sobkowicz, B., additional, Chang, S.-A., additional, Lee, S.-C., additional, Kim, E.-Y., additional, Hahm, S.-H., additional, Ahn, G.-T., additional, Sohn, M.-K., additional, Park, S.-J., additional, Choi, J.-O., additional, Park, S.-W., additional, Oh, J.-K., additional, Gursoy, M. O., additional, Gokdeniz, T., additional, Astarcioglu, M., additional, Bayram, Z., additional, Cakal, B., additional, Karakoyun, S., additional, Kalcik, M., additional, Kahveci, G., additional, Yildiz, M., additional, Ozkan, M., additional, Skidan, V., additional, Borowski, A., additional, Park, M., additional, Thomas, J., additional, Ranjbar, S., additional, Hassantash, S., additional, Karvandi, M., additional, Foroughi, M., additional, Davidsen, E. S., additional, Cramariuc, D., additional, Bleie, O., additional, Gerdts, E., additional, Matre, K., additional, Cusma' Piccione, M., additional, Bagnato, G., additional, Mohammed, M., additional, Piluso, S., additional, Oreto, L., additional, Bitter, T., additional, Carvalho, S., additional, Canada, M., additional, Santisteban Sanchez De Puerta, M., additional, Mesa Rubio, M. D., additional, Ruiz Ortiz, M., additional, Delgado Ortega, M., additional, Pena Pena, M. L., additional, Puentes Chiachio, M., additional, Suarez De Lezo Cruz-Conde, J., additional, Pan Alvarez-Ossorio, M., additional, Mazuelos Bellido, F., additional, Suarez De Lezo Herreros De Tejada, J., additional, Altekin, E., additional, Yanikoglu, A., additional, Karakas, S., additional, Oncel, C., additional, Akdemir, B., additional, Belgi Yildirim, A., additional, Cilli, A., additional, Yilmaz, H., additional, Lenartowska, L., additional, Furdal, M., additional, Knysz, B., additional, Konieczny, A., additional, Lewczuk, J., additional, Severino, S., additional, Cavallaro, M., additional, Coppola, M., additional, Motoki, H., additional, To, A., additional, Bhargava, M., additional, Wazni, O., additional, Marwick, T., additional, Klein, A., additional, Sinkovskaya, E., additional, Horton, S., additional, Abuhamad, A., additional, Mingo Santos, S., additional, Monivas Palomero, V., additional, Beltran Correas, B., additional, Mitroi, C., additional, Gutierrez Landaluce, C., additional, Garcia Lunar, I., additional, Gonzalez Mirelis, J., additional, Cavero, M., additional, Segovia Cubero, J., additional, Alonso Pulpon, L., additional, Gurel, E., additional, Karaahmet, T., additional, Tigen, K., additional, Kirma, C., additional, Dundar, C., additional, Pala, S., additional, Isiklar, I., additional, Cevik, C., additional, Kilicgedik, A., additional, Basaran, Y., additional, Brambatti, M., additional, Romandini, A., additional, Barbarossa, A., additional, Molini, S., additional, Urbinati, A., additional, Giovagnoli, A., additional, Cipolletta, L., additional, Capucci, A., additional, Park, S., additional, Choi, E., additional, Ahn, C., additional, Hong, S., additional, Kim, M., additional, Lim, D., additional, Shim, W., additional, Xie, J., additional, Fang, F., additional, Zhang, Q., additional, Chan, J., additional, Yip, G., additional, Sanderson, J., additional, Lam, Y., additional, Yan, B., additional, Yu, C., additional, Jorge Perez, P., additional, De La Rosa Hernandez, A., additional, Hernandez Garcia, C., additional, Duque Garcia, A., additional, Barragan Acea, A., additional, Arroyo Ucar, E., additional, Jimenez Rivera, J., additional, Lacalzada Almeida, J., additional, Laynez Cerdena, I., additional, Carminati, C., additional, Capoulade, R., additional, Larose, E., additional, Clavel, M., additional, Dumesnil, J., additional, Arsenault, M., additional, Bedard, E., additional, Mathieu, P., additional, Pibarot, P., additional, Gargani, L., additional, Baldi, G., additional, Forfori, F., additional, Caramella, D., additional, D'errico, L., additional, Abramo, A., additional, Sicari, R., additional, Giunta, F., additional, Lee, W.-N., additional, Larrat, B., additional, Messas, E., additional, Pernot, M., additional, Tanter, M., additional, Velagic, V., additional, Cikes, M., additional, Matasic, R., additional, Skorak, I., additional, Samardzic, J., additional, Puljevic, D., additional, Lovric Bencic, M., additional, Biocina, B., additional, Milicic, D., additional, Roosens, B., additional, Bala, G., additional, Droogmans, S., additional, Hostens, J., additional, Somja, J., additional, Delvenne, E., additional, Schiettecatte, J., additional, Lahoutte, T., additional, Van Camp, G., additional, Cosyns, B., additional, Ghosh, A., additional, Hardy, R., additional, Chaturvedi, N., additional, Deanfield, J., additional, Pellerin, D., additional, Kuh, D., additional, Hughes, A., additional, Malmgren, A., additional, Dencker, M., additional, Stagmo, M., additional, Gudmundsson, P., additional, Seo, Y., additional, Ishizu, T., additional, Aonuma, K., additional, Schuuring, M. J., additional, Vis, J., additional, Van Dijk, A., additional, Van Melle, J., additional, Pieper, P., additional, Vliegen, H., additional, Sieswerda, G., additional, Foukarakis, E., additional, Pitarokilis, A., additional, Kafarakis, P., additional, Kiritsi, A., additional, Klironomos, E., additional, Manousakis, A., additional, Fragiadaki, X., additional, Papadakis, E., additional, and Dermitzakis, A., additional

Published
2011
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38. In vivoblockade of pemphigus vulgaris acantholysis by inhibition of intracellular signal transduction cascades.

Author

Sánchez-Carpintero, I., España, A., Pelacho, B., López Moratalla, N., Rubenstein, D. S., Diaz, L. A., and López-Zabalza, M. J.

Subjects
AUTOIMMUNE diseases, BLISTERS, PEMPHIGUS, AUTOANTIBODIES, LABORATORY mice, IMMUNOGLOBULIN G, SKIN diseases
Abstract

Pemphigus vulgaris (PV) is an autoimmune disease characterized by mucocutaneous intraepithelial blisters and pathogenic autoantibodies against desmoglein 3. The mechanism of blister formation in pemphigus has not been defined; however,in vitrodata suggest a role for activation of intracellular signalling cascades.To investigate the contribution of these signalling pathways to the mechanism of PV IgG-induced acantholysisin vivo.We used the passive transfer mouse model. Mice were injected with IgG fractions of sera from a patient with PV, with or without pretreatment with inhibitors of proteins that mediate intracellular signalling cascades.Inhibitors of tyrosine kinases, phospholipase C, calmodulin and the serine/threonine kinase protein kinase C prevented PV IgG-induced acantholysisin vivo.These observations strongly support the role of intracellular signalling cascades in the molecular mechanism of PV IgG-induced acantholysis. [ABSTRACT FROM AUTHOR]

Published
2004
Full Text
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41. P347 Epicardial-derived interstitial fibroblasts and bone marrow-derived cell interaction determines post-infarction ventricular remodeling.

Author

Perez-Pomares, J M, Ruiz-Villalba, A, Simon, AM, Pogontke, C, Abizanda, G, Castillo, MI, Cano, S, Pelacho, B, Prosper, F, and Segovia, JC

Subjects
MYOCARDIAL infarction, FIBROBLASTS, BONE marrow cells, CELL communication, VENTRICULAR remodeling, HEART failure
Abstract

Myocardial infarction is a prevalent cardiovascular disease. Mechanisms of repair in the post-infarcted heart include a progressive fibrosis that severely affects cardiac performance, eventually leading to cardiac failure. Cardiac fibrosis in the context of ventricular remodeling after infarction depends on fibroblasts of the cardiac interstitium (cardiac fibroblasts), a heterogeneous population of cells which, upon interaction with other interstitial cell types, initiates a massive deposition of extracellular matrix promoting the formation of a characteristic scar. In this work we have studied the cellular components of the cardiac interstitium from the embryo to the adult. Our results show that Wilms tumor supresor (Wt1) positive epicardial-derived mesenchymal cells pioneer the formation of the cardiac interstitium along embryogenesis, followed by the peri- and post-natal incorporation of bone-marrow derived cells. Adult epicardial-derived cells robustly differentiate into cardiac fibroblasts under normal and pathologic conditions, and become the predominant fibroblast type in the post-infarction scar. Furthermore, epicardial-derived cardiac fibroblasts are shown to display stromal properties respect to bone marrow-derived cells, critically contributing to the homing and persistence of circulating cells after infarction. [ABSTRACT FROM PUBLISHER]

Published
2014
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42. Stem Cells and Cardiac Disease: Where are We Going?

Author

Pelacho, B. (Beatriz)

Subjects
Materias Investigacion::Ciencias de la Salud::Oncología
Abstract

During the last 10 years we have witnessed the development of a new field in research termed Stem Cell Therapy. Classically, it was considered that cells had a limited division and differentiation ability; however, this dogma was challenged when new exciting results about cell multi/pluripotency were presented to the scientific community. It was found that cells from one adult tissue source were able to originate cells of a very different type. The possibility of transplanting these cells into damaged organs with the aim of substituting sick or dead tissue, triggered many studies to understand the plasticity of the stem cells and their potential in pathological situations. Nowadays, much more is understood about stem cells, although of course, many questions, especially about their mechanism of action, still need to be answered. Their benefit after transplantation has been shown experimentally and even clinically in some cases; however, the degree of stem cell contribution through their own differentiation into the transplanted tissue, has turned out to be generally low, and increasing evidence indicates that a trophic effect must play an important role in such a benefit. A better understanding of the paracrine mechanisms involved could be of great relevance in order to develop new therapies focused on stimulating endogenous cells. On the other hand, more sophisticated methods for cell transplantation combined with bio-engineering techniques have been devised in cardiac disease models. In this review we will try to provide a critical overview of the stem cell studies performed until now and to discuss some of the questions raised about the mechanisms that are involved in their putative reparative effect in cardiovascular diseases, and their origin.

Published
2008

43. Plasticity and cardiovascular applications of multipotent adult progenitor cells

Author

Pelacho, B. (Beatriz)

Subjects
Cardiovascular regeneration, Ischemia, multipotent adult progenitor cells (MAPCs)
Abstract

Cardiovascular disease is the leading cause of death worldwide, which has encouraged the search for new therapies that enable the treatment of patients in palliative and curative ways. In the past decade, the potential benefit of transplantation of cells that are able to substitute for the injured tissue has been studied with several cell populations, such as stem cells. Some of these cell populations, such as myoblasts and bone marrow cells, are already being used in clinical trials. The laboratory of CM Verfaillie has studied primitive progenitors, termed multipotent adult progenitor cells, which can be isolated from adult bone marrow. These cells can differentiate in vitro at the single-cell level into functional cells that belong to the three germ layers and contribute to most, if not all, somatic cell types after blastocyst injection. This remarkably broad differentiation potential makes this particular cell population a candidate for transplantation in tissues in need of regeneration. Here, we focus on the regenerative capacity of multipotent adult progenitor cells in several ischemic mouse models, such as acute and chronic myocardial infarction and limb ischemia.

Published
2007

44. Pemphigus vulgaris autoantibodies induce apoptosis in HaCaT keratinocytes

Author

Pelacho, B. (Beatriz)

Subjects
Autoantibodies/immunology/pharmacology, Cytoplasm/metabolism, Keratinocytes/cytology/immunology/metabolism/ultrastructure
Abstract

Pemphigus vulgaris (PV) is an autoimmune disease characterized by binding of IgG autoantibodies to epidermal keratinocyte desmosomes. IgG autoantibodies obtained from a patient with mucocutaneous PV reacted with plakoglobin (Plkg) in addition to desmoglein-3 (Dsg3) and Dsg1. Immunofluorescence analysis confirmed that IgG autoantibodies, unlike antibodies from a healthy volunteer, caused disruption of cell-cell contacts in HaCaT keratinocytes. Moreover, apoptosis was enhanced in cells treated with autoantibodies compared to those treated with normal antibodies. The apoptotic process induced by IgG autoantibodies was characterized by caspase-3 activation, Bcl-2 depletion and Bax expression. The present report demonstrates that PV IgG autoantibodies promote apoptosis in HaCaT keratinocytes.

Published
2004

47. Fibroblast Diversity and Epigenetic Regulation in Cardiac Fibrosis.

Author

Aguado-Alvaro LP, Garitano N, and Pelacho B

Subjects
Humans, Animals, Myocardium metabolism, Myocardium pathology, DNA Methylation, Epigenesis, Genetic, Fibrosis, Fibroblasts metabolism, Fibroblasts pathology
Abstract

Cardiac fibrosis, a process characterized by excessive extracellular matrix (ECM) deposition, is a common pathological consequence of many cardiovascular diseases (CVDs) normally resulting in organ failure and death. Cardiac fibroblasts (CFs) play an essential role in deleterious cardiac remodeling and dysfunction. In response to injury, quiescent CFs become activated and adopt a collagen-secreting phenotype highly contributing to cardiac fibrosis. In recent years, studies have been focused on the exploration of molecular and cellular mechanisms implicated in the activation process of CFs, which allow the development of novel therapeutic approaches for the treatment of cardiac fibrosis. Transcriptomic analyses using single-cell RNA sequencing (RNA-seq) have helped to elucidate the high cellular diversity and complex intercellular communication networks that CFs establish in the mammalian heart. Furthermore, a significant body of work supports the critical role of epigenetic regulation on the expression of genes involved in the pathogenesis of cardiac fibrosis. The study of epigenetic mechanisms, including DNA methylation, histone modification, and chromatin remodeling, has provided more insights into CF activation and fibrotic processes. Targeting epigenetic regulators, especially DNA methyltransferases (DNMT), histone acetylases (HAT), or histone deacetylases (HDAC), has emerged as a promising approach for the development of novel anti-fibrotic therapies. This review focuses on recent transcriptomic advances regarding CF diversity and molecular and epigenetic mechanisms that modulate the activation process of CFs and their possible clinical applications for the treatment of cardiac fibrosis.

Published
2024
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48. Generation of heart and vascular system in rodents by blastocyst complementation.

Author

Coppiello G, Barlabé P, Moya-Jódar M, Abizanda G, Pogontke C, Barreda C, Iglesias E, Linares J, Arellano-Viera E, Larequi E, San Martín-Úriz P, Carvajal-Vergara X, Pelacho B, Mazo MM, Pérez-Pomares JM, Ruiz-Villalba A, Ullate-Agote A, Prósper F, and Aranguren XL

Subjects
Animals, Mice, Rats, Rodentia, Endothelial Cells, Blastocyst, Myocytes, Cardiac, Pluripotent Stem Cells
Abstract

Generating organs from stem cells through blastocyst complementation is a promising approach to meet the clinical need for transplants. In order to generate rejection-free organs, complementation of both parenchymal and vascular cells must be achieved, as endothelial cells play a key role in graft rejection. Here, we used a lineage-specific cell ablation system to produce mouse embryos unable to form both the cardiac and vascular systems. By mouse intraspecies blastocyst complementation, we rescued heart and vascular system development separately and in combination, obtaining complemented hearts with cardiomyocytes and endothelial cells of exogenous origin. Complemented chimeras were viable and reached adult stage, showing normal cardiac function and no signs of histopathological defects in the heart. Furthermore, we implemented the cell ablation system for rat-to-mouse blastocyst complementation, obtaining xenogeneic hearts whose cardiomyocytes were completely of rat origin. These results represent an advance in the experimentation towards the in vivo generation of transplantable organs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2023
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49. Compartmentalized drug localization studies in extracellular vesicles for anticancer therapy.

Author

Pitchaimani A, Ferreira M, Palange A, Pannuzzo M, De Mei C, Spano R, Marotta R, Pelacho B, Prosper F, and Decuzzi P

Abstract

In the development of therapeutic extracellular vesicles (EVs), drug encapsulation efficiencies are significantly lower when compared with synthetic nanomedicines. This is due to the hierarchical structure of the EV membrane and the physicochemical properties of the candidate drug (molecular weight, hydrophilicity, lipophilicity, and so on). As a proof of concept, here we demonstrated the importance of drug compartmentalization in EVs as an additional parameter affecting the therapeutic potential of drug-loaded EVs. In human adipose mesenchymal stem cell (hADSC) derived EVs, we performed a comparative drug loading analysis using two formulations of the same chemotherapeutic molecule - free doxorubicin (DOX) and 1,2-distearoyl- sn-glycero -3-phosphoethanolamine (DSPE) lipid-conjugated doxorubicin (L-DOX) - to enhance the intracellular uptake and therapeutic efficacy. By nano surface energy transfer (NSET) and molecular simulation techniques, along with cryo-TEM analysis, we confirmed the differential compartmentalization of these two molecules in hADSC EVs. L-DOX was preferentially adsorbed onto the surface of the EV, due to its higher lipophilicity, whereas free DOX was mostly encapsulated within the EV core. Also, the L-DOX loaded EV (LDOX@EV) returned an almost three-fold higher DOX content as compared to the free DOX loaded EV (DOX@EV), for a given input mass of drug. Based on the cellular investigations, L-DOX@EV showed higher cell internalization than DOX@EV. Also, in comparison with free L-DOX, the magnitude of therapeutic potential enhancement displayed by the surface compartmentalized L-DOX@EV is highly promising and can be exploited to overcome the sensitivity of many potential drugs, which are impermeable in nature. Overall, this study illustrates the significance of drug compartmentalization in EVs and how this could affect intracellular delivery, loading efficiency, and therapeutic effect. This will further lay the foundation for the future systematic investigation of EV-based biotherapeutic delivery platforms for personalized medicine., Competing Interests: All authors declared no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Published
2023
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50. Cardiac Progenitor Cell Exosomal miR-935 Protects against Oxidative Stress.

Author

Aguilar S, García-Olloqui P, Amigo-Morán L, Torán JL, López JA, Albericio G, Abizanda G, Herrero D, Vales Á, Rodríguez-Diaz S, Higuera M, García-Martín R, Vázquez J, Mora C, González-Aseguinolaza G, Prosper F, Pelacho B, and Bernad A

Abstract

Oxidative stress-induced myocardial apoptosis and necrosis are critically involved in ischemic infarction, and several sources of extracellular vesicles appear to be enriched in therapeutic activities. The central objective was to identify and validate the differential exosome miRNA repertoire in human cardiac progenitor cells (CPC). CPC exosomes were first analyzed by LC-MS/MS and compared by RNAseq with exomes of human mesenchymal stromal cells and human fibroblasts to define their differential exosome miRNA repertoire (exo-miR SEL ). Proteomics demonstrated a highly significant representation of cardiovascular development functions and angiogenesis in CPC exosomes, and RNAseq analysis yielded about 350 different miRNAs; among the exo-miR SEL population, miR-935 was confirmed as the miRNA most significantly up-regulated; interestingly, miR-935 was also found to be preferentially expressed in mouse primary cardiac Bmi1 +high CPC, a population highly enriched in progenitors. Furthermore, it was found that transfection of an miR-935 antagomiR combined with oxidative stress treatment provoked a significant increment both in apoptotic and necrotic populations, whereas transfection of a miR-935 mimic did not modify the response. Conclusion. miR-935 is a highly differentially expressed miRNA in exo-miR SEL , and its expression reduction promotes oxidative stress-associated apoptosis. MiR-935, together with other exosomal miRNA members, could counteract oxidative stress-related apoptosis, at least in CPC surroundings.

Published
2023
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