Andreu, E.J. (Enrique José)

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    Epigenetic Signatures Associated with Different Levels of Differentiation Potential in Human Stem Cells
    (Public Library of Science, 2009) Cigudosa, J.C. (Juan Cruz); Roman-Gomez, J. (José); Ballestar, E. (E.); Aranda, P. (P.); Prieto, I. (Inés); Andreu, E.J. (Enrique José); Siebert, R. (Reiner); Esteller, M. (Manel); Prosper-Cardoso, F. (Felipe); Aguirre-Ena, X. (Xabier); Martin-Subero, J.I. (Jose Ignacio)
    The therapeutic use of multipotent stem cells depends on their differentiation potential, which has been shown to be variable for different populations. These differences are likely to be the result of key changes in their epigenetic profiles.
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    Mesenchymal stem cells expanded in vitro with human serum for the treatment of acute and chronic graft-versus-host disease: results of a phase I/II clinical trial
    (Ferrata Storti Foundation, 2011-07) Cañizo, C. (C.) del; Martinez, C. (Carmen); Perez-Simon, J.A. (José Antonio); Diez-Campelo, M. (M.); Rifon, J. J. (Jose J.); Andreu, E.J. (Enrique José); Valcarcel, D. (David); Muntion, S. (Sandra); Lopez-Villar, O. (Olga); Sanchez-Guijo, F.M. (Fermín M.)
    This trial evaluated the feasibility and efficacy of the infusion of mesenchymal stem cells expanded using human serum for the treatment of refractory acute or chronic graft-versus-host disease. Twenty-eight expansions were started. In 22, a minimum of more than 1 x 10⁶ mesenchymal stem cells/kg were obtained after a median of 26 days; this threshold was not obtained in the remaining cases. Ten patients received cells for the treatment of refractory or relapsed acute graft-versus-host disease and 8 for chronic disease. One patient treated for acute graft-versus-host disease obtained a complete response, 6 had a partial response and 3 did not respond. One of the chronic patients achieved complete remision, 3 a partial response, and 4 did not respond. The current study supports the use of this approach in less heavily treated patients for both acute and chronic graft-versus-host disease. The trial has been registered at ClinicalTrials.gov: identifier NCT00447460.
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    Comparison of ex vivo expansion culture conditions of mesenchymal stem cells for human cell therapy
    (Wiley-Blackwell, 2009) Cañizo, C. (C.) del; Perez-Simon, J.A. (José Antonio); Diez-Campelo, M. (M.); Aranda, P. (P.); Andreu, E.J. (Enrique José); Perez-Ilzarbe, M. (Maitane); Lopez, T. (Tania); Tabera, S. (Soraya); Prosper-Cardoso, F. (Felipe); Merino, J. (Juana); Moreno, C. (Cristina)
    Mesenchymal stem cells (MSCs) are multipotent stem cells. Based on their properties, several clinical trials have been designed to explore their potential therapeutic effect. Fetal calf serum (FCS, commonly used for in vitro expansion) is an undesirable source of xenogeneic antigens and bears the risk of transmitting contaminations. As an alternative for FCS, platelet lysate (PL) and both autologous and allogeneic human serum have been proposed. The aim of this study is to compare the culture of bone marrow (BM)- derived MSCs in the presence of different serum supplements to determine the effect on cell growth, differentiation potential, and immunologic function.
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    Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: long-term follow up of a multicenter randomized controlled clinical trial (phase I/II)
    (BMC, 2018) Cañizo, C. (C.) del; Granero-Moltó, F. (Froilán); Bondia, J.M. (J. M.); Aquerreta, D. (Dámaso); López-Elío, S. (Silvia); Villarón, E. (Eva); Mora, G. (Gonzalo); Andreu, E.J. (Enrique José); Blanco, J.F. (J. F.); Valentí-Nin, J.R. (Juan Ramón); Prosper-Cardoso, F. (Felipe); Nuñez-Cordoba, J.M. (Jorge M.); Lamo-Espinosa, J.M. (J. M.); Sanchez-Guijo, F.M. (Fermín M.); Valentí-Azcárate, A. (Andrés)
    Background: Mesenchymal stromal cells (MSCs) are a promising option to treat knee osteoarthritis (OA). Their safety and usefulness have been reported in several short-term clinical trials but less information is available on the longterm efects of MSC in patients with osteoarthritis. We have evaluated patients included in our previous randomized clinical trial (CMM-ART, NCT02123368) to determine their long-term clinical efect. Materials: A phase I/II multicenter randomized clinical trial with active control was conducted between 2012 and 2014. Thirty patients diagnosed with knee OA were randomly assigned to Control group, intraarticularly administered hyaluronic acid alone, or to two treatment groups, hyaluronic acid together with 10×106 or 100×106 cultured autol‑ ogous bone marrow-derived MSCs (BM-MSCs), and followed up for 12 months. After a follow up of 4 years adverse efects and clinical evolution, assessed using VAS and WOMAC scorings are reported. Results: No adverse efects were reported after BM-MSCs administration or during the follow-up. BM-MSCs-adminis‑ tered patients improved according to VAS, median value (IQR) for Control, Low-dose and High-dose groups changed from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 7 (6, 7), 2 (2, 5) and 3 (3, 4), respectively at the end of follow up (Low-dose vs Control group, p=0.01; High-dose vs Control group, p=0.004). Patients receiving BM-MSCs also improved clinically accord‑ ing to WOMAC. Control group showed an increase median value of 4 points (−11;10) while Low-dose and Highdose groups exhibited values of −18 (−28;−9) and −10 (−21;−3) points, respectively (Low-dose vs Control group p=0.043). No clinical diferences between the BM-MSCs receiving groups were found. Conclusions: Single intraarticular injection of in vitro expanded autologous BM-MSCs is a safe and feasible proce‑ dure that results in long-term clinical and functional improvement of knee OA.
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    Resistance to Imatinib Mesylate-induced apoptosis in acute lymphoblastic leukemia is associated with PTEN down-regulation due to promoter hypermethylation
    (Elsevier, 2008) Cordeu, L. (Lucía); Jimenez-Velasco, A. (A.); Montiel-Duarte, C. (Cristina); Roman-Gomez, J. (José); San-Jose-Eneriz, E. (Edurne); Heiniger, A. (A.); Garate, L. (Leire); Andreu, E.J. (Enrique José); Prosper-Cardoso, F. (Felipe); Torres, A. (Antonio); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier)
    The aim of our study was to determine the potential mechanism(s) implicated in Imatinib resistance in patients with Ph+ ALL. Resistance of Ph+ ALL cells to Imatinib-induced apoptosis was associated with lack of inhibition of Akt phosphorylation. Addition of the PI3K inhibitor LY294002 to Imatinib significantly increased apoptosis of Ph+ ALL cells. Interestingly, expression of PTEN was reduced in Ph+ ALL cells whichwas due to PTEN promoter hypermethylation. Treatment of Ph+ ALLcells with 5-Aza-2 -deoxycytidinewas associated with an increased expression of PTEN and an increase in cell apoptosis. These results suggest that Imatinib resistance in patients with ALL may be dependent at least in part to PTEN down-regulation due to the abnormal promoter hypermethylation and support the potential role of de-methylating agents for the treatment of patients with Ph+ ALL.
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    Mechanical properties of cross-linked collagen meshes after human adipose derived stromal cells seeding
    (Wiley-Blackwell, 2010) Ochoa, I. (Ignacio); Doblare, M. (M.); Alcaine, C. (C.); Andreu, E.J. (Enrique José); Perez-Ilzarbe, M. (Maitane); Lopez, T. (Tania); Peña, E. (Estefanía); Prosper-Cardoso, F. (Felipe); Robles-Garcia, J.E. (José Enrique)
    The main goal of this study was to evaluate the potential of collagen meshes derived from porcine dermis as scaffolds for repairing pelvic organ prolapses. Mechanical properties of collagen meshes with different cross-linking percentages before and after Adipose Derived Stromal Cells (ADSC) seeding were studied as well as the cell-scaffold interaction. Uniaxial tensile tests of the collagen meshes with three different cross-linking percentages (full-, partial-, and noncross-linked) were carried out along orthogonal directions. Their mechanical properties were studied with the same tests before and after seeding with human derived adipose stem cells (ADSC) after 1 and 7 days. Histological analyses were performed to determine adhesion and proliferation of ADSC. Significant differences in mechanical properties of the unseeded meshes were observed between each orthogonal direction independently of the cross-linking percentage. A better cell adhesion rate was observed in the cross-linked meshes. An increase in the mechanical properties after cell seeding was observed with a direct relation with the degree of cross-linking. All meshes analyzed showed a marked anisotropy that should be taken into account during the surgical procedure. The cross-linking treatment increased cell adhesion and the mechanical properties of the collagen meshes after seeding. These results suggest that the mechanical properties of this type of collagen mesh could be useful as scaffolds for repair of pelvic organ prolapse
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    Cost-effective, safe, and personalized cell therapy for critical limb ischemia in type 2 diabetes mellitus
    (Frontiers Media SA, 2019) Bedoya, F.J. (Francisco J.); Hmadcha, A. (Abdelkrim); Aguilera, Y. (Yolanda); Tejedo, J.R. (Juan R.); Juan, V. (Verónica); Soria-Juan, B. (Bárbara); Soria, V. (Vernat); Llanos, L. (Lucía); Andreu, E.J. (Enrique José); Sackstein, R. (Robert); Castellanos, G. (Gregorio); Garcia-Olmos, D. (Damián); Cuesta, A. (Antonio) de la; Miralles, M. (Manuel); Lozano, F.S. (Francisco S.); Capilla-González, V. (Vivian); Martín, F. (Franz); Prosper-Cardoso, F. (Felipe); Ruiz-Salmerón, R. (Rafael); García-Arranz, M. (Mariano); Moraleda, J. M. (José M.); Grochowicz, L. (Lukasz); Escacena, N. (Natalia); Sanchez-Guijo, F.M. (Fermín M.); Río-Solá, L. (Lourdes) del
    Cell therapy is a progressively growing field that is rapidly moving from preclinical model development to clinical application. Outcomes obtained from clinical trials reveal the therapeutic potential of stem cell-based therapy to deal with unmet medical treatment needs for several disorders with no therapeutic options. Among adult stem cells, mesenchymal stem cells (MSCs) are the leading cell type used in advanced therapies for the treatment of autoimmune, inflammatory and vascular diseases. To date, the safety and feasibility of autologous MSC-based therapy has been established; however, their indiscriminate use has resulted in mixed outcomes in preclinical and clinical studies. While MSCs derived from diverse tissues share common properties depending on the type of clinical application, they markedly differ within clinical trials in terms of efficacy, resulting in many unanswered questions regarding the application of MSCs. Additionally, our experience in clinical trials related to critical limb ischemia pathology (CLI) shows that the therapeutic efficacy of these cells in different animal models has only been partially reproduced in humans through clinical trials. Therefore, it is crucial to develop new research to identify pitfalls, to optimize procedures and to clarify the repair mechanisms used by these cells, as well as to be able to offer a next generation of stem cell that can be routinely used in a cost-effective and safe manner in stem cell-based therapies targeting CLI.
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    Phase II multicenter randomized controlled clinical trial on the efficacy of intra-articular injection of autologous bone marrow mesenchymal stem cells with platelet rich plasma for the treatment of knee osteoarthritis
    (Springer Nature, 2020) Granero-Moltó, F. (Froilán); Dámaso-Aquerreta, J. (Jesús); Pompei-Fernández, O. (Orlando); Mora, G. (Gonzalo); Moreno, V. (V.); Andreu, E.J. (Enrique José); Blanco, J.F. (J. F.); Sánchez, M. (Mikel); Vitoria-Sola, M. (María); Cañizo, M.C. (María del Consuelo) del; Valentí-Nin, J.R. (Juan Ramón); Crespo-Cullel, Í. (Íñigo); Prosper-Cardoso, F. (Felipe); Delgado-San-Vicente, D. (Diego); Nuñez-Cordoba, J.M. (Jorge M.); Lamo-Espinosa, J.M. (J. M.); Sanchez-Guijo, F.M. (Fermín M.); Valentí-Azcárate, A. (Andrés)
    Background: Mesenchymal stromal cells are a safe and promising option to treat knee osteoarthritis as previously demonstrated in different clinical trials. However, their efficacy, optimal dose and addition of adjuvants must be determined. Here, we evaluated the clinical effects of a dose of 100 × 106 bone marrow mesenchymal stromal cells (BM-MSCs) in combination with Platelet Rich Plasma (PRGF®) as adjuvant in a randomized clinical trial. Methods: A phase II, multicenter, randomized clinical trial with active control was conducted. Sixty patients diagnosed with knee OA were randomly assigned to 3 weekly doses of PRGF® or intraarticular administration of 100 × 106 cultured autologous BM-MSCs plus PRGF®. Patients were followed up for 12 months, and pain and function were assessed using VAS and WOMAC and by measuring the knee range of motion range. X-ray and magnetic resonance imaging analyses were performed to analyze joint damage. Results: No adverse effects were reported after BM-MSC administration or during follow-up. According to VAS, the mean value (SD) for PRGF® and BM-MSC with PRGF® went from 5 (1.8) to 4.5 (2.2) (p = 0.389) and from 5.3 (1.9) to 3.5 (2.5) (p = 0.01), respectively at 12 months. In WOMAC, the mean (SD) baseline and 12-month overall WOMAC scores in patients treated with PRGF® was 31.9 (16.2) and 22.3 (15.8) respectively (p = 0.002) while that for patients treated with BM-MSC plus PRGF® was 33.4 (18.7) and 23.0 (16.6) (p = 0.053). Although statistical significances between groups have been not detected, only patients being treated with BM-MSC plus PRGF® could be considered as a OA treatment responders following OARSI criteria. X-ray and MRI (WORMS protocol) revealed no changes in knee joint space width or joint damage. Conclusions: Treatment with BM-MSC associated with PRGF® was shown to be a viable therapeutic option for osteoarthritis of the knee, with clinical improvement at the end of follow-up. Further phase III clinical trials would be necessary to confirm the efficacy. Trial registration Clinical Trials.gov identifier NCT02365142. Nº EudraCT: 2011-006036-23.
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    Lack of Bcr-Abl point mutations in chronic myeloid leukemia patients in chronic phase before imatinib treatment is not predictive of response
    (Ferrata Storti Foundation, 2003) Montiel-Duarte, C. (Cristina); Andreu, E.J. (Enrique José); Fernandez-Luna, J.L. (J.L.); Larrayoz, M.J. (María J.); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores); Aguirre-Ena, X. (Xabier); Fontalba, A. (A.)
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    RUNX/AML and C/EBP factors regulate CD11a integrin expression in myeloid cells through overlapping regulatory elements
    (American Society of Hematology, 2003) Drabkin, H. (H.); Erickson, P. (P.); Jensen, U.B. (U. B.); Puig-Kröger, A. (Amaya); Sanchez-Elsner, T. (Tilman); Groner, Y. (Y.); Andreu, E.J. (Enrique José); Ruiz, N. (Natividad); Gil, J. (Juana); Prosper-Cardoso, F. (Felipe); Corbi, A.L. (Angel L.)
    The CD11a/CD18 (leukocyte functionassociated antigen 1 [LFA-1]) integrin mediates critical leukocyte adhesive interactions during immune and inflammatory responses. The CD11a promoter directs CD11a/CD18 integrin expression, and its activity in lymphoid cells depends on a functional RUNX1/AML-1–binding site (AML-110) within the MS7 sequence. We now report that MS7 contains a C/EBPbinding site (C/EBP-100), which overlaps with AML-110 and is bound by C/EBP factors in myeloid cells. C/EBP and RUNX/ AML factors compete for binding to their respective cognate elements and bind to the CD11a promoter MS7 sequence in a cell lineage- and differentiation-dependent manner. In myeloid cells MS7 is primarily recognized by C/EBP factors in proliferating cells whereas RUNX/AMLfactors (especially RUNX3/AML-2) bind to MS7 in differentiated cells. RUNX3/AML-2 binding to the CD11a promoter correlates with increased RUNX3/AML-2 protein levels and enhanced CD11a/CD18 cell surface expression. The relevance of the AML-110 element is underscored by the ability of AML-1/ETO to inhibit CD11a promoter activity, thus explaining the low CD11a/CD18 expression in t(8;21)–containing myeloid leukemia cells. Therefore, the expression of the CD11a/CD18 integrin in myeloid cells is determined through the differential occupancy of the CD11a proximal promoter by transcription factors implicated in the pathogenesis of myeloid leukemia.