Cáceres, Spain
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Sanchez-Correa B.,University of Extremadura | Campos C.,University of Cordoba, Spain | Pera A.,University of Cordoba, Spain | Bergua J.M.,Hospital San Pedro Of Alcantara | And 8 more authors.
Cancer Immunology, Immunotherapy | Year: 2015

Several age-associated changes in natural killer (NK) cell phenotype have been reported that contribute to the defective NK cell response observed in elderly patients. A remodelling of the NK cell compartment occurs in the elderly with a reduction in the output of immature CD56bright cells and an accumulation of highly differentiated CD56dim NK cells. Acute myeloid leukaemia (AML) is generally a disease of older adults. NK cells in AML patients show diminished expression of several activating receptors that contribute to impaired NK cell function and, in consequence, to AML blast escape from NK cell immunosurveillance. In AML patients, phenotypic changes in NK cells have been correlated with disease progression and survival. NK cell-based immunotherapy has emerged as a possibility for the treatment of AML patients. The understanding of age-associated alterations in NK cells is therefore necessary to define adequate therapeutic strategies in older AML patients. © 2015 Springer-Verlag Berlin Heidelberg


Blazquez R.,Stem Cell Therapy Unit | Sanchez-Margallo F.M.,Stem Cell Therapy Unit | de la Rosa O.,TiGenix | Dalemans W.,TiGenix | And 3 more authors.
Frontiers in Immunology | Year: 2014

In the recent years, it has been demonstrated that the biological activity of mesenchymal stem cells (MSCs) is mediated through the release of paracrine factors. Many of these factors are released into exosomes, which are small membranous vesicles that participate in cell-cell communication. Exosomes from MSCs are thought to have similar functions to MSCs such as repairing and regeneration of damaged tissue, but little is known about the immunomodulatory effect of these vesicles. Based on an extensive bibliography where the immunomodulatory capacity of MSCs has been demonstrated, here we hypothesized that released exosomes from MSCs may have an immunomodulatory role on the differentiation, activation and function of different lymphocyte subsets. According to this hypothesis, in vitro experiments were performed to characterize the immunomodulatory effect of human adipose MSCs derived exosomes (exo-hASCs) on in vitro stimulated T cells. The phenotypic characterization of cytotoxic and helper T cells (activation and differentiation markers) together with functional assays (proliferation and IFN-γ production) demonstrated that exo-hASCs exerted an inhibitory effect in the differentiation and activation of T cells as well as a reduced T cell proliferation and IFN-γ release on in vitro stimulated cells. In summary, here we demonstrate that MSCs-derived exosomes are a cell-derived product that could be considered as a therapeutic agent for the treatment of inflammation-related diseases. © 2014 Blazquez, Sanchez-Margallo, de la Rosa, Dalemans, Álvarez, Tarazona and Casado.


Casado J.G.,Stem Cell Therapy Unit | Tarazona R.,University of Extremadura | Sanchez-Margallo F.M.,Stem Cell Therapy Unit
Stem Cell Reviews and Reports | Year: 2013

Several clinical trials are currently evaluating the safety and efficacy of mesenchymal stem cells (MSCs) in different diseases. The MSCs are guided by inflammatory mediators and specific interactions with immune cells occur, especially between MSCs and the cells of the innate immune system. At the present many of these interactions remain to be determined. This review summarizes the current knowledge in relation to the susceptibility of MSCs to NK cell mediated lysis as well as the immunomodulatory activity of MSCs and its control over NK cell function. Here we hypothesize that the inflammatory context will regulate the outcome of NK-MSC interactions. © 2013 Springer Science+Business Media New York.


Casado J.G.,Stem Cell Therapy Unit | Blazquez R.,Stem Cell Therapy Unit | Jorge I.,Stem Cell Therapy Unit | Alvarez V.,Stem Cell Therapy Unit | And 4 more authors.
Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society | Year: 2014

Sutures are commonly used for surgical procedures and new sutures are being developed to improve wound healing. In the past decade, it has been extensively shown that mesenchymal stem cells (MSCs) have a wound healing potential. To benefit the overall wound healing process, we aimed to analyze the usage of pretreated sutures for improving the implantation of MSCs in the tissues. Our results firstly showed that suture pretreatments with gelatin, poly-L-lysine, and NaOH improved the adhesive strength of MSCs to sutures. These cells remained surrounding the sutured tissue and no significant phenotypic changes were found in those cells cultured onto pretreated sutures. In vivo experiments showed that the implantation of MSCs by suturing increases the collagen content in the sutured tissue. Moreover, proteomics analysis of secreted proteins showed that collagen alpha-1(I) chain was the most abundant collagen found. To our knowledge, this is the first report that aimed to improve the implantation of MSCs in tissue by suture pretreatments. Moreover, in vivo experiments suggest that MSC-coated sutures may enhance wound healing and tissue remodeling through the release of different collagen types being applicable for those patients that tend to have difficulty healing. © 2014 by the Wound Healing Society.


Sanchez-Correa B.,University of Extremadura | Bergua J.M.,Hospital San Pedro Of Alcantara | Campos C.,University of Cordoba, Spain | Gayoso I.,University of Cordoba, Spain | And 7 more authors.
Cytokine | Year: 2013

Background: Several evidences support the existence of cytokine deregulation in acute myeloid leukemia (AML) patients that may be associated with pathogenesis, disease progression and patient survival. Methods: In the present study, we analyzed plasma levels of pro- and anti-inflammatory cytokines in AML patients and age-matched healthy donors. TNF-α, IL-6, IL-1β, IL-2, IFN-γ, IL-17A, IL-12p70, IL-8, IL-10, IL-4 and IL-5 were analyzed using fluorescent bead-based technology and TGF-β by ELISA technique. Because age-associated differences in cytokine profiles have been described, patients and healthy individuals were divided into two age groups: up to 65. years and over 65. years. Results: Our results showed that plasma TNF-α, IL-6 and IL-10 levels were higher in AML patients from both groups of age. IL-8 was increased in AML patients less than 65. years while the plasma concentrations of IL-4, IL-5 and IL-12p70 were significantly higher only in elderly AML patients compared with aged-matched healthy controls. Moreover, plasma levels of IL-6 and IL-10 were associated with patient survival and event-free survival. Conclusions: An aberrant production of the pro-inflammatory cytokines IL-6 and TNF-α and the anti-inflammatory cytokine IL-10 is observed in AML patients. Low levels of IL-6 and high levels of IL-10 represent favorable prognostic factors for survival in AML patients. These results support the idea that cytokine deregulation may be useful as a marker for predicting clinical evolution in AML patients. © 2013 Elsevier Ltd.


Blazquez R.,Stem Cell Therapy Unit | Sanchez-Margallo F.M.,Stem Cell Therapy Unit | Alvarez V.,Stem Cell Therapy Unit | Uson A.,Stem Cell Therapy Unit | Casado J.G.,Stem Cell Therapy Unit
Acta Biomaterialia | Year: 2016

Surgical meshes are widely used in clinics to reinforce soft tissue's defects, and to give support to prolapsed organs. However, the implantation of surgical meshes is commonly related with an inflammatory response being difficult to eradicate without removing the mesh. Here we hypothesize that the combined use of surgical meshes and mesenchymal stem cells (MSCs) could be a useful tool to reduce the inflammatory reaction secondary to mesh implantation. In vitro determinations of viability, metabolic activity and immunomodulation assays were performed on MSCs-coated meshes. Magnetic resonance imaging, evaluation by laparoscopic optical system and histology were performed for safety assessment. Finally, flow cytometry and qRT-PCR were used to elucidate the mechanism of action of MSCs-coated meshes. Our results demonstrate the feasibility to obtain MSCs-coated surgical meshes and their cryopreservability to be used as an 'off the shelf' product. These biological meshes fulfill the safety aspects as non-adverse effects were observed when compared to controls. Moreover, both in vitro and in vivo studies demonstrated that, local immunomodulation of implanted meshes is mediated by a macrophage polarization towards an anti-inflammatory phenotype. In conclusion, the combined usage of surgical meshes with MSCs fulfills the safety requirements for a future clinical application, providing an anti-inflammatory environment that could reduce the inflammatory processes commonly observed after surgical mesh implantation. Statement of Significance Surgical meshes are medical devices widely used in clinics to resolve hernias and organs' prolapses, among other disorders. However, the implantation of surgical meshes is commonly related with an inflammatory response being difficult to eradicate without removing the mesh, causing pain and discomfort in the patient. Previously, the anti-inflammatory, immunomodulatory and pro-regenerative ability of mesenchymal stem cells (MSCs) have been described. To our knowledge, this is the first report where the anti-inflammatory and pro-regenerative ability of MSCs have been successfully applied in combination with surgical meshes, reducing the inflammatory processes commonly observed after mesh implantation. Moreover, our in vitro and in vivo results highlight the safety and efficacy of these bioactive meshes as a 'ready to use' medical product. © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.


PubMed | TiGenix, Stem Cell Therapy Unit and University of Extremadura
Type: | Journal: Frontiers in immunology | Year: 2014

In the recent years, it has been demonstrated that the biological activity of mesenchymal stem cells (MSCs) is mediated through the release of paracrine factors. Many of these factors are released into exosomes, which are small membranous vesicles that participate in cell-cell communication. Exosomes from MSCs are thought to have similar functions to MSCs such as repairing and regeneration of damaged tissue, but little is known about the immunomodulatory effect of these vesicles. Based on an extensive bibliography where the immunomodulatory capacity of MSCs has been demonstrated, here we hypothesized that released exosomes from MSCs may have an immunomodulatory role on the differentiation, activation and function of different lymphocyte subsets. According to this hypothesis, in vitro experiments were performed to characterize the immunomodulatory effect of human adipose MSCs derived exosomes (exo-hASCs) on in vitro stimulatedT cells. The phenotypic characterization of cytotoxic and helper T cells (activation and differentiation markers) together with functional assays (proliferation and IFN- production) demonstrated that exo-hASCs exerted an inhibitory effect in the differentiation and activation of T cells as well as a reduced T cell proliferation and IFN- release on in vitro stimulated cells. In summary, here we demonstrate that MSCs-derived exosomes are a cell-derived product that could be considered as a therapeutic agent for the treatment of inflammation-related diseases.


PubMed | Stem Cell Therapy Unit and University of Extremadura
Type: | Journal: Veterinary immunology and immunopathology | Year: 2016

The mesenchymal stem cells (MSCs) are one of the most promising cell types for human and veterinary use and their therapeutic effect is associated with their immunomodulatory properties. Farm animal models, such as pigs, have become a valuable tool to evaluate the safety and efficacy of adoptively transferred MSCs in the setting of veterinary medicine. In order to evaluate the immunomodulatory effect of stem cell-based therapies in porcine breeds, a deep analysis and comparison of MSCs and leukocyte subsets are absolutely necessary. Here we provide a detailed analysis of bone-marrow derived MSCs and leukocyte subsets from Large White pigs and Gttingen Minipigs. Significant differences were observed between the two pig breeds in terms of T cell subsets that need to be considered for immune monitoring of stem cell-based therapies.


PubMed | Stem Cell Therapy Unit, Anaesthetics Unit and Minimally Invasive Surgery Center
Type: Journal Article | Journal: PloS one | Year: 2015

The appropriate administration route for cardiovascular cell therapy is essential to ensure the viability, proliferative potential, homing capacity and implantation of transferred cells. At the present, the intrapericardial administration of pharmacological agents is considered an efficient method for the treatment of cardiovascular diseases. However, only a few reports have addressed the question whether the intrapericardial delivery of Mesenchymal Stem Cells (MSCs) could be an optimal administration route. This work firstly aimed to analyze the pericardial fluid as a cell-delivery vehicle. Moreover, the in vivo biodistribution pattern of intrapericardially administered MSCs was evaluated in a clinically relevant large animal model. Our in vitro results firstly showed that, MSCs viability, proliferative behavior and phenotypic profile were unaffected by exposure to pericardial fluid. Secondly, in vivo cell tracking by magnetic resonance imaging, histological examination and Y-chromosome amplification clearly demonstrated the presence of MSCs in pericardium, ventricles (left and right) and atrium (left and right) when MSCs were administered into the pericardial space. In conclusion, here we demonstrate that pericardial fluid is a suitable vehicle for MSCs and intrapericardial route provides an optimal retention and implantation of MSCs.


PubMed | Stem Cell Therapy Unit and Jesus Uson Minimally Invasive Surgery Center
Type: Journal Article | Journal: PloS one | Year: 2016

The intrapericardial delivery has been defined as an efficient method for pharmacological agent delivery. Here we hypothesize that intrapericardial administration of cardiosphere-derived cells (CDCs) may have an immunomodulatory effect providing an optimal microenvironment for promoting cardiac repair. To our knowledge, this is the first report studying the effects of CDCs for myocardial repair using the intrapericardial delivery route.CDCs lines were isolated, expanded and characterized by flow cytometry and PCR. Their differentiation ability was determined using specific culture media and differential staining. 300,000 CDCs/kg were injected into the pericardial space of a swine myocardial infarcted model. Magnetic resonance imaging, biochemical analysis of pericardial fluid and plasma, cytokine measurements and flow cytometry analysis were performed.Our results showed that, phenotype and differentiation behavior of porcine CDCs were equivalent to previously described CDCs. Moreover, the intrapericardial administration of CDCs fulfilled the safety aspects as non-adverse effects were reported. Finally, the phenotypes of resident lymphocytes and TH1 cytokines in the pericardial fluid were significantly altered after CDCs administration.The pericardial fluid could be considered as a safe and optimal vehicle for CDCs administration. The observed changes in the studied immunological parameters could exert a modulation in the inflammatory environment of infarcted hearts, indirectly benefiting the endogenous cardiac repair.

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