Pablo Mancheño‐Corvo

TiGenix (Spain)

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Ramón Menta

TiGenix (Spain)

Eleuterio Lombardo

TiGenix (Spain)

Olga DelaRosa

TiGenix (Spain)

Wilfried Dalemans

KU Leuven

Cristina M. Ramírez

IMDEA Food

Marina I. Garín

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas

Dirk Büscher

Grifols (Spain)

Juan A. Bueren

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas

Mercedes López‐Santalla

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas

Pilar Martín‐Duque

Instituto de Investigación Sanitaria Aragón

Cooperative Institutions

Universidad Autónoma de Madrid

Consejo Superior de Investigaciones Científicas

Instituto de Salud Carlos III

TiGenix (Spain)

Hospital Universitario La Paz

University of Wisconsin–Madison

Institute of Clinical and Experimental Medicine

Centro Nacional de Biotecnología

Spanish National Centre for Cardiovascular Research

Centre for Biomedical Network Research on Rare Diseases

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Toll-like Receptor–Mediated Signaling in Human Adipose-Derived Stem Cells: Implications for Immunogenicity and Immunosuppressive Potential

Tissue Engineering Part A (2008)

Eleuterio Lombardo Olga DelaRosa Pablo Mancheño‐Corvo Ramón Menta Cristina M. Ramírez

Human adipose-derived stem cells (hASCs) are mesenchymal stem cells with reduced immunogenicity and the capability to modulate immune responses. These properties make hASCs of special interest as therapeutic agents in the settings of chronic inflammatory and autoimmune diseases. Exogenous and endogenous toll-like receptor (TLR) ligands have been linked with the perpetuation of inflammation in a number of chronic inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis because of the permanent exposure of the immune system to TLR-specific stimuli. Therefore, hASCs employed in therapy are potentially exposed to TLR ligands, which may result in the modulation of hASC activity and therapeutic potency. In this study, we demonstrate that hASCs possess active TLR2, TLR3, and TLR4, because activation with specific ligands resulted in induction of nuclear factor kappa B-dependent genes, such as manganese superoxide dismutase and the release of interleukin (IL)-6 and IL-8. TLR3 and TLR4 ligands increased osteogenic differentiation, but no effect on adipogenic differentiation or proliferation was observed. Moreover, we show that TLR activation does not impair the immunogenic and immunosuppressive properties of hASCs. These results may have important implications with respect to the safety and efficacy of hASC-based cell therapies.

10.1089/ten.tea.2008.0340

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Citations (146)

Tryptophan concentration is the main mediator of the capacity of adipose mesenchymal stromal cells to inhibit T-lymphocyte proliferation in vitro

Cytotherapy (2014)

Ramón Menta Pablo Mancheño‐Corvo Borja del Río Cristina M. Ramírez Olga DelaRosa

Indoleamine 2,3-dioxygenase

Mediator

10.1016/j.jcyt.2014.07.004

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Citations (27)

Intralymphatic Administration of Adipose Mesenchymal Stem Cells Reduces the Severity of Collagen-Induced Experimental Arthritis

Frontiers in Immunology (2017)

Pablo Mancheño‐Corvo Mercedes López‐Santalla Ramón Menta Olga DelaRosa Francisca Mulero

Mesenchymal stem cells (MSCs) are multipotent stromal cells with immunomodulatory properties. They have emerged as a very promising treatment for autoimmunity and inflammatory diseases such as rheumatoid arthritis. Previous studies have demonstrated that MSCs, administered systemically, migrate to lymphoid tissues associated to the inflammatory site where functional MSC-induced immune cells with a regulatory phenotype were increased mediating the immunomodulatory effects of MSCs. These results suggest that homing of MSCs to the lymphatic system plays an important role in the mechanism of action of MSCs in vivo. Thus, we hypothesized that direct intralymphatic (also referred as intranodal) administration of MSCs could be an alternative and effective route of administration for MSC-based therapy. Here, we report the feasibility and efficacy of the intralymphatic administration of human expanded adipose-derived mesenchymal stem cells (eASCs) in a mouse model of collagen-induced arthritis. Intralymphatic administration of eASCs attenuated the severity and progression of arthritis, reduced bone destruction and increased the levels of regulatory T cells (CD25+Foxp3+CD4+ cells) and Tr1 cells (IL10+CD4+), in spleen and draining lymph nodes. Taken together, these results indicate that intralymphatic administration of eASCs is very effective in modulating established collagen-induced arthritis and may represent an alternative treatment modality for cell therapy with eASCs.

Systemic administration

Cell therapy

10.3389/fimmu.2017.00462

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Citations (22)

Human Adipose-Derived Mesenchymal Stem Cells Modulate Experimental Autoimmune Arthritis by Modifying Early Adaptive T Cell Responses

Stem Cells (2015)

Mercedes López‐Santalla Pablo Mancheño‐Corvo Ramón Menta Juan Luis López-Belmonte Olga DelaRosa

Mesenchymal stem cells (MSCs) are multipotent stromal cells with immunosuppressive properties. They have emerged as a very promising treatment for autoimmunity and inflammatory diseases such as rheumatoid arthritis. Recent data have identified that GM-CSF-expressing CD4 T cells and Th17 cells have critical roles in the pathogenesis of arthritis and other inflammatory diseases. Although many studies have demonstrated that MSCs can either prevent or suppress inflammation, no studies have addressed their modulation on GM-CSF-expressing CD4 T cells and on the plasticity of Th17 cells. To address this, a single dose of human expanded adipose-derived mesenchymal stem cells (eASCs) was administered to mice with established collagen-induced arthritis. A beneficial effect was observed soon after the infusion of the eASCs as shown by a significant decrease in the severity of arthritis. This was accompanied by reduced number of pathogenic GM-CSF(+) CD4(+) T cells in the spleen and peripheral blood and by an increase in the number of different subsets of regulatory T cells like FOXP3(+) CD4(+) T cells and IL10(+) IL17(-) CD4(+) T cells in the draining lymph nodes (LNs). Interestingly, increased numbers of Th17 cells coexpressing IL10 were also found in draining LNs. These results demonstrate that eASCs ameliorated arthritis after the onset of the disease by reducing the total number of pathogenic GM-CSF(+) CD4(+) T and by increasing the number of different subsets of regulatory T cells in draining LNs, including Th17 cells expressing IL10. All these cellular responses, ultimately, lead to the reestablishment of the regulatory/inflammatory balance in the draining LNs.

10.1002/stem.2113

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Citations (66)

T Lymphocyte Prestimulation Impairs in a Time-Dependent Manner the Capacity of Adipose Mesenchymal Stem Cells to Inhibit Proliferation: Role of Interferon γ, Poly I:C, and Tryptophan Metabolism in Restoring Adipose Mesenchymal Stem Cell Inhibitory Effect

Stem Cells and Development (2015)

Pablo Mancheño‐Corvo Ramón Menta Borja del Río Marcella Franquesa Cristina M. Ramírez

The immunomodulatory properties of mesenchymal stem/stromal cells (MSCs) make them an attractive therapeutic tool to treat chronic inflammatory diseases, such as rheumatoid arthritis or Crohn's disease. These indications are characterized by a chronic activation of immune cells that perpetuates the disease. In vitro, when adipose mesenchymal stem cells (ASCs) are cultured with T lymphocytes at the time of stimulation, their proliferation is inhibited. However, these experimental settings do not necessarily fit with what ASCs will face in inflammatory conditions in vivo, where ASCs will likely encounter and interact with already activated immune cells which might affect their immunomodulatory capacity. In most in vitro studies, MSCs have been cultured with peripheral blood mononuclear cells at the time of lymphocyte stimulation and information about the interaction between MSCs and prestimulated lymphocytes in vitro is scarce. Therefore, a better understanding of the capacity of MSCs to modulate the responses of preactivated immune cells is needed. In this study we focused on the effects of ASCs on prestimulated lymphocytes and systematically investigated the potential mechanisms involved. We report that prestimulation of T lymphocytes 48 h before the coculture with ASCs impairs the capacity of ASCs to inhibit proliferation. Preactivation of ASCs with interferon γ or the toll-like receptor ligand Poly I:C, but not other stimuli tested, enhanced the ability to inhibit the proliferation of 48 h-stimulated T lymphocytes. The inhibitory effect of ASCs was shown to be time dependent and mediated through the actual magnitude of tryptophan degradation by indoleamine 2,3-dioxygenase.

10.1089/scd.2014.0508

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Citations (23)

Human adipose mesenchymal stem cells modulate myeloid cells toward an anti-inflammatory and reparative phenotype: role of IL-6 and PGE2

Stem Cell Research & Therapy (2020)

Maitane Ortiz‐Virumbrales Ramón Menta Laura M. Pérez Ornella Lucchesi Pablo Mancheño‐Corvo

Abstract Background Mesenchymal stem cells (MSCs) activate the endogenous immune regulatory system, inducing a therapeutic effect in recipients. MSCs have demonstrated the ability to modulate the differentiation of myeloid cells toward a phagocytic and anti-inflammatory profile. Allogeneic, adipose-derived MSCs (ASCs) have been investigated for the management of complex perianal fistula, with darvadstrocel being the first ASC therapy approved in Europe in March 2018. Additionally, ASCs are being explored as a potential treatment in other indications. Yet, despite these clinical advances, their mechanism of action is only partially understood. Methods Freshly isolated human monocytes from the peripheral blood were differentiated in vitro toward M0 non-polarized macrophages (Mphs), M1 pro-inflammatory Mphs, M2 anti-inflammatory Mphs, or mature dendritic cells (mDCs) in the presence or absence of ASCs, in non-contact conditions. The phenotype and function of the differentiated myeloid populations were determined by flow cytometry, and their secretome was analyzed by OLINK technology. We also investigated the capacity of ASCs to modulate the phenotype and function of terminally differentiated M1 Mphs. The role of soluble factors interleukin (IL)-6 and prostaglandin E2 (PGE2) on the ability of ASCs to modulate myeloid cells was assessed using neutralization assays, CRISPR/Cas9 knock-down of cyclooxygenase 2 (COX-2), and ASC-conditioned medium assays using pro-inflammatory stimulus. Results Co-culture of monocytes in the presence of ASCs resulted in the polarization of Mphs and mDCs toward an anti-inflammatory and phagocytic phenotype. This was characterized by an increase in phagocytic receptors on the cell surface of Mphs (M0, M1, and M2) and mDCs, as well as modulation of chemokine receptors and reduced expression of pro-inflammatory, co-stimulatory molecules. ASCs also modulated the secretome of Mphs and mDCs, demonstrated by reduced expression of pro-inflammatory factors and increased expression of anti-inflammatory and reparative factors. Chemical inhibition of PGE2 with indomethacin abolished this modulatory effect, whereas treatment with a neutralizing anti-IL-6 antibody resulted in a partial abolishment. The knock-down of COX-2 in ASCs and the use of IL-1β-activated ASC-conditioned media confirmed the key role of PGE2 in ASC-mediated myeloid modulation. In our in vitro experimental settings, ASCs failed to modulate the phenotype and function of terminally polarized M1 Mphs. Conclusions The results demonstrate that ASCs are able to modulate the in vitro differentiation of myeloid cells toward an anti-inflammatory and reparative profile. This modulatory effect was mediated mainly by PGE2 and, to a lesser extent, IL-6.

10.1186/s13287-020-01975-2

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Citations (40)

Molecular Biology of Malignant Melanoma

Advances in experimental medicine and biology (2009)

Mar Pons Pablo Mancheño‐Corvo Pilar Martín‐Duque Miguel Quintanilla

10.1007/978-0-387-77574-6_20

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Citations (11)

Table of Contents

Cytotherapy (2014)

Natividad Cuende C. Boniface Christopher A. Bravery Miguel Forte Raquel L. C. Giordano

Table (database)

10.1016/s1465-3249(14)00815-9

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La actividad de la Caspasa-1 como gen sensibilizador a radio y quimioterapia es independiente de las vías de JNK y p38

Oncología (Barcelona) (2005)

Georges Vassaux Pablo Mancheño‐Corvo M López-Barahona Miguel Quintanilla R. Francisco‐Álvarez

El efecto citotóxico de las drogas antitumorales es producido mediante la inducción de apoptosis.Esta observación implica la posibilidad de que los factores que afecten la activación de caspasas pueden ser determinantes importantes como sensibilizantes a los tratamientos antitumorales.Aquí, examinamos el efecto de la sobreexpresión de caspasa-1 en la respuesta a la quimio y radioterapia.La expresión de la caspasa-1 mediada por un vector adenoviral fue capaz de matar directamente a las células y de sensibilizar las restantes a cisplatino o radiación gamma in vitro.En células HeLa transfectadas establemente con caspasa-1, la sensibilización a cisplatino fue debida a una amplificación en la vía mitocondrial de apoptosis inducida por cisplatino pero este efecto es independiente del estado de p53, JNK o p38 en la célula.

10.4321/s0378-48352005000800004

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Comparative Analysis between the In Vivo Biodistribution and Therapeutic Efficacy of Adipose-Derived Mesenchymal Stromal Cells Administered Intraperitoneally in Experimental Colitis

International Journal of Molecular Sciences (2018)

Mercedes López‐Santalla Pablo Mancheño‐Corvo Amelia Escolano Ramón Menta Olga DelaRosa

Mesenchymal stem cells (MSCs) have emerged as a promising treatment for inflammatory diseases. The immunomodulatory effect of MSCs takes place both by direct cell-to-cell contact and by means of soluble factors that leads to an increased accumulation of regulatory immune cells at the sites of inflammation. Similar efficacy of MSCs has been described regardless of the route of administration used, the inflammation conditions and the major histocompatibility complex context. These observations raise the question of whether the migration of the MSCs to the inflamed tissues is a pre-requisite to achieve their beneficial effect. To address this, we examined the biodistribution and the efficacy of intraperitoneal luciferase-expressing human expanded adipose-derived stem cells (Luci-eASCs) in a mouse model of colitis. Luci-eASC-infused mice were stratified according to their response to the Luci-eASC treatment. According to the stratification criteria, there was a tendency to increase the bioluminescence signal in the intestine at the expense of a decrease in the bioluminescence signal in the liver in the “responder” mice. These data thus suggest that the accumulation of the eASCs to the inflamed tissues is beneficial for achieving an optimal modulation of inflammation.

Biodistribution

Bioluminescence imaging

10.3390/ijms19071853

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Citations (13)