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Barrio L¹, Cuevas VD¹, Menta R², Mancheño-Corvo P², delaRosa O², Dalemans W³, Lombardo E², Carrasco YR4.
¹ B Cell Dynamics Laboratory, Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB)-CSIC, UAM-Campus Cantoblanco, Madrid, Spain.
² TiGenix SAU, Parque Tecnológico de Madrid, Madrid, Spain.
³ TiGenix NV, Leuven, Belgium.
4 B Cell Dynamics Laboratory, Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB)-CSIC, UAM-Campus Cantoblanco, Madrid, Spain.
Cytotherapy. 2014 Dec;16(12):1692-9. doi: 10.1016/j.jcyt.2014.07.012.
Mesenchymal stromal cells hold special interest for cell-based therapy because of their tissue-regenerative and immunosuppressive abilities. B-cell involvement in chronic inflammatory and autoimmune pathologies makes them a desirable target for cell-based therapy. Mesenchymal stromal cells are able to regulate B-cell function; although the mechanisms are little known, they imply cell-to-cell contact.
We studied the ability of human adipose tissue-derived mesenchymal stromal cells (ASCs) to attract B cells.
We show that ASCs promote B-cell migration through the secretion of chemotactic factors. Inflammatory/innate signals do not modify ASC capacity to mediate B-cell motility and chemotaxis. Analysis of a panel of B cell-related chemokines showed that none of them appeared to be responsible for B-cell motility. Other ASC-secreted factors able to promote cell motility and chemotaxis, such as the cytokine interleukin-8 and prostaglandin E2, did not appear to be implicated.
We propose that ASC promotion of B-cell migration by undefined secreted factors is crucial for ASC regulation of B-cell responses
Menta R¹, Mancheño-Corvo P¹, Del Río B¹, Ramírez C¹, DelaRosa O¹, Dalemans W², Lombardo E³.
¹ TiGenix SAU, Parque Tecnológico de Madrid, Madrid, Spain.
² TiGenix NV, Leuven, Belgium.
³ TiGenix SAU, Parque Tecnológico de Madrid, Madrid, Spain.
Cytotherapy. 2014 Dec;16(12):1679-91. doi: 10.1016/j.jcyt.2014.07.004.
Mesenchymal stromal cells (MSCs) have immunomodulatory properties that are mediated by cell-to-cell interactions and paracrine effects through soluble factors, among which tryptophan (Trp) conversion into kynurenine (Kyn) through the enzymatic activity of indoleamine 2,3-dioxygenase has been proven to be of special relevance. However, the respective role of Trp depletion and/or Kyn accumulation on the inhibition of T-cell proliferation by MSCs remains unclear.
The effect of supplementation with increasing concentrations of Trp on the capacity of MSCs to inhibit T-lymphocyte proliferation in vitro was investigated.
We report that Trp supplementation impairs the capacity of adipose mesenchymal stromal cells (ASCs) to inhibit T-cell proliferation, despite the accumulation of very high concentrations of Kyn in the medium (>200 μmol/L). Moreover, Trp supplementation after 72 h of peripheral blood mononuclear cell:ASC co-culture, once the inhibitory effect of ASCs was established, reverted ASC inhibition and restored T-cell proliferation. Addition to stimulated lymphocytes of Kyn inhibited T proliferation in 3 of 10 peripheral blood mononuclear cell donors, but at different concentrations, suggesting that sensitivity of lymphocytes to Kyn might be donor-dependent.
Our results confirm the relevance of Trp metabolism as a key mediator of the immunomodulatory properties of ASCs and clarify the respective roles of the Trp/Kyn balance.
Karine Toupet¹², Marie Maumus¹², Patricia Luz-Crawford¹², Eleuterio Lombardo³, Juan Lopez-Belmonte4, Peter van Lent5, Marina I. Garin6, Wim van den Berg5, Wilfried Dalemans7, Christian Jorgensen¹²8, Danièle Noël¹².
¹ U 844, Inserm, Hôpital Saint-Eloi, Montpellier, France
² UFR de Médecine, Université Montpellier1, Montpellier, France
³ TiGenix, Madrid, Spain
4 Farma-cros Iberica, Albacete, Spain
5 Experimental Rheumatology, Radboud University Medical Center, Nijmegen, Netherlands
6 CIEMAT/CIBERER, Madrid, Spain
7 TiGenix, Leuven, Belgium
8 Service d’Immuno-Rhumatologie Thérapeutique, Hôpital Lapeyronie, Montpellier, France
PLoS One. 2015 Jan 5;10(1):e0114962. doi: 10.1371/journal.pone.0114962. eCollection 2015
Application of mesenchymal stem/stromal cells (MSCs) in treating different disorders, in particular osteo-articular diseases, is currently under investigation. We have already documented the safety of administrating human adipose tissue-derived stromal MSCs (hASCs) in immunodeficient mice. In the present study, we investigated whether the persistence of MSC is affected by the degree of inflammation and related to the therapeutic effect in two inflammatory models of arthritis.
We used C57BL/6 or DBA/1 mice to develop collagenase-induced osteoarthritis (CIOA) or collagen-induced arthritis (CIA), respectively. Normal and diseased mice were administered 2.5×105 hASCs in the knee joints (IA) or 106 in the tail vein (IV). For CIA, clinical scores were monitored during the time course of the disease while for CIOA, OA scores were assessed by histology at euthanasia. Thirteen tissues were recovered at different time points and processed for real-time PCR and Alu sequence detection. Immunological analyses were performed at euthanasia. After IV infusion, no significant difference in the percentage of hASCs was quantified in the lungs of normal and CIA mice at day 1 while no cell was detected at day 10 taking into account the sensitivity of the assay, indicating that a high level of inflammation did not affect the persistence of cells. In CIOA mice, we reported the therapeutic efficacy of hASCs at reducing OA clinical scores at day 42 when hASCs were not detected in the joints. However, the percentage and distribution of hASCs were similar in osteoarthritic and normal mice at day 1 and 10 after implantation indicating that moderate inflammation does not alter hASC persistence in vivo.
While inflammatory signals are required for the immunosuppressive function of MSCs, they do not enhance their capacity to survive in vivo, as evaluated in two xenogeneic inflammatory pre-clinical models of arthritis.
On 11TH November Professor Peter Taylor explained the key points of RA and current treatments he made special focus on the scope of mesenchymal stem cells as RA treatment.
If you missed our Webinar you can watch it now clicking HERE
This project has received funding from the European Union's Seventh Programme for research, technological development and demonstration under grant agreement No 279174.