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[Background]: Mesenchymal Stromal/Stem Cells (MSCs), isolated under the criteria established by the ISCT, still have a poorly characterized phenotype that is difficult to distinguish from similar cell populations. Although the field of transcriptomics and functional genomics has quickly grown in the last decade, a deep comparative analysis of human MSCs expression profiles in a meaningful cellular context has not been yet performed. There is also a need to find a well-defined MSCs gene-signature because many recent biomedical studies show that key cellular interaction processes (i.e. inmuno-modulation, cellular cross-talk, cellular maintenance, differentiation, epithelial-mesenchymal transition) are dependent on the mesenchymal stem cells within the stromal niche. [Results]: In this work we define a core mesenchymal lineage signature of 489 genes based on a deep comparative analysis of multiple transcriptomic expression data series that comprise: (i) MSCs of different tissue origins; (ii) MSCs in different states of commitment; (iii) other related non-mesenchymal human cell types. The work integrates several public datasets, as well as de-novo produced microarray and RNA-Seq datasets. The results present tissue-specific signatures for adipose tissue, chorionic placenta, and bone marrow MSCs, as well as for dermal fibroblasts; providing a better definition of the relationship between fibroblasts and MSCs. Finally, novel CD marker patterns and cytokine-receptor profiles are unravelled, especially for BM-MSCs; with MCAM (CD146) revealed as a prevalent marker in this subtype of MSCs. [Conclusions]: The improved biomolecular characterization and the released genome-wide expression signatures of human MSCs provide a comprehensive new resource that can drive further functional studies and redesigned cell therapy applications. ; We acknowledge the funding provided to Dr. J. De Las Rivas group by the Local Government, "Junta de Castilla y Leon" (JCyL, Valladolid, Spain, grants number BIO/SA68/13 and BIO/SA08/14); and by the Spanish Government, "Ministerio de Economia y Competitividad" (MINECO) with grants of the "Instituto de Salud Carlos III" (ISCiii) co-funded by FEDER (grants PI12/00624 and PI15/00328). We also acknowledge a PhD research grant to B. Roson from JCyL ("Ayudas a la contratación de Personal Investigador") provided with the support of the "Fondo Social Europeo" (FSE). The publication charges for this article were funded by the research grant PI15/00328, from the Instituto de Salud Carlos III (ISCiii) co-funded by the Fondo Europeo de Desarrollo Regional (FEDER). ; Peer Reviewed

This article belongs to the Special Issue Bioinformatics and Precision Computational Biology: Selected Papers from the X International Conference on Bioinformatics #SoIBio+10. ; Mesenchymal Stromal Cells (MSC) are multipotent cells characterized by self-renewal, multilineage differentiation, and immunomodulatory properties. To obtain a gene regulatory profile of human MSCs, we generated a compendium of more than two hundred cell samples with genome-wide expression data, including a homogeneous set of 93 samples of five related primary cell types: bone marrow mesenchymal stem cells (BM-MSC), hematopoietic stem cells (HSC), lymphocytes (LYM), fibroblasts (FIB), and osteoblasts (OSTB). All these samples were integrated to generate a regulatory gene network using the algorithm ARACNe (Algorithm for the Reconstruction of Accurate Cellular Networks; based on mutual information), that finds regulons (groups of target genes regulated by transcription factors) and regulators (i.e., transcription factors, TFs). Furtherly, the algorithm VIPER (Algorithm for Virtual Inference of Protein-activity by Enriched Regulon analysis) was used to inference protein activity and to identify the most significant TF regulators, which control the expression profile of the studied cells. Applying these algorithms, a footprint of candidate master regulators of BM-MSCs was defined, including the genes EPAS1, NFE2L1, SNAI2, STAB2, TEAD1, and TULP3, that presented consistent upregulation and hypomethylation in BM-MSCs. These TFs regulate the activation of the genes in the bone marrow MSC lineage and are involved in development, morphogenesis, cell differentiation, regulation of cell adhesion, and cell structure. ; This research was funded by Fondo de Investigación Sanitaria—Instituto de Salud Carlos III (FIS—ISCIII, Spanish Ministry of Health, project reference PI18/00591) where J.D.L.R. was the PI. The research was also partially funded by Fondo de Investigación Sanitaria (FIS—ISCIII, project reference PI16/01407). The work within these projects was also cofunded by the FEDER program of the European Union. J.D.L.R. lab acknowledges also the support given by the European Project H2020 ArrestAD (Project ID: 737390, H2020-FETOPEN-1-2016-2017). ; Peer reviewed

In the current article we summarize the 15-year experience of the Spanish Cell Therapy Network (TerCel), a successful collaborative public initiative funded by the Spanish government for the support of nationwide translational research in this important area. Thirty-two research groups organized in three programs devoted to cardiovascular, neurodegenerative and immune-inflammatory diseases, respectively, currently form the network. Each program has three working packages focused on basic science, pre-clinical studies and clinical application. TerCel has contributed during this period to boost the translational research in cell therapy in Spain, setting up a network of Good Manufacturing Practice-certified cell manufacturing facilities- and increasing the number of translational research projects, publications, patents and clinical trials of the participating groups, especially those in collaboration. TerCel pays particular attention to the public-private collaboration, which, for instance, has led to the development of the first allogeneic cell therapy product approved by the European Medicines Agency, Darvadstrocel. The current collaborative work is focused on the development of multicenter phase 2 and 3 trials that could translate these therapies to clinical practice for the benefit of patients. ; This manuscript has been supported by the Instituto de Salud Carlos III (ISCIII) through the project"RD16/0011/0001: Red de TerapiaCelular", from the sub-program RETICS, integrated in the"Plan Estatalde I+D+I 2013-2016"and co-financed by the European RegionalDevelopment Fund"A way to make Europe". D.G.O. has been an Advi-sory Board member of TiGenix SAU, and received consulting feesfrom Takeda. He also holds patents 10157355957US and US11/167061 related to Darvadstrocel. ; Sí