title: Transcriptional profiling reveals intrinsic mRNA alterations in multipotent mesenchymal stromal cells isolated from bone marrow of newly-diagnosed type 1 diabetes patients.
abstract: BACKGROUND
  Bone marrow multipotent mesenchymal stromal cells (MSCs) are a diverse subset of precursors that contribute to the homeostasis of the hematopoietic niche. MSCs can be isolated and expanded in vitro and have unique immunomodulatory and regenerative properties that make them attractive for the treatment of autoimmune diseases, including type 1 diabetes (T1D). Whether autologous or allogeneic MSCs are more suitable for therapeutic purposes has not yet been established. While autologous MSCs may present abnormal function, allogeneic cells may be recognized and rejected by the host immune system. Thus, studies that investigate biological characteristics of MSCs isolated from T1D patients are essential to guide future clinical applications.
  
  
  METHODS
  Bone marrow-derived MSCs from recently diagnosed type 1 diabetes patients (T1D-MSCs) were compared with those from healthy individuals (C-MSCs) for morphological and immunophenotypic characteristics and for differentiation potential. Bioinformatics approaches allowed us to match absolute and differential gene expression of several adhesion molecules, immune mediators, growth factors, and their receptors involved with hematopoietic support and immunomodulatory properties of MSCs. Finally, the differentially expressed genes were collated for functional pathway enrichment analysis.
  
  
  RESULTS
  T1D-MSCs and C-MSCs were similar for morphology, immunophenotype, and differentiation potential. Our absolute gene expression results supported previous literature reports, while also detecting new potential molecules related to bone marrow-derived MSC functions. T1D-MSCs showed intrinsic abnormalities in mRNA expression, including the immunomodulatory molecules VCAM-1, CXCL12, HGF, and CCL2. Pathway analyses revealed activation of sympathetic nervous system and JAK STAT signaling in T1D-MSCs.
  
  
  CONCLUSIONS
  Collectively, our results indicate that MSCs isolated from T1D patients present intrinsic transcriptional alterations that may affect their therapeutic potential. However, the implications of these abnormalities in T1D development as well as in the therapeutic efficacy of autologous MSCs require further investigation.
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirao Preto, Ribeirao Preto Medical, University of Sao Paulo, Ribeirao Preto, Brazil. kalil.lima@usp.br.|Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil. kalil.lima@usp.br.|, Tenente Catao Roxo, 2501, Monte Alegre, 14051-140, Ribeirao Preto, Sao Paulo, Brazil. kalil.lima@usp.br.
authors.forename: Kalil A
authors.initials: KA
authors.lastname: de Lima
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirao Preto, Ribeirao Preto Medical, University of Sao Paulo, Ribeirao Preto, Brazil.|Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Gislane L V
authors.initials: GL
authors.lastname: de Oliveira
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirao Preto, Ribeirao Preto Medical, University of Sao Paulo, Ribeirao Preto, Brazil.|Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.|Department of Clinical and Toxicological Analysis, Federal University of Ceará, Fortaleza, Ceara, Brazil.
authors.forename: Juliana N U
authors.initials: JN
authors.lastname: Yaochite
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirao Preto, Ribeirao Preto Medical, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Pinheiro
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirao Preto, Ribeirao Preto Medical, University of Sao Paulo, Ribeirao Preto, Brazil.|Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Júlia T C
authors.initials: JT
authors.lastname: de Azevedo
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirao Preto, Ribeirao Preto Medical, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Wilson Araujo
authors.initials: WA
authors.lastname: Silva
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirao Preto, Ribeirao Preto Medical, University of Sao Paulo, Ribeirao Preto, Brazil.|Department of Clinical Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Dimas T
authors.initials: DT
authors.lastname: Covas
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirao Preto, Ribeirao Preto Medical, University of Sao Paulo, Ribeirao Preto, Brazil.|Department of Clinical Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Carlos E B
authors.initials: CE
authors.lastname: Couri
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirao Preto, Ribeirao Preto Medical, University of Sao Paulo, Ribeirao Preto, Brazil.|Department of Clinical Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Belinda P
authors.initials: BP
authors.lastname: Simões
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirao Preto, Ribeirao Preto Medical, University of Sao Paulo, Ribeirao Preto, Brazil.|Department of Clinical Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Voltarelli
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirao Preto, Ribeirao Preto Medical, University of Sao Paulo, Ribeirao Preto, Brazil.|Department of Clinical Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Oliveira
authors.affiliation: Center for Cell-Based Research, Regional Blood Center of Ribeirao Preto, Ribeirao Preto Medical, University of Sao Paulo, Ribeirao Preto, Brazil.|Department of Clinical, Toxicological and Bromatological Analysis, Faculty of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Kelen C R
authors.initials: KC
authors.lastname: Malmegrim
mesh_terms: D000293:Adolescent; D000328:Adult; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; C515255:CXCL12 protein, human; D018932:Chemokine CCL2; D054377:Chemokine CXCL12; C066855:HGF protein, human; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; D017228:Hepatocyte Growth Factor; C507904:JAK1 protein, human; D053613:Janus Kinase 1
keywords: Bone marrow; Cell therapy; Mesenchymal stromal cells; Microarrays; Transcriptome; Type 1 diabetes