Human mesenchymal stem cells modulate B-cell functions.

Human mesenchymal stem cells (hMSCs) suppress T-cell and dendritic-cell function and represent a promising strategy for cell therapy of autoimmune diseases. Nevertheless, no information is currently available on the effects of hMSCs on B cells, which may have a large impact on the clinical use of these cells. hMSCs isolated from the bone marrow and B cells purified from the peripheral blood of healthy donors were cocultured with different B-cell tropic stimuli. B-cell proliferation was inhibited by hMSCs through an arrest in the G0/G1 phase of the cell cycle and not through the induction of apoptosis. A major mechanism of B-cell suppression was hMSC production of soluble factors, as indicated by transwell experiments. hMSCs inhibited B-cell differentiation because IgM, IgG, and IgA production was significantly impaired. CXCR4, CXCR5, and CCR7 B-cell expression, as well as chemotaxis to CXCL12, the CXCR4 ligand, and CXCL13, the CXCR5 ligand, were significantly down-regulated by hMSCs, suggesting that these cells affect chemotactic properties of B cells. B-cell costimulatory molecule expression and cytokine production were unaffected by hMSCs. These results further support the potential therapeutic use of hMSCs in immune-mediated disorders, including those in which B cells play a major role.

[1]  G. Mancardi,et al.  Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. , 2005, Blood.

[2]  R. Burt.  Finding a less toxic stem cell therapy for multiple sclerosis , 2005 .

[3]  Yi Zhang,et al.  Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. , 2005, Blood.

[4]  R. Cancedda,et al.  Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway , 2005, European journal of immunology.

[5]  Andrea Bacigalupo,et al.  Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. , 2005, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[6]  E. Lam,et al.  Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. , 2005, Blood.

[7]  D. Mevorach,et al.  Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. , 2005, Blood.

[8]  C. Berek,et al.  Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response. , 2005, Blood.

[9]  Dan R. Littman,et al.  The Role of CXCR4 in Maintaining Peripheral B Cell Compartments and Humoral Immunity , 2004, The Journal of experimental medicine.

[10]  J. Cyster,et al.  Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5 , 2004, Nature Immunology.

[11]  Moustapha Hassan,et al.  Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells , 2004, The Lancet.

[12]  D. Rossi,et al.  CCL19 and CXCL12 Trigger in Vitro Chemotaxis of Human Mantle Cell Lymphoma B Cells , 2004, Clinical Cancer Research.

[13]  A. Lanzavecchia,et al.  A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. , 2003, Blood.

[14]  M. Krampera,et al.  Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. , 2003, Blood.

[15]  E. Guinan,et al.  Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation , 2003, Transplantation.

[16]  J. Spivak,et al.  Polycythemia vera: myths, mechanisms, and management. , 2002, Blood.

[17]  F. Malavasi,et al.  Chemotaxis of human tonsil B lymphocytes to CC chemokine receptor (CCR) 1, CCR2 and CCR4 ligands is restricted to non-germinal center cells. , 2002, International immunology.

[18]  H. Stein,et al.  Systemic immunoregulatory and pathogenic functions of homeostatic chemokine receptors , 2002, Journal of leukocyte biology.

[19]  J. Cyster,et al.  Chemokine Requirements for B Cell Entry to Lymph Nodes and Peyer's Patches , 2002, The Journal of experimental medicine.

[20]  C. Carlo-Stella,et al.  Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. , 2002, Blood.

[21]  J. Cyster,et al.  Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position , 2002, Nature.

[22]  G. Sukhikh,et al.  Mesenchymal Stem Cells , 2002, Bulletin of Experimental Biology and Medicine.

[23]  J. Cyster,et al.  A Coordinated Change in Chemokine Responsiveness Guides Plasma Cell Movements , 2001, The Journal of experimental medicine.

[24]  R. Hoffman,et al.  Role of mesenchymal stem cells in hematopoietic stem cell transplantation , 2000, Current opinion in hematology.

[25]  Jason G. Cyster,et al.  A chemokine-driven positive feedback loop organizes lymphoid follicles , 2000, Nature.

[26]  Johannes Gerdes,et al.  The Ki‐67 protein: From the known and the unknown , 2000, Journal of cellular physiology.

[27]  J. Cyster,et al.  Chemokines and cell migration in secondary lymphoid organs. , 1999, Science.

[28]  D. Kurosaka,et al.  Comparative studies of different stromal cell microenvironments in support of human B-cell development. , 1999, Experimental hematology.

[29]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[30]  R. Bronson,et al.  Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Kouji Matsushima,et al.  The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract , 1998, Nature.

[32]  Masahiko Kuroda,et al.  Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development , 1998, Nature.

[33]  E. Butcher,et al.  6-C-kine (SLC), a Lymphocyte Adhesion-triggering Chemokine Expressed by High Endothelium, Is an Agonist for the MIP-3β Receptor CCR7 , 1998, The Journal of cell biology.

[34]  M. Baggiolini.  Chemokines and leukocyte traffic , 1998, Nature.

[35]  V. Pistoia,et al.  Production of cytokines by human B cells in health and disease. , 1997, Immunology today.

[36]  P. Sperryn,et al.  Blood. , 1989, British journal of sports medicine.

[37]  K. Dorshkind,et al.  B lymphocyte precursors and myeloid progenitors survive in diffusion chamber cultures but B cell differentiation requires close association with stromal cells. , 1987, Blood.

[38]  Catherine M. Verfaillie,et al.  Pluripotency of mesenchymal stem cells derived from adult marrow , 2007, Nature.

[39]  Kevin McIntosh,et al.  Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. , 2002, Experimental hematology.

[40]  bloodjournal.hematologylibrary.org at PENN STATE UNIVERSITY on February 20, 2013. For personal use , 2002 .

[41]  M. Greaves,et al.  Compartmentalization of a haematopoietic growth factor (GM-CSF) by glycosaminoglycans in the bone marrow microenvironment , 1987, Nature.