Transplantation of umbilical cord mesenchymal stem cells alleviates lupus nephritis in MRL/lpr mice

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, which, despite the advances in immunosuppressive medical therapies, remains potentially fatal in some patients, especially in treatment-refractory patients. This study found that transplantation of umbilical cord mesenchymal stem cells (UC-MSCs) has the same therapeutic effect as transplantation of bone marrow mesenchymal stem cells (BM-MSCs), which has been reported to be efficient in treating SLE-related symptoms in MRL/lpr mice. Multi-treatment (at the 18th, 19th, and 20th weeks of age) of 1 × 106 UC-MSCs was able to decrease the levels of 24-h proteinuria, serum creatinine, and anti-double-stranded DNA (dsDNA) antibody, and the extent of renal injury such as crescent formation in MRL/lpr mice. A lower, but still significant, reduction in these parameters was also observed in mice receiving a single dose of UC-MSCs (at the 18th week). UC-MSCs treatment also inhibited expression of monocyte chemotactic protein-1 (MCP-1) and high-mobility group box 1 (HMGB-1) expression in a similar fashion. UC-MSCs labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE) were found in the lungs and kidneys 1 week post infusion. In addition, after 11 weeks post UC-MSCs infusion, human cells were found in kidney of UC-MSCs-treated mice. These findings indicated that UC-MSCs transplantation might be a potentially promising approach in the treatment of lupus nephritis, possibly by inhibiting MCP-1 and HMGB-1 production. Lupus (2010) 19, 1502—1514.

[1]  L. Morel,et al.  Murine Models of Systemic Lupus Erythematosus , 2011, Journal of biomedicine & biotechnology.

[2]  F. Carrión,et al.  Autologous mesenchymal stem cell treatment increased T regulatory cells with no effect on disease activity in two systemic lupus erythematosus patients , 2010, Lupus.

[3]  Lingyun Sun,et al.  Mesenchymal Stem Cell Transplantation Reverses Multiorgan Dysfunction in Systemic Lupus Erythematosus Mice and Humans , 2009, Stem cells.

[4]  I. Ito,et al.  Lupus antibodies to the HMGB1 chromosomal protein: epitope mapping and association with disease activity , 2009, Modern rheumatology.

[5]  Lingyun Sun,et al.  Transplantation of Human Bone Marrow Mesenchymal Stem Cell Ameliorates the Autoimmune Pathogenesis in MRL/lpr Mice , 2008, Cellular and Molecular Immunology.

[6]  N. Sebire,et al.  Glomerular expression of monocyte chemoattractant protein-1 is predictive of poor renal prognosis in pediatric lupus nephritis. , 2008, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[7]  G. Dini,et al.  Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study , 2008, The Lancet.

[8]  Liwen Chen,et al.  Paracrine Factors of Mesenchymal Stem Cells Recruit Macrophages and Endothelial Lineage Cells and Enhance Wound Healing , 2008, PloS one.

[9]  A. Martini,et al.  Bone Marrow‐Derived Mesenchymal Stem Cells Induce Both Polyclonal Expansion and Differentiation of B Cells Isolated from Healthy Donors and Systemic Lupus Erythematosus Patients , 2008, Stem cells.

[10]  Paul G Scott,et al.  Mesenchymal Stem Cells Enhance Wound Healing Through Differentiation and Angiogenesis , 2007, Stem cells.

[11]  R. Angeletti,et al.  α-Actinin Immunization Elicits Anti-Chromatin Autoimmunity in Nonautoimmune Mice1 , 2007, The Journal of Immunology.

[12]  L. Audoly,et al.  Toll-like receptor 9–dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE , 2007, Nature Immunology.

[13]  P. Lipsky,et al.  Deficient CD4+CD25high T Regulatory Cell Function in Patients with Active Systemic Lupus Erythematosus1 , 2007, The Journal of Immunology.

[14]  Ly Sun,et al.  Abnormality of bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus , 2007, Lupus.

[15]  X. Chen,et al.  Mesenchymal stem cells in immunoregulation , 2006, Immunology and cell biology.

[16]  B. Chiang,et al.  The role of CD4+CD25+ T cells in autoantibody production in murine lupus , 2006, Clinical and experimental immunology.

[17]  Peter Boor,et al.  Transplanted mesenchymal stem cells accelerate glomerular healing in experimental glomerulonephritis. , 2006, Journal of the American Society of Nephrology : JASN.

[18]  E. Abraham,et al.  High mobility group box 1 protein interacts with multiple Toll-like receptors. , 2006, American journal of physiology. Cell physiology.

[19]  H. Hirakata,et al.  Amelioration of autoimmune nephritis by imatinib in MRL/lpr mice. , 2005, Arthritis and rheumatism.

[20]  L. Padyukov,et al.  Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus. , 2005, Arthritis and rheumatism.

[21]  Joshua M Hare,et al.  Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

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

[23]  M. Pittenger,et al.  Human mesenchymal stem cells modulate allogeneic immune cell responses. , 2005, Blood.

[24]  Yi Li,et al.  Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells , 2005, Glia.

[25]  S. Müller,et al.  HMGB1 is an endogenous immune adjuvant released by necrotic cells , 2004, EMBO Reports.

[26]  S. Sakaguchi Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. , 2004, Annual review of immunology.

[27]  J. Alcocer-Varela,et al.  Quantification of regulatory T cells in patients with systemic lupus erythematosus. , 2003, Journal of autoimmunity.

[28]  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.

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

[30]  O. Ringdén,et al.  Mesenchymal Stem Cells Inhibit and Stimulate Mixed Lymphocyte Cultures and Mitogenic Responses Independently of the Major Histocompatibility Complex , 2003, Scandinavian journal of immunology.

[31]  M. Bianchi,et al.  The nuclear protein HMGB1 is secreted by monocytes via a non‐classical, vesicle‐mediated secretory pathway , 2002, EMBO reports.

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

[33]  K. Tracey,et al.  HMGB1 as a late mediator of lethal systemic inflammation. , 2001, American journal of respiratory and critical care medicine.

[34]  R. Hoffman T cells in the pathogenesis of systemic lupus erythematosus. , 2001, Clinical immunology.

[35]  H. Maier,et al.  Chemokine expression precedes inflammatory cell infiltration and chemokine receptor and cytokine expression during the initiation of murine lupus nephritis. , 2001, Journal of the American Society of Nephrology : JASN.

[36]  M. Mattson,et al.  Stem cells and aging: expanding the possibilities , 2001, Mechanisms of Ageing and Development.

[37]  K. Tracey,et al.  High Mobility Group 1 Protein (Hmg-1) Stimulates Proinflammatory Cytokine Synthesis in Human Monocytes , 2000, The Journal of experimental medicine.

[38]  T. Kislinger,et al.  Blockade of RAGE–amphoterin signalling suppresses tumour growth and metastases , 2000, Nature.

[39]  B. Rollins,et al.  Monocyte Chemoattractant Protein 1–Dependent Leukocytic Infiltrates Are Responsible for Autoimmune Disease in Mrl-Faslpr Mice , 1999, The Journal of experimental medicine.

[40]  M. Shlomchik,et al.  The central and multiple roles of B cells in lupus pathogenesis , 1999, Immunological reviews.

[41]  M. Yoshida,et al.  Prevalence and characterization of novel pANCA, antibodies to the high mobility group non-histone chromosomal proteins HMG1 and HMG2, in systemic rheumatic diseases. , 1998, The Journal of rheumatology.

[42]  D. Prockop Marrow Stromal Cells as Stem Cells for Nonhematopoietic Tissues , 1997, Science.

[43]  A. Abbas,et al.  Role of Fas-mediated cell death in the regulation of immune responses. , 1996, Current opinion in immunology.

[44]  K. Matsushima,et al.  Monitoring urinary levels of monocyte chemotactic and activating factor reflects disease activity of lupus nephritis. , 1996, Kidney international.

[45]  S. Rajagopalan,et al.  Structure and specificity of T cell receptors expressed by potentially pathogenic anti-DNA autoantibody-inducing T cells in human lupus. , 1995, The Journal of clinical investigation.

[46]  A. Friedenstein,et al.  STROMAL CELLS RESPONSIBLE FOR TRANSFERRING THE MICROENVIRONMENT OF THE HEMOPOIETIC TISSUES: Cloning In Vitro and Retransplantation In Vivo , 1974, Transplantation.

[47]  T. Misteli,et al.  Release of chromatin protein HMGB1 by necrotic cells triggers inflammation , 2010, Nature.

[48]  S. Yamada,et al.  HMGB1, a novel inflammatory cytokine. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[49]  Qin-jun Zhao,et al.  Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. , 2006, Haematologica.

[50]  F. Benvenuto,et al.  Human mesenchymal stem cells modulate B-cell functions. , 2006, Blood.

[51]  清水 早希子 Anti-monocyte chemoattractant protein-1 gene therapy attenuates nephritis in MRL/lpr mice , 2005 .

[52]  A. Friedenstein,et al.  Stromal stem cells: marrow-derived osteogenic precursors. , 1988, Ciba Foundation symposium.

[53]  T. Takahashi [Erythematosus]. , 1971, Nihon rinsho. Japanese journal of clinical medicine.