Defectiveness of bone marrow mesenchymal stem cells in acquired aplastic anemia
ZHANG Jing-Liao, ZHU Xiao-Fan
Diagnosis and Treatment Center of Pediatric Blood Diseases, Institute of Hematology and Blood Disease Hospital, Pecking Union Medical College, Chinese Academy of Medical Sciences, Tianjin 300021, China
Abstract:The defectiveness of bone marrow mesenchymal stem cells (BM-MSCs) in acquired aplastic anemia (AA) has been a frequent research topic in recent years. This review summarizes the defectiveness of BM-MSCs which is responsible for the mechanism of acquired AA and the prospective application of BM-MSCs in the treatment of acquired AA. An increasingly number of laboratory statistics has demonstrated that the defectiveness of BM-MSCs is more likely to play an important role in the pathogenesis of AA, namely, the apparently different biological characteristics and gene expression profiles, the decreased ability of supporting hematopoiesis as well as self-renewal and differentiation, and the exhaustion of regulating immune response of hematopoietic environment. Those abnormalities continuously prompt AA to become irreversible bone marrow failure along with the imbalanced immunity. With deepening research on MSCs, infusion of MSCs for the primary purpose of recovering hematopoietic microenvironment may become a new approach for the treatment of AA.
Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia[J]. Blood, 2006, 108(8): 2509-2519.
[2]
Li JP, Zheng CL, Han ZC. Abnormal immunity and stem/progenitor cells in acquired aplastic anemia[J]. Crit Rev Oncol Hematol, 2010, 75(2): 79-93.
[3]
Zoumbos NC, Gascon P, Djeu JY, et al. Interferon is a mediator of hematopoietic suppression in aplastic anemia in vitro and possibly in vivo[J]. Proc Natl Acad Sci U S A., 1985, 82(1): 188-192.
[4]
Verma A, Deb DK, Sassano A, et al. Cutting edge: activation of the p38 mitogen-activated protein kinase signaling pathway mediates cytokine-induced hemopoietic suppression in aplastic anemia[J]. J Immunol, 2002, 168(12): 5984-5988.
[5]
Sloand E, Kim S, Maciejewski JP, et al. Intracellular interferon-γ in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia[J]. Blood, 2002, 100(4): 1185-1191.
[6]
Zeng W, Chen G, Kajigaya S, et al. Gene expression profiling in CD34 cells to identify differences between aplastic anemia patients and healthy volunteers[J]. Blood, 2004, 103(1): 325-332.
[7]
Young NS, Bacigalupo A, Marsh JCW. Aplastic anemia: pathophysiology and treatment[J]. Biol Blood Marrow Transplant, 2010, 16(1): S119-S125.
Li JP, Lu SH, Yang SG, et al. Impaired immunomodulatory ability of bone marrow mesenchymal stem cells on CD4+ T cells in aplastic anemia[J]. Results Immunol, 2012, 2: 142-147.
[12]
Li J, Yang S, Lu S, et al. Differential gene expression profile associated with the abnormality of bone marrow mesenchymal stem cells in aplastic anemia[J]. PloS One, 2012, 7(11): e47764.
[13]
De Lima M, McNiece I, Robinson SN, et al. Cord-blood engraftment with ex vivo mesenchymal cell coculture[J]. N Engl J Med, 2012, 367: 2305e15.
[14]
Bernardo ME, Fibbe WE. Safety and efficacy of mesenchymal stromal cell therapy in autoimmune disorders[J]. Ann N Y Acad Sci, 2012, 1266(1): 107-117.
[15]
Nimer SD, Leung DH, Wolin MJ, et al. Serum stem cell factor levels in patients with aplastic anemia[J]. Int J Hematol, 1994, 60(3): 185-189.
Kojima S, Matsuyama T, Kodera Y. Plasma levels and production of soluble stem cell factor by marrow stromal cells in patients with aplastic anaemia[J]. Br J Haematol, 1997, 99(2): 440-446.
Chen YF, Wu ZM, Xie C, et al. Expression level of IL-6 secreted by bone marrow stromal cells in mice with aplastic anemia[J]. ISRN Hematol, 2013, 2013: 986219.
Di Maggio N, Mehrkens A, Papadimitropoulos A, et al. Fibroblast growth factor-2 maintains a niche-dependent population of self-renewing highly potent non-adherent mesenchymal progenitors through FGFR2c[J]. Stem Cells, 2012, 30(7): 1455-1464.
[22]
Jiang SY, Xie XT, Jiang H, et al. Low expression of basic fibroblastic growth factor in mesenchymal stem cells and bone marrow of children with aplastic anemia[J]. Pediatr Hematol Oncol, 2014, 31(1): 11-19.
[23]
Liu L, Sun Z, Han Q, et al. T-cell suppression mediated by mesenchymal stem cells in patients with chronic aplastic anemia[J]. Basic Clin Med, 2007, 27(9): 1006-1010.
Chao YH, Peng CT, Harn HJ, et al. Poor potential of proliferation and differentiation in bone marrow mesenchymal stem cells derived from children with severe aplastic anemia[J]. Ann Hematol, 2010, 89(7): 715-723.
[26]
El-Mahgoub ER, Ahmed E, Afifi RAEA, et al. Mesenchymal stem cells from pediatric patients with aplastic anemia: isolation, characterization, adipogenic, and osteogenic differentiation[J]. Fetal Pediatr Pathol, 2014, 33(1): 9-15.
Tripathy NK, Singh SP, Nityanand S. Enhanced adipogenicity of bone marrow mesenchymal stem cells in aplastic anemia[J]. Stem Cells In, 2014, 2014: 276862.
[31]
Xu Y, Takahashi Y, Wang Y, et al. Downregulation of GATA-2 and overexpression of adipogenic gene PPARgamma in mesenchymal stem cells from patients with aplastic anemia[J]. Exp Hematol, 2009, 37(12): 1393-1399
[32]
Zhang J, Niu C, Ye L, et al. Identification of the haematopoietic stem cell niche and control of the niche size[J]. Nature, 2003, 425(6960): 836-841.
[33]
Visnjic D, Kalajzic Z, Rowe DW, et al. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency[J]. Blood, 2004, 103(9): 3258-3264.
Bacigalupo A, Valle M, Podestà M, et al. T-cell suppression mediated by mesenchymal stem cells is deficient in patients with severe aplastic anemia[J]. Exp Hematol, 2005, 33(7): 819-827.
[36]
Xu Y, Takahashi Y, Yoshimi A, et al. Immunosuppressive activity of mesenchymal stem cells is not decreased in children with aplastic anemia[J]. Int J Hematol, 2009, 89(1): 126-127.
[37]
Kordasti S, Marsh J, Al-Khan S, et al . Functional characterization of CD4+ T cells in aplastic anemia[J]. Blood, 2012, 119(9): 2033-2043.
[38]
Guo Z, Zheng C, Chen Z, et al. Fetal BM-derived mesenchymal stem cells promote the expansion of human Th17 cells, but inhibit the production of Th1 cells[J]. Eur J Immunol, 2009, 39(10): 2840-2849.
[39]
Chen K, Wang D, Du WT, et al. Human umbilical cord mesenchymal stem cells hUC-MSCs exert immunosuppressive activities through a PGE2-dependent mechanism[J]. Clin Immunol, 2010, 135(3): 448–458.
[40]
Gieseke F, Bohringer J, Bussolari R, et al. Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells[J]. Blood, 2010, 116 (19): 3770–3779.
[41]
Gebler A, Zabel O, Seliger B. The immunomodulatory capacity of mesenchymal stem cells[J]. Trends Mol Med, 2012, 18(2): 128-134.
[42]
Singer NG, Caplan AI. Mesenchymal stem cells: mechanisms of inflammation[J]. Annu Rev Pathol, 2011, 6: 457-478..
[43]
Jaganathan BG, Tisato V, Vulliamy T, et al. Effects of MSC co-injection on the reconstitution of aplastic anemia patient following hematopoietic stem cell transplantation[J]. Leukemia, 2010, 24(10): 1791-1795.
[44]
Wang H, Wang Z, Xue M, et al. Co-transfusion of haploidentical hematopoietic and mesenchymal stromal cells to treat a patient with severe aplastic[J]. Cytotherapy, 2010, 12(4): 563-565.
[45]
Chao YH, Tsai C, Peng CT, et al. Cotransplantation of umbilical cord MSCs to enhance engraftment of hematopoietic stem cells in patients with severe aplastic anemia[J]. Bone Marrow Transp, 2011, 46(10): 1391-1392.
[46]
Wang H, Yan H, Wang Z, et al. Cotransplantation of allogeneic mesenchymal and hematopoietic stem cells in children with aplastic anemia[J]. Pediatrics, 2012, 129(6): e1612-1615.
[47]
de Latour RP, Visconte V, Takaku T, et al. Th17 immune responses contribute to the pathophysiology of aplastic anemia[J]. Blood, 2010, 116(20): 4175-4184 .
[48]
Scheinberg P, Young NS. How I treat acquired aplastic anemia[J]. Blood, 2012, 120(6): 1185-1196
[49]
Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells[J]. Nature, 2006, 441(7090): 235-238.
[50]
Yan Z, Zhuansun Y, Chen R, et al. Immunomodulation of mesenchymal stromal cells on regulatory T cells and its possible mechanism[J]. Exp Cell Res, 2014, 324(1): 65-74.
[51]
Zhang B, Yin Y, Lai RC, et al. Mesenchymal stem cell secretes immunologically active exosomes[J]. Stem Cells Dev, 2014, 23(11): 1233-1244.
Bueno C, Roldan M, Anguita E, et al. Bone marrow mesenchymal stem cells from aplastic anemia patients preserve functional and immune properties and do not contribute to the pathogenesis of the disease[J]. Haematologica, 2014, 99(7): 1168-1175.
[55]
Si Y, Yang K, Qin M, et al. Efficacy and safety of human umbilical cord derived mesenchymal stem cell therapy in children with severe aplastic anemia following allogeneic hematopoietic stem cell transplantation: a retrospective case series of 37 patients[J]. Pediatr Hematol Oncol, 2014, 31(1): 39-49.