Immune-mediated bone marrow failure syndromes (BMFS) are characterized by ineffective marrow haemopoiesis and subsequent peripheral cytopenias. Ineffective haemopoiesis is the result of a complex marrow deregulation including genetic, epigenetic, and immune-mediated alterations in haemopoietic stem/progenitor cells, as well as abnormal haemopoietic-to-stromal cell interactions, with abnormal release of haemopoietic growth factors, chemokines, and inhibitors. Mesenchymal stem/stromal cells (MSCs) and their progeny (i.e., osteoblasts, adipocytes, and reticular cells) are considered as key cellular components of the bone marrow haemopoietic niche. MSCs may interfere with haemopoietic as well as immune regulation. Evidence suggests that bone marrow MSCs may be involved in immune-mediated BMFS underlying pathophysiology, harboring either native abnormalities and/or secondary defects, caused by exposure to activated marrow components. This review summarizes previous as well as more recent information related to the biologic/functional characteristics of bone marrow MSCs in myelodysplastic syndromes, acquired aplastic anemia, and chronic idiopathic neutropenia. 1. Introduction Immune-mediated bone marrow failure syndromes (BMFS), such as the myelodysplastic syndromes, acquired aplastic anemia, or chronic idiopathic neutropenia, are characterized by ineffective marrow haemopoiesis and subsequent peripheral cytopenias. Pathogenetic mechanisms involve a complex marrow deregulation, including genetic and epigenetic alterations, resulting in aberrant release of haemopoietic growth factors and inhibitors in the marrow, deregulated immune manifestations, all resulting in defective haemopoietic maturation and increased haemopoietic cell apoptosis. Normal haemopoiesis is regulated in the marrow by an extended network of specialized niches, maintaining haemopoietic stem cell (HSC) self-renewal and orchestrating HSC proliferation and differentiation to all blood cell types. Key cellular components of the bone marrow (BM) haemopoietic microenvironment include osteoblasts, sinusoidal endothelial cells, macrophages, adipocytes, and reticular cells, orchestrating the maintenance, proliferation, and differentiation of haemopoietic stem and progenitor cells (HSPCs). Osteoblasts, adipocytes, and reticular cells of the marrow stroma derive from a common progenitor cell, the mesenchymal stem/stromal cell (MSC) [1–5]. Since MSCs and their progeny are among the main components of the marrow stroma, it is reasonable to assume that patient BM MSCs may be partially defective,
References
[1]
S. L. Ellis and S. K. Nilsson, “The location and cellular composition of the hemopoietic stem cell niche,” Cytotherapy, vol. 14, no. 2, pp. 135–143, 2012.
[2]
D. Cook and P. Genever, “Regulation of mesenchymal stem cell differentiation,” Advances in Experimental Medicine and Biology, vol. 786, pp. 213–229, 2013.
[3]
M. F. Pittenger, A. M. Mackay, S. C. Beck et al., “Multilineage potential of adult human mesenchymal stem cells,” Science, vol. 284, no. 5411, pp. 143–147, 1999.
[4]
C. Pontikoglou, B. Delorme, and P. Charbord, “Human bone marrow native mesenchymal stem cells,” Regenerative Medicine, vol. 3, no. 5, pp. 731–741, 2008.
[5]
P. S. Frenette, S. Pinho, D. Lucas, et al., “Mesenchymal stem cell: keystone of the hematopoietic stem cell niche and a stepping-stone for regenerative medicine,” Annual Review of Immunology, vol. 31, pp. 285–316, 2013.
[6]
G. Thanabalasundaram, N. Arumalla, H. D. Tailor, and W. S. Khan, “Regulation of differentiation of mesenchymal stem cells into musculoskeletal cells,” Current Stem Cell Research and Therapy, vol. 7, no. 2, pp. 95–102, 2012.
[7]
D. Woodbury, E. J. Schwarz, D. J. Prockop, et al., “Adult rat and human bone marrow stromal cells differentiate into neurons,” Journal of Neuroscience Research, vol. 61, pp. 364–370, 2000.
[8]
L. Zhang, J. S. Ye, V. Decot, et al., “Research on stem cells as candidates to be differentiated into hepatocytes,” Bio-Medical Materials and Engineering, vol. 22, pp. 105–111, 2012.
[9]
A. J. Friedenstein, U. F. Gorskaja, and N. N. Kulagina, “Fibroblast precursors in normal and irradiated mouse hematopoietic organs,” Experimental Hematology, vol. 4, no. 5, pp. 267–274, 1976.
[10]
G. T. Huang, S. Gronthos, and S. Shi, “Critical reviews in oral biology & medicine: mesenchymal stem cells derived from dental tissues vs. those from other sources: their biology and role in Regenerative Medicine,” Journal of Dental Research, vol. 88, no. 9, pp. 792–806, 2009.
[11]
C. S. Lin, G. Lin, and T. F. Lue, “Allogeneic and xenogeneic transplantation of adipose-derived stem cells in immunocompetent recipients without immunosuppressants,” Stem Cells and Development, vol. 21, no. 15, pp. 2770–2778, 2012.
[12]
F. Sabatini, L. Petecchia, M. Tavian, V. J. De Villeroché, G. A. Rossi, and D. Brouty-Boyé, “Human bronchial fibroblasts exhibit a mesenchymal stem cell phenotype and multilineage differentiating potentialities,” Laboratory Investigation, vol. 85, no. 8, pp. 962–971, 2005.
[13]
S. Karahuseyinoglu, O. Cinar, E. Kilic et al., “Biology of stem cells in human umbilical cord stroma: in situ and in vitro surveys,” Stem Cells, vol. 25, no. 2, pp. 319–331, 2007.
[14]
M. Dominici, K. Le Blanc, I. Mueller et al., “Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement,” Cytotherapy, vol. 8, no. 4, pp. 315–317, 2006.
[15]
V. L. Battula, S. Treml, P. M. Bareiss et al., “Isolation of functionally distinct mesenchymal stem cell subsets using antibodies against CD56, CD271, and mesenchymal stem cell antigen-1,” Haematologica, vol. 94, no. 2, pp. 173–184, 2009.
[16]
A. Hatzfeld, P. Eid, I. Peiffer et al., “A sub-population of high proliferative potential-quiescent human mesenchymal stem cells is under the reversible control of interferon α/β,” Leukemia, vol. 21, no. 4, pp. 714–724, 2007.
[17]
T. Sugiyama, H. Kohara, M. Noda, and T. Nagasawa, “Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches,” Immunity, vol. 25, no. 6, pp. 977–988, 2006.
[18]
L. M. Calvi, G. B. Adams, K. W. Weibrecht et al., “Osteoblastic cells regulate the haematopoietic stem cell niche,” Nature, vol. 425, no. 6960, pp. 841–846, 2003.
[19]
B. Sacchetti, A. Funari, S. Michienzi et al., “Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment,” Cell, vol. 131, no. 2, pp. 324–336, 2007.
[20]
S. R. Mayack and A. J. Wagers, “Osteolineage niche cells initiate hematopoietic stem cell mobilization,” Blood, vol. 112, no. 3, pp. 519–531, 2008.
[21]
B. R. Chitteti, Y. Cheng, B. Poteat et al., “Impact of interactions of cellular components of the bone marrow microenvironment on hematopoietic stem and progenitor cell function,” Blood, vol. 115, no. 16, pp. 3239–3248, 2010.
[22]
O. Naveiras, V. Nardi, P. L. Wenzel, P. V. Hauschka, F. Fahey, and G. Q. Daley, “Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment,” Nature, vol. 460, no. 7252, pp. 259–263, 2009.
[23]
Y. Omatsu, T. Sugiyama, H. Kohara et al., “The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche,” Immunity, vol. 33, no. 3, pp. 387–399, 2010.
[24]
Y. S. Tzeng, H. Li, Y. L. Kang, W. Chen, W. Cheng, and D. Lai, “Loss of Cxcl12/Sdf-1 in adult mice decreases the quiescent state of hematopoietic stem/progenitor cells and alters the pattern of hematopoietic regeneration after myelosuppression,” Blood, vol. 117, no. 2, pp. 429–439, 2011.
[25]
S. Méndez-Ferrer, T. V. Michurina, F. Ferraro et al., “Mesenchymal and haematopoietic stem cells form a unique bone marrow niche,” Nature, vol. 466, no. 7308, pp. 829–834, 2010.
[26]
M. Sharma, F. Afrin, N. Satija, R. P. Tripathi, and G. U. Gangenahalli, “Stromal-derived factor-1/CXCR4 signaling: indispensable role in homing and engraftment of hematopoietic stem cells in bone marrow,” Stem Cells and Development, vol. 20, no. 6, pp. 933–946, 2011.
[27]
A. Chabanon, C. Desterke, E. Rodenburger et al., “A cross-talk between stromal cell-derived factor-1 and transforming growth factor-β controls the quiescence/cycling switch of CD34+ progenitors through FoxO3 and mammalian target of rapamycin,” Stem Cells, vol. 26, no. 12, pp. 3150–3161, 2008.
[28]
J. J. Lataillade, D. Clay, C. Dupuy et al., “Chemokine SDF-1 enhances circulating CD34+ cell proliferation in synergy with cytokines: possible role in progenitor survival,” Blood, vol. 95, no. 3, pp. 756–768, 2000.
[29]
J. J. Lataillade, D. Clay, P. Bourin et al., “Stromal cell-derived factor 1 regulates primitive hematopoiesis by suppressing apoptosis and by promoting G0/G1 transition in CD34+ cells: evidence for an autocrine/paracrine mechanism,” Blood, vol. 99, no. 4, pp. 1117–1129, 2002.
[30]
E. Flores-Figueroa, S. Varma, K. Montgomery, et al., “Distinctive contact between CD34+ hematopoietic progenitors and CXCL12+ CD271+ mesenchymal stromal cells in benign and myelodysplastic bone marrow,” Laboratory Investigation, vol. 92, pp. 1330–1341, 2012.
[31]
F. Dazzi, R. Ramasamy, S. Glennie, S. P. Jones, and I. Roberts, “The role of mesenchymal stem cells in haemopoiesis,” Blood Reviews, vol. 20, no. 3, pp. 161–171, 2006.
[32]
K. C. Kemp, J. Hows, and C. Donaldson, “Bone marrow-derived mesenchymal stem cells,” Leukemia and Lymphoma, vol. 46, no. 11, pp. 1531–1544, 2005.
[33]
L. da Silva Meirelles, A. M. Fontes, D. T. Covas, and A. I. Caplan, “Mechanisms involved in the therapeutic properties of mesenchymal stem cells,” Cytokine and Growth Factor Reviews, vol. 20, no. 5-6, pp. 419–427, 2009.
[34]
L. von Bahr, B. Sundberg, L. L？nnies et al., “Long-term complications, immunologic effects, and role of passage for outcome in mesenchymal stromal cell therapy,” Biology of Blood and Marrow Transplantation, vol. 18, no. 4, pp. 557–564, 2012.
[35]
M. Di Nicola, C. Carlo-Stella, M. Magni et al., “Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli,” Blood, vol. 99, no. 10, pp. 3838–3843, 2002.
[36]
S. Asari, S. Itakura, K. Ferreri et al., “Mesenchymal stem cells suppress B-cell terminal differentiation,” Experimental Hematology, vol. 37, no. 5, pp. 604–615, 2009.
[37]
A. Corcione, F. Benvenuto, E. Ferretti et al., “Human mesenchymal stem cells modulate B-cell functions,” Blood, vol. 107, no. 1, pp. 367–372, 2006.
[38]
G. M. Spaggiari and L. Moretta, “Cellular and molecular interactions of mesenchymal stem cells in innate immunity,” Immunology & Cell Biology, vol. 91, pp. 27–31, 2013.
[39]
P. Luz-Crawford, M. Kurte, J. Bravo-Alegria, et al., “Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells,” Stem Cell Research & Therapy, vol. 4, p. 65, 2013.
[40]
D. Chabannes, M. Hill, E. Merieau et al., “A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells,” Blood, vol. 110, no. 10, pp. 3691–3694, 2007.
[41]
B. J. Jones, G. Brooke, K. Atkinson, and S. J. McTaggart, “Immunosuppression by placental indoleamine 2,3-dioxygenase: a role for mesenchymal stem cells,” Placenta, vol. 28, no. 11-12, pp. 1174–1181, 2007.
[42]
K. Sato, K. Ozaki, I. Oh et al., “Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells,” Blood, vol. 109, no. 1, pp. 228–234, 2007.
[43]
Z. Selmani, A. Naji, I. Zidi et al., “Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+ CD25highFOXP3+ regulatory T cells,” Stem Cells, vol. 26, no. 1, pp. 212–222, 2008.
[44]
R. S. Waterman, S. L. Tomchuck, S. L. Henkle, and A. M. Betancourt, “A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype,” PLoS ONE, vol. 5, no. 4, Article ID e10088, 2010.
[45]
J. L. Chan, K. C. Tang, A. P. Patel et al., “Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-γ,” Blood, vol. 107, no. 12, pp. 4817–4824, 2006.
[46]
M. Krampera, L. Cosmi, R. Angeli et al., “Role for interferon-γ in the immunomodulatory activity of human bone marrow mesenchymal stem cells,” Stem Cells, vol. 24, no. 2, pp. 386–398, 2006.
[47]
S. J. Prasanna, D. Gopalakrishnan, S. R. Shankar, and A. B. Vasandan, “Pro-inflammatory cytokines, IFNγ and TNFα, influence immune properties of human bone marrow and Wharton jelly mesenchymal stem cells differentially,” PLoS ONE, vol. 5, no. 2, Article ID e9016, 2010.
[48]
E. Campo, S. H. Swerdlow, N. L. Harris, S. Pileri, H. Stein, and E. S. Jaffe, “The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications,” Blood, vol. 117, no. 19, pp. 5019–5032, 2011.
[49]
P. Greenberg, C. Cox, M. M. LeBeau et al., “International scoring system for evaluating prognosis in myelodysplastic syndromes,” Blood, vol. 89, no. 6, pp. 2079–2088, 1997.
[50]
P. Beris and G. Georgiou, “Overview of myelodysplastic syndromes,” Seminars in Hematology, vol. 49, no. 4, pp. 287–294, 2012.
[51]
H. Khan, C. Vale, T. Bhagat, et al., “Role of DNA methylation in the pathogenesis and treatment of myelodysplastic syndromes,” Seminars in Hematology, vol. 50, no. 1, pp. 16–37, 2013.
[52]
S. D. Nimer, “Myelodysplastic syndromes,” Blood, vol. 111, no. 10, pp. 4841–4851, 2008.
[53]
F. Nolte and W. Hofmann, “Myelodysplastic syndromes: molecular pathogenesis and genomic changes,” Annals of Hematology, vol. 87, no. 10, pp. 777–795, 2008.
[54]
R. Tiu, L. Gondek, C. O'Keefe, and J. P. Maciejewski, “Clonality of the stem cell compartment during evolution of myelodysplastic syndromes and other bone marrow failure syndromes,” Leukemia, vol. 21, no. 8, pp. 1648–1657, 2007.
[55]
C. Fozza and M. Longinotti, “The role of T-cells in the pathogenesis of myelodysplastic syndromes: passengers and drivers,” Leukemia Research, vol. 37, no. 2, pp. 201–203, 2013.
[56]
S. Tauro, M. D. Hepburn, C. M. Peddie, D. T. Bowen, and M. J. Pippard, “Functional disturbance of marrow stromal microenvironment in the myelodysplastic syndromes,” Leukemia, vol. 16, no. 5, pp. 785–790, 2002.
[57]
S. Aizawa, M. Nakano, O. Iwase et al., “Bone marrow stroma from refractory anemia of myelodysplastic syndrome is defective in its ability to support normal CD34-positive cell proliferation and differentiation in vitro,” Leukemia Research, vol. 23, no. 3, pp. 239–246, 1999.
[58]
M. H. Raaijmakers, S. Mukherjee, S. Guo et al., “Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia,” Nature, vol. 464, no. 7290, pp. 852–857, 2010.
[59]
C. R. Walkley, G. H. Olsen, S. Dworkin et al., “A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor γ deficiency,” Cell, vol. 129, no. 6, pp. 1097–1110, 2007.
[60]
E. Flores-Figueroa, R. M. Arana-Trejo, G. Gutiérrez-Espíndola, A. Pérez-Cabrera, and H. Mayani, “Mesenchymal stem cells in myelodysplastic syndromes: phenotypic and cytogenetic characterization,” Leukemia Research, vol. 29, no. 2, pp. 215–224, 2005.
[61]
E. Flores-Figueroa, J. J. Montesinos, P. Flores-Guzmán et al., “Functional analysis of myelodysplastic syndromes-derived mesenchymal stem cells,” Leukemia Research, vol. 32, no. 9, pp. 1407–1416, 2008.
[62]
M. Klaus, E. Stavroulaki, M. Kastrinaki et al., “Reserves, functional, immunoregulatory, and cytogenetic properties of bone marrow mesenchymal stem cells in patients with myelodysplastic syndromes,” Stem Cells and Development, vol. 19, no. 7, pp. 1043–1054, 2010.
[63]
D. Campioni, S. Moretti, L. Ferrari, M. Punturieri, G. L. Castoldi, and F. Lanza, “Immunophenotypic heterogeneity of bone marrow-derived mesenchymal stromal cells from patients with hematologic disorders: correlation with bone marrow microenvironment,” Haematologica, vol. 91, no. 3, pp. 364–368, 2006.
[64]
D. Campioni, R. Rizzo, M. Stignani et al., “A decreased positivity for CD90 on human mesenchymal stromal cells (MSCs) is associated with a loss of immunosuppressive activity by MSCs,” Cytometry B, vol. 76, no. 3, pp. 225–230, 2009.
[65]
O. Lopez-Villar, J. L. Garcia, F. M. Sanchez-Guijo et al., “Both expanded and uncultured mesenchymal stem cells from MDS patients are genomically abnormal, showing a specific genetic profile for the 5q- syndrome,” Leukemia, vol. 23, no. 4, pp. 664–672, 2009.
[66]
S. Geyh, S. Oz, R. P. Cadeddu, et al., “Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells,” Leukemia, vol. 27, pp. 1841–1851, 2013.
[67]
Z. G. Zhao, W. Xu, H. P. Yu et al., “Functional characteristics of mesenchymal stem cells derived from bone marrow of patients with myelodysplastic syndromes,” Cancer Letters, vol. 317, no. 2, pp. 136–143, 2012.
[68]
C. M. Aanei, F. Z. Eloae, P. Flandrin-Gresta et al., “Focal adhesion protein abnormalities in myelodysplastic mesenchymal stromal cells,” Experimental Cell Research, vol. 317, no. 18, pp. 2616–2629, 2011.
[69]
M. K. Yüksel, P. Top？uo？lu, M. Kurdal, and O. Ilhan, “The clonogenic potential of hematopoietic stem cells and mesenchymal stromal cells in various hematologic diseases: a pilot study,” Cytotherapy, vol. 12, no. 1, pp. 38–44, 2010.
[70]
G. Varga, J. Kiss, J. Várkonyi et al., “Inappropriate Notch activity and limited mesenchymal stem cell plasticity in the bone marrow of patients with myelodysplasia syndromes,” Pathology and Oncology Research, vol. 13, no. 4, pp. 311–319, 2007.
[71]
C. M. Aanei, P. Flandrin, F. Z. Eloae, et al., “Intrinsic growth deficiencies of mesenchymal stromal cells in myelodysplastic syndromes,” Stem Cells and Development, vol. 21, no. 10, pp. 1604–1615, 2012.
[72]
Z. Zhao, Z. Wang, Q. Li, et al., “The different immunoregulatory functions of mesenchymal stem cells in patients with low-risk or high-risk myelodysplastic syndromes,” PLoS ONE, vol. 7, no. 9, Article ID e45675, 2012.
[73]
A. M. Marcondes, S. Bair, P. S. Rabinovitch, T. Gooley, H. J. Deeg, and R. Risques, “No telomere shortening in marrow stroma from patients with MDS,” Annals of Hematology, vol. 88, no. 7, pp. 623–628, 2009.
[74]
B. Delorme, J. Ringe, C. Pontikoglou et al., “Specific lineage-priming of bone marrow mesenchymal stem cells provides the molecular framework for their plasticity,” Stem Cells, vol. 27, no. 5, pp. 1142–1151, 2009.
[75]
A. Ramakrishnan, N. Awaya, E. Bryant, and B. Torok-Storb, “The stromal component of the marrow microenvironment is not derived from the malignant clone in MDS,” Blood, vol. 108, no. 2, pp. 772–773, 2006.
[76]
V. Soenen-Cornu, C. Tourino, M. Bonnet et al., “Mesenchymal cells generated from patients with myelodysplastic syndromes are devoid of chromosomal clonal markers and support short- and long-term hematopoiesis in vitro,” Oncogene, vol. 24, no. 15, pp. 2441–2448, 2005.
[77]
O. Blau, C. D. Baldus, W. Hofmann et al., “Mesenchymal stromal cells of myelodysplastic syndrome and acute myeloid leukemia patients have distinct genetic abnormalities compared with leukemic blasts,” Blood, vol. 118, no. 20, pp. 5583–5592, 2011.
[78]
O. Blau, W. Hofmann, C. D. Baldus et al., “Chromosomal aberrations in bone marrow mesenchymal stroma cells from patients with myelodysplastic syndrome and acute myeloblastic leukemia,” Experimental Hematology, vol. 35, no. 2, pp. 221–229, 2007.
[79]
Q. Han, Z. Sun, L. Liu et al., “Impairment in immuno-modulatory function of Flk1+CD31-CD34- MSCs from MDS-RA patients,” Leukemia Research, vol. 31, no. 11, pp. 1469–1478, 2007.
[80]
Z. Wang, X. Tang, W. Xu, et al., “The different immunoregulatory functions on dendritic cells between mesenchymal stem cells derived from bone marrow of patients with low-risk or high-risk myelodysplastic syndromes,” PLoS ONE, vol. 8, no. 3, Article ID e57470, 2013.
[81]
Z. Zhi-Gang, L. Wei-Ming, C. Zhi-Chao, Y. Yong, and Z. Ping, “Immunosuppressive properties of mesenchymal stem cells derived from bone marrow of patient with hematological malignant diseases,” Leukemia and Lymphoma, vol. 49, no. 11, pp. 2187–2195, 2008.
[82]
C. Santamaria, S. Muntion, B. Roson, et al., “Impaired expression of DICER, DROSHA, SBDS and some microRNAs in mesenchymal stromal cells from myelodysplastic syndrome patients,” Haematologica, vol. 97, no. 8, pp. 1218–1224, 2012.
[83]
E. C. Guinan, “Diagnosis and management of aplastic anemia,” Hematology, vol. 2011, pp. 76–81, 2011.
[84]
J. P. Li, C. L. Zheng, and Z. C. Han, “Abnormal immunity and stem/progenitor cells in acquired aplastic anemia,” Critical Reviews in Oncology/Hematology, vol. 75, no. 2, pp. 79–93, 2010.
[85]
N. C. Giannakoulas, M. Karakantza, G. L. Theodorou et al., “Clinical relevance of balance between type 1 and type 2 immune responses of lymphocyte subpopulations in aplastic anaemia patients,” British Journal of Haematology, vol. 124, no. 1, pp. 97–105, 2004.
[86]
H. Kook, W. Zeng, C. Guibin, M. Kirby, N. S. Young, and J. P. Maciejewski, “Increased cytotoxic T cells with effector phenotype in aplastic anemia and myelodysplasia,” Experimental Hematology, vol. 29, no. 11, pp. 1270–1277, 2001.
[87]
S. Zonghong, T. Meifeng, W. Huaquan et al., “Circulating myeloid dendritic cells are increased in individuals with severe aplastic anemia,” International Journal of Hematology, vol. 93, no. 2, pp. 156–162, 2011.
[88]
E. E. Solomou, K. Rezvani, S. Mielke et al., “Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia,” Blood, vol. 110, no. 5, pp. 1603–1606, 2007.
[89]
S. Dubey, P. Shukla, and S. Nityanand, “Expression of interferon-γ and tumor necrosis factor-α in bone marrow T cells and their levels in bone marrow plasma in patients with aplastic anemia,” Annals of Hematology, vol. 84, no. 9, pp. 572–577, 2005.
[90]
E. Sloand, S. Kim, J. P. Maciejewski, J. Tisdale, D. Follmann, and N. S. Young, “Intracellular interferon-γ in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia,” Blood, vol. 100, no. 4, pp. 1185–1191, 2002.
[91]
W. Zeng, A. Miyazato, G. Chen, S. Kajigaya, N. S. Young, and J. P. Maciejewski, “Interferon-γ-induced gene expression in CD34 cells: identification of pathologic cytokine-specific signature profiles,” Blood, vol. 107, no. 1, pp. 167–175, 2006.
[92]
N. C. Zoumbos, P. Gascon, J. Y. Djeu, and N. S. Young, “Interferon is a mediator of hematopoietic suppression in aplastic anemia in vitro and possibly in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 82, no. 1, pp. 188–192, 1985.
[93]
S. Rizzo, J. Scopes, M. O. Elebute, H. A. Papadaki, E. C. Gordon-Smith, and F. M. Gibson, “Stem cell defect in aplastic anemia: reduced long term culture-initiating cells (LTC-IC) in CD34+ cells isolated from aplastic anemia patient bone marrow,” Hematology Journal, vol. 3, no. 5, pp. 230–236, 2002.
[94]
W. H. Matsui, R. A. Brodsky, B. D. Smith, M. J. Borowitz, and R. J. Jones, “Quantitative analysis of bone marrow CD34 cells in aplastic anemia and hypoplastic myelodysplastic syndromes,” Leukemia, vol. 20, no. 3, pp. 458–462, 2006.
[95]
J. Scopes, M. Bagnara, E. C. Gordon-Smith, S. E. Ball, and F. M. Gibson, “Haemopoietic progenitor cells are reduced in aplastic anaemia,” British Journal of Haematology, vol. 86, no. 2, pp. 427–430, 1994.
[96]
F. Timeus, N. Crescenzio, A. Doria et al., “Flow cytometric evaluation of circulating CD34+ cell counts and apoptotic rate in children with acquired aplastic anemia and myelodysplasia,” Experimental Hematology, vol. 33, no. 5, pp. 597–604, 2005.
[97]
S. B. Killick, C. V. Cox, J. C. W. Marsh, E. C. Gordon-Smith, and F. M. Gibson, “Mechanisms of bone marrow progenitor cell apoptosis in aplastic anaemia and the effect of anti-thymocyte globulin: examination of the role of the Fas-Fas-L interaction,” British Journal of Haematology, vol. 111, no. 4, pp. 1164–1169, 2000.
[98]
A. M. Risitano, H. Kook, W. Zeng, G. Chen, N. S. Young, and J. P. Maciejewski, “Oligoclonal and polyclonal CD4 and CD8 lymphocytes in aplastic anemia and paroxysmal nocturnal hemoglobinuria measured by Vβ CDR3 spectratyping and flow cytometry,” Blood, vol. 100, no. 1, pp. 178–183, 2002.
[99]
W. Zeng, J. P. Maciejewski, G. Chen, and N. S. Young, “Limited heterogeneity of T cell receptor BV usage in aplastic anemia,” Journal of Clinical Investigation, vol. 108, no. 5, pp. 765–773, 2001.
[100]
N. C. Zoumbos, P. Gascon, and J. Y. Djeu, “Circulating activated suppressor T lymphocytes in aplastic anemia,” New England Journal of Medicine, vol. 312, no. 5, pp. 257–265, 1985.
[101]
A. Luther-Wyrsch, C. Nissen, and A. Wodnar-Filipowicz, “Intracellular Fas ligand is elevated in T lymphocytes in severe aplastic anaemia,” British Journal of Haematology, vol. 114, no. 4, pp. 884–890, 2001.
[102]
J. P. Maciejewski, C. Selleri, T. Sato, S. Anderson, and N. S. Young, “Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anaemia,” British Journal of Haematology, vol. 91, no. 1, pp. 245–252, 1995.
[103]
A. Bacigalupo, M. Valle, M. Podestà et al., “T-cell suppression mediated by mesenchymal stem cells is deficient in patients with severe aplastic anemia,” Experimental Hematology, vol. 33, no. 7, pp. 819–827, 2005.
[104]
Y. Xu, Y. Takahashi, Y. Wang et al., “Downregulation of GATA-2 and overexpression of adipogenic gene-PPARγ in mesenchymal stem cells from patients with aplastic anemia,” Experimental Hematology, vol. 37, no. 12, pp. 1393–1399, 2009.
[105]
J. Li, S. Yang, S. Lu, et al., “Differential gene expression profile associated with the abnormality of bone marrow mesenchymal stem cells in aplastic anemia,” PLoS ONE, vol. 7, no. 11, Article ID e47764, 2012.
[106]
Y. Chao, C. Peng, H. Harn, C. Chan, and K. Wu, “Poor potential of proliferation and differentiation in bone marrow mesenchymal stem cells derived from children with severe aplastic anemia,” Annals of Hematology, vol. 89, no. 7, pp. 715–723, 2010.
[107]
I. N. Shipounova, T. V. Petrova, D. A. Svinareva, K. S. Momotuk, E. A. Mikhailova, and N. I. Drize, “Alterations in hematopoietic microenvironment in patients with aplastic anemia,” Clinical and Translational Science, vol. 2, no. 1, pp. 67–74, 2009.
[108]
Y. Xu, Y. Takahashi, A. Yoshimi, M. Tanaka, H. Yagasaki, and S. Kojima, “Immunosuppressive activity of mesenchymal stem cells is not decreased in children with aplastic anemia,” International Journal of Hematology, vol. 89, no. 1, pp. 126–127, 2009.
[109]
H. A. Papadaki, J. Palmblad, and G. D. Eliopoulos, “Non-immune chronic idiopathic neutropenia of adult: an overview,” European Journal of Haematology, vol. 67, no. 1, pp. 35–44, 2001.
[110]
H. A. Papadaki, A. G. Eliopoulos, T. Kosteas et al., “Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells,” Blood, vol. 101, no. 7, pp. 2591–2600, 2003.
[111]
E. Stavroulaki, M. Kastrinaki, C. Pontikoglou et al., “Mesenchymal stem cells contribute to the abnormal bone marrow microenvironment in patients with chronic idiopathic neutropenia by overproduction of transforming growth factor-β1,” Stem Cells and Development, vol. 20, no. 8, pp. 1309–1318, 2011.
