Mesenchymal stem cells contribute to the abnormal bone marrow microenvironment in patients with chronic idiopathic neutropenia by overproduction of transforming growth factor-β1.
Chronic idiopathic neutropenia (CIN) is a granulopoiesis disorder associated with an inhibitory bone marrow (BM) microenvironment consisting of activated T-lymphocytes and pro-inflammatory mediators. In this study, we investigated the possible involvement of BM mesenchymal stem cells (MSCs) in the pathophysiology of CIN by assessing the frequency and function of BM MSCs in terms of the proliferative/clonogenic characteristics, the differentiation capacity, the potential to produce pro-inflammatory cytokines, and the ability to suppress T-cell proliferation. The frequency, differentiation capacity toward adipocytes, chondrocytes, or osteoblasts, and immunosuppressive potential to inhibit mitogen-induced T-cell proliferation did not differ significantly between patient (n = 14) and normal (n = 21) MSCs. Tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels in MSC supernatants did not differ significantly between patients and controls; however, transforming growth factor (TGF)-β1 levels were significantly elevated in patients, particularly in those displaying the -509C/T TGF-β1 polymorphism. Patient MSCs displayed defective proliferative/clonogenic potential, which could not be attributed to altered cellular survival characteristics or to increased TGF-β1 production as TGF-β1 neutralization did not restore the impaired colony formation by patient MSCs. We conclude that although BM MSCs do not exert a significant role in the immune deregulation associated with CIN, they contribute to the inhibitory microenvironment by overproducing TGF-β1, at least in patients displaying the -509C/T polymorphism.
Department of Hematology, University of Crete School of Medicine, Heraklion, Greece.
Emily
E
Stavroulaki
Maria-Christina
MC
Kastrinaki
Charalampos
C
Pontikoglou
Dimitrios
D
Eliopoulos
Athina
A
Damianaki
Irene
I
Mavroudi
Katerina
K
Pyrovolaki
Pavlos
P
Katonis
Helen A
HA
Papadaki
D000293:Adolescent; D000328:Adult; D000368:Aged; D001853:Bone Marrow / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D009503:Neutropenia / Q000276:immunology* / Q000378:metabolism*; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000276:immunology*
D016207:Cytokines; D053773:Transforming Growth Factor beta1