Altered Expression and Signalling of Bone Morphogenetic Protein Receptor 1A (BMPR-1A) and Enhanced Hematopoietic Progenitor Cell Growth in Long-Term Stromal Culture Assays from Two Patients with a Myeloproliferative Syndrome and Pulmonary Hypertension
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Titel:
Altered Expression and Signalling of Bone Morphogenetic Protein Receptor 1A (BMPR-1A) and Enhanced Hematopoietic Progenitor Cell Growth in Long-Term Stromal Culture Assays from Two Patients with a Myeloproliferative Syndrome and Pulmonary Hypertension
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<jats:title>Abstract</jats:title>
<jats:p>The rare association of pulmonary hypertension and myeloproliferative syndromes (MPS) has been described previously (Garcia-Manero G et al., Am J Hematol1999; 60(2): 130-5, Dingli D et al., Chest2001, 120(3): 801-8), but the mechanisms contributing to this potentially hazardous condition await further elucidation. Bone morphogenetic protein receptors (BMPR) modulate the size of the hematopoetic niche (Zhang J et al., Nature2003, 425(6960): 836-41), with an inhibitory effect on myeloproliferation. In the pulmonary vascular bed, a decreased or deficient expression of BMPR has been shown to result in the proliferation of vascular smooth-muscle cells, asymmetric neointimal hyperplasia in small pulmonary arteries and subsequent pulmonary hypertension (Lane KB et al., Nat Genet2000, 26(1):81-4; Du L et al, N Engl J Med2003, 348(6): 500-9). We hypothesized that, in patients suffering from MPS and pulmonary hypertension, changes in the expression of BMPR and subsequent signalling molecules Angiopoietin-1 (Ang-1) and its receptor, TIE-2, may occur not only in the lung, but also in the bone marrow and correspond with enhanced myeloproliferation in vitro.</jats:p>
<jats:p>Bone marrow stromal cells were cultured frompatients with pulmonary hypertension and MPS (n=2),patients with MPS and no evidence of pulmonary hypertension (n=3) andhealthy controls (n=3).The cultured cells were subjected to Western Blot analysis for the expression of BMP receptors BMPR-1A and BMPR-2, Angiopoietin-1 and TIE-2. Furthermore, a modified long-term culture initiating cell (LTC-IC) assay was established using the cultured bone marrow stromal cells as layers for autologous and allogeneic progenitor cell assays.</jats:p>
<jats:p>The two patients suffering from both, MPS and pulmonary hypertension, showed a diminished expression of BMPR-1A and an enhanced expression of Ang-1 and TIE-2 in cultured stromal cells when compared to patients with MPS alone and to healthy controls. In one of the two patients, a three- to fourfold increase in the number of long-term culture-initiating cells after seeding of CD34-positive cells and of bone marrow mononuclear cells from healthy donors and from the other patients included was observed in modified LTC-IC assays.</jats:p>
<jats:p>Our observations argue in favour of changes in BMP receptor expression and signalling with impact not only on pulmonary hypertension as described before, but also on the emergence of a myeloproliferative state.</jats:p>