Inappropriate notch activity and limited mesenchymal stem cell plasticity in the bone marrow of patients with myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDSs) are a heterogeneous group of hematological disorders characterized by ineffective hematopoiesis, enhanced bone marrow apoptosis and frequent progression to acute myeloid leukemia. Several recent studies suggested that, besides the abnormal development of stem cells, microenvironmental alterations are also present in the MDS bone marrow. In this study, we have examined the relative frequencies of stem and progenitor cell subsets of MDS and normal hematopoietic cells growing on stromal cell layers established from MDS patients and from normal donors. When hematopoietic cells from MDS patients were co-cultured with normal stromal cells, the frequency of either early or late cobblestone area-forming cells (CAFC) was significantly lower compared to the corresponding normal control values in 4 out of 8 patients. In the opposite situation, when normal hematopoietic cells were incubated on MDS stromal cells, the CAFC frequencies were decreased in 5 out of 6 patients, compared to normal stromal layer-containing control cultures. Moreover, a soluble Notch ligand (Jagged-1 protein) was an inhibitor of day-35-42 CAFC when normal hematopoietic cells were cultured with normal or MDS stromal cells, but was unable to inhibit MDS stem and early progenitor cell growth (day-35-42 CAFC) on pre-established stromal layers. These findings suggest that in early hematopoietic cells isolated from MDS patients the Notch signal transduction pathway is disrupted. Furthermore, there was a marked reduction in the plasticity of mesenchymal stem cells of MDS patients compared with those of normal marrow donors, in neurogenic and adipogenic differentiation ability and hematopoiesis supporting capacity in vitro. These results are consistent with the hypothesis that when alterations are present in the myelodysplastic stroma environment along with intrinsic changes in a hematopoietic stem/progenitor cell clone, both factors might equally contribute to the abnormal hematopoiesis in MDS.

Down-regulation of Dicer1 promotes cellular senescence and decreases the differentiation and stem cell-supporting capacities of mesenchymal stromal cells in patients with myelodysplastic syndrome

“…These observations agree with the findings of several previously published studies, 7,10,12,29,30 but contrast with the data from others 6,9,13 in which MDS-MSC had normal growth. The contradiction might be attributed to the heterogeneity of MDS patients.…”

Mesenchymal stromal cells from patients with myelodyplastic syndrome display distinct functional alterations that are modulated by lenalidomide

“…Mellibovsky et al showed that MDS patients have a typical adynamic bone with decreased mineral deposition 31 and a recent study by Raaijmakers demonstrated how Dicer1 deletion in mice osteoprogenitors leads to bone dysfunction and development of MDS that progresses to AML. 10 Varga et al 25 previously described similar defective adipogenic differentiation in MDS-MSC. Defects of differentiation potential of MSC might have a role in MDS pathophysiology.…”

“…20,23,32,33 Varga et al showed that MDS-MSC provide reduced hematopoietic support. 25 Regarding the influence of MSC on CD34 + cell differentiation, we provide the first evidence of a specific deficiency of MDS-MSC correlating with disease category. It remains to be investigated which pathways are involved in the dysregulated induction of differentiation.…”

“…10 Varga et al 25 previously described similar defective adipogenic differentiation in MDS-MSC. Defects of differentiation potential of MSC might have a role in MDS pathophysiology.…”

“…22,23 In other studies it was shown that MDS-MSC have reduced proliferative capacity although the investigators succeeded in expanding them in vitro. 22,24,25 Two studies by Aanei et al demonstrated again that MDS-MSC present intrinsic growth deficiencies that are related to focal adhesion protein abnormalities; the MSC from patients with refractory cytopenia (mostly LR-MDS patients) had reduced proliferation capacity while cells from patients with an excess of blasts (HR-MDS patients) had increased proliferation. 26,27 This differs from our observations and may be explained by differences in the patients' characteristics, cell sorting strategy, and culture conditions.…”