It has been shown that bone marrow mesenchymal stromal cells (MSCs) from patients with myelodysplastic syndromes (MDSs) display defective proliferative potential. We have probed the impaired replicative capacity of culture-expanded MSCs in MDS patients (n=30) compared with healthy subjects (n=32) by studying senescence characteristics and gene expression associated with WNT/transforming growth factor-β1 (TGFB1) signaling pathways. We have also explored the consequences of the impaired patient MSC proliferative potential by investigating their differentiation potential and the capacity to support normal CD34(+) cell growth under coculture conditions. Patient MSCs displayed decreased gene expression of the senescence-associated cyclin-dependent kinase inhibitors CDKN1A, CDKN2A, and CDKN2B, along with PARG1, whereas the mean telomere length was upregulated in patient MSCs. MDS-derived MSCs exhibited impaired capacity to support normal CD34(+) myeloid and erythroid colony formation. No significant changes were observed between patients and controls in gene expression related to TGFB1 pathway. Patient MSCs displayed upregulated non-canonical WNT expression, combined with downregulated canonical WNT expression and upregulated canonical WNT inhibitors. MDS-derived MSCs displayed defective osteogenic and adipogenic lineage priming under non-differentiating culture conditions. Pharmacological activation of canonical WNT signaling in patient MDSs led to an increase in cell proliferation and upregulation in the expression of early osteogenesis-related genes. This study indicates abnormal WNT signaling in MSCs of MDS patients and supports the concept of a primary MSC defect that might have a contributory effect in MDS natural history.
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