title: Impaired proliferative potential of bone marrow mesenchymal stromal cells in patients with myelodysplastic syndromes is associated with abnormal WNT signaling pathway.
abstract: 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.
authors.affiliation: 1 Department of Haematology, University of Crete School of Medicine , Heraklion, Greece .
authors.forename: Konstantia
authors.initials: K
authors.lastname: Pavlaki
authors.forename: Charalampos G
authors.initials: CG
authors.lastname: Pontikoglou
authors.forename: Anthi
authors.initials: A
authors.lastname: Demetriadou
authors.forename: Aristea K
authors.initials: AK
authors.lastname: Batsali
authors.forename: Athina
authors.initials: A
authors.lastname: Damianaki
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Simantirakis
authors.forename: Michail
authors.initials: M
authors.lastname: Kontakis
authors.forename: Athanasios
authors.initials: A
authors.lastname: Galanopoulos
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kotsianidis
authors.forename: Maria-Christina
authors.initials: MC
authors.lastname: Kastrinaki
authors.forename: Helen A
authors.initials: HA
authors.lastname: Papadaki
mesh_terms: D050156:Adipogenesis / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D001854:Bone Marrow Cells / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics*