Impaired proliferative potential of bone marrow mesenchymal stem cells in patients with myelodysplastic syndromes is associated with abnormal WNT signaling pathway | Aplastic Anemia and MDS International Foundation

Impaired proliferative potential of bone marrow mesenchymal stem cells in patients with myelodysplastic syndromes is associated with abnormal WNT signaling pathway

Journal Title: 
Stem Cells Dev
Author(s): 
Pavlaki K, Pontikoglou CG, Demetriadou A, Batsali AK, Damianaki A, Simantirakis E, Kontakis M, Galanopoulos A, Kotsianidis I, Kastrinaki MC, Papadaki HA
Primary Author: 
Pavlaki K
Original Publication Date: 
Wednesday, March 12, 2014

It has been shown that bone marrow mesenchymal stem cells (MSCs) from patients with myelodysplastic syndromes (MDS) display defective proliferative potential. We have probed the impaired replicative capacity of culture-expanded MSCs in MDS patients (n=30) compared to healthy subjects (n=32) by studying senescence characteristics and gene expression associated with WNT/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 co-culture conditions. Patient MSCs displayed decreased gene expression of the senescence-associated cyclin-dependent kinase inhibitors CDKN1A, CDKN2A, CDKN2B, along with PARG1, whereas the mean telomere length was up-regulated 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 up-regulated non-canonical WNT expression, combined with down-regulated canonical WNT expression and up-regulated 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 MDS led to an increase in cell proliferation and up-regulation 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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