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.

Development of Cytogenetic Abnormalities in Myelodysplastic Syndromes

“…Research data also supports the view that abnormal microenvironment selectively supports the expansion of the malignant clone through altered signaling between diseased HSCs and malfunctioning MSCs [16][17][18][19][20][21]. Impaired capacity of MSCs to support normal hematopoiesis in MDS is attributed to abnormal signaling, altered interactions with the hematopoietic cells, altered proliferative and differentiation potential, changes in epigenetic regulation and abnormalities in cytokine secretion [16][17][18][19][20][21]. Gene expression analyses of MDS derived MSCs have shown altered RNA levels in both canonical and non-canonical WNT signaling pathways and is thought to be associated with impaired proliferative potential of MDS derived MSCs [20].…”

“…However difficulties in duplicating the pathological features of the disease by simple transplantation of hematopoietic stem cells to immunodefficient mice models have highlighted the involvement of the abnormal marrow microenvironment in the disease origin and progression with pivotal yet unexplained role for marrow stroma [14,15]. Research data also supports the view that abnormal microenvironment selectively supports the expansion of the malignant clone through altered signaling between diseased HSCs and malfunctioning MSCs [16][17][18][19][20][21]. Impaired capacity of MSCs to support normal hematopoiesis in MDS is attributed to abnormal signaling, altered interactions with the hematopoietic cells, altered proliferative and differentiation potential, changes in epigenetic regulation and abnormalities in cytokine secretion [16][17][18][19][20][21].…”

“…Impaired capacity of MSCs to support normal hematopoiesis in MDS is attributed to abnormal signaling, altered interactions with the hematopoietic cells, altered proliferative and differentiation potential, changes in epigenetic regulation and abnormalities in cytokine secretion [16][17][18][19][20][21]. Gene expression analyses of MDS derived MSCs have shown altered RNA levels in both canonical and non-canonical WNT signaling pathways and is thought to be associated with impaired proliferative potential of MDS derived MSCs [20]. Geyh et al in 2013 showed that MSCs derived from all MDS subtypes exhibit decreased growth and proliferative capacities with premature replicative cellular senescence with altered expression in Osteopontin, Jagged1, Kit-ligand and Angiopoietin which involve in the interaction with hematopoietic lineages [21].…”

“…The immune-modulatory properties, cytokine secretion and cytogenetic profiles of MSCs have shown to be altered in MDS [16][17][18][19][20][21][22][23]. The groups which claim the genetic susceptibility of MSCs argue on the potential involvement of these cells in the pathogenesis of the disease [16][17][18][19][20][21][22].…”

“…The groups which claim the genetic susceptibility of MSCs argue on the potential involvement of these cells in the pathogenesis of the disease [16][17][18][19][20][21][22]. In spite of data that show MDS-MSCs are functionally…”