Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells

Abstract

Ineffective hematopoiesis is a major characteristic of myelodysplastic syndromes (MDS) causing relevant morbidity and mortality. Mesenchymal stromal cells (MSC) have been shown to physiologically support hematopoiesis, but their contribution to the pathogenesis of MDS remains elusive. We show that MSC from patients across all MDS subtypes (n=106) exhibit significantly reduced growth and proliferative capacities accompanied by premature replicative senescence. Osteogenic differentiation was significantly reduced in MDS-derived MSC, indicated by cytochemical stainings and reduced expressions of Osterix and Osteocalcin. This was associated with specific methylation patterns that clearly separated MDS-MSC from healthy controls and showed a strong enrichment for biological processes associated with cellular phenotypes and transcriptional regulation. Furthermore, in MDS-MSC, we detected altered expression of key molecules involved in the interaction with hematopoietic stem and progenitor cells (HSPC), in particular Osteopontin, Jagged1, Kit-ligand and Angiopoietin as well as several chemokines. Functionally, this translated into a significantly diminished ability of MDS-derived MSC to support CD34+ HSPC in long-term culture-initiating cell assays associated with a reduced cell cycle activity. Taken together, our comprehensive analysis shows that MSC from all MDS subtypes are structurally, epigenetically and functionally altered, which leads to impaired stromal support and seems to contribute to deficient hematopoiesis in MDS.

Development of Cytogenetic Abnormalities in Myelodysplastic Syndromes

“…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].…”

“…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].…”

“…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].…”

“…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].…”

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

“…We have recently demonstrated that mesenchymal stromal cells from patients with MDS and AML are aberrantly methylated [60][61][62]. Along with this, Verma et al showed that Aza might mediate at least some of its efficacy via demethylation of the BM stroma [3].…”