Reserves, Functional, Immunoregulatory, and Cytogenetic Properties of Bone Marrow Mesenchymal Stem Cells in Patients with Myelodysplastic Syndromes

Abstract

Defective hematopoiesis supporting capacity of bone marrow (BM) stroma has been implicated in the pathophysiology of myelodysplastic syndromes (MDS). The aim of this study is to explore whether the BM stroma progenitors, namely the mesenchymal stem cells (MSCs), are primarily affected in MDS by evaluating the reserves, the functional properties, as well as the cytogenetic characteristics, in comparison to BM hematopoietic cells, in patients with de novo MDS (n = 13). The number, differentiation potential toward adipocytes/chondrocytes/osteoblasts and immunosuppressive function in terms of inhibition of mitogen-induced T-cell proliferation did not differ significantly between patient and normal (n = 20) MSCs. Patient MSCs did not show any aberrations in the production of proinflammatory or growth-promoting cytokines and did not harbor the cytogenetic abnormalities present in hematopoietic cells. Occasional patient and normal MSC cultures, however, developed irrelevant chromosomal alterations (trisomies 5 and 7) with uncertain pathophysiologic significance. Compared to controls, patient MSCs displayed impaired proliferative and clonogenic potential through passages that might represent a nonspecific abnormality associated with the chronic inflammatory process present in patients' BM. These data suggest that BM MSCs from MDS patients do not belong to the abnormal clone and do not represent the main cellular source contributing to the inflammatory marrow microenvironment.

Development of Cytogenetic Abnormalities in Myelodysplastic Syndromes

“…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].…”

“…normal with respect to the ability of sustaining the growth of CD34 + cells in co-cultures and secretion of normal levels of cytokines and growth factors (TNF-α, IL-6, stem cell factor, GM-CSF, VEGF, collagen and fibronectin) [24,25] some other studies show that MDS-MSCs are unable to support hematopoiesis [16][17][18][19][20][21][22][23]. Further, some studies have shown that the MSCs of MDS secrete increased levels of certain cytokines such as TNFα, IL-6, IFN-γ and angiogenic cytokines [17,18].…”

“…MDS derivation may be a multi step process, but believed to be originated at the hematopoietic stem/progenitor level [6,[19][20][21][22][23][24][25]. The cell type which should be considered as anMDS "stem" cell is yet to be disclosed.…”

“…These groups declare that the clonal cytogenetic abnormalities found in MSC populations are mostly numerical and are different from that of their hematopoietic counterparts with no overlap between clonal chromosomal abnormalities of the MSCs from those observed in their HSC counterparts [22,44,48]. It is important to highlight that most of the reported cytogenetic abnormalities in MDS-MSCs are not commonly-reported abnormalities of MDS or unique to MDS [49] but may have adverse prognostic impact [23]. Interestingly, no cytogenetic abnormalities have been reported in MSCs from healthy individuals [44][45][46][47].…”

“…Hence, analysis of abnormal clones of MDS-MSCs in separation is required to answer the question; whether the abnormal MSCs derived from MDS are functionally normal or not [24]. Further, analyzing genetically aberrant clones in isolation will also allow understanding the contribution and the mechanisms of the genetic abnormalities in relation to the function of MSCs in marrow stroma although the aberrations seem to have no growth advantage over the normal clones of MDS-MSCs [23,24].…”