ABSTRACT
Two different reports, including one from our own group, have recently demonstrated the presence of severe chromosomal abnormalities in mesenchymal stem cells (MSC) from patients with myelodysplastic syndromes (MDS). In the present study, we have assessed whether such cytogenetic abnormalities result in functional deficiencies in vitro. We found that both normal and MDS MSC showed similar expression patterns of cell adhesion molecules and extracellular matrix proteins. MDS MSC layers showed the capability to differentiate towards adipocytes, chondrocytes and osteoblasts, and supported the growth of early umbilical cord blood progenitors in a co-culture system. Unstimulated MDS MSC secreted more IL-1beta and after treatment with TNFalpha, they secreted more SCF, as compared to their normal counterparts. The present study demonstrates that, in spite of harboring severe chromosomal alterations, most of the functional properties of MDS-derived MSC remain normal, including their ability to support normal hematopoiesis in vitro.
Subject(s)
Cell Differentiation , Mesenchymal Stem Cells/metabolism , Myelodysplastic Syndromes/metabolism , Adipocytes/cytology , Adipocytes/metabolism , Adolescent , Adult , Cell Adhesion Molecules/metabolism , Cells, Cultured , Chondrocytes/cytology , Chondrocytes/metabolism , Coculture Techniques , Colony-Forming Units Assay , Cytogenetic Analysis , Extracellular Matrix Proteins/metabolism , Fetal Blood/cytology , Fetal Blood/metabolism , Humans , Interleukin-1beta/metabolism , Middle Aged , Myelodysplastic Syndromes/pathology , Osteoblasts/cytology , Osteoblasts/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: The mechanism for maintaining telomere integrity is controlled by telomerase, a ribonucleoprotein enzyme that specifically restores telomere sequences, lost during replication by means of an intrinsic RNA component as a template for polymerization. Among the telomerase subunits, hTERT (human telomerase reverse transcriptase) is expressed concomitantly with the activation of telomerase. The role of estrogens and their receptors in the transcriptional regulation of hTERT has been demonstrated. The current study determines the possible association between telomerase activity, the expression of both molecular forms of estrogen receptor (ERalpha and ERbeta) and the protein bcl-2, and their relative associations with clinical parameters. METHODS: Tissue samples from 44 patients with breast cancer were used to assess telomerase activity using the TRAP method and the expression of ERalpha, ERbeta and bcl-2 by means of immunocytochemical techniques. RESULTS: Telomerase activity was detected in 59% of the 44 breast tumors examined. Telomerase activity ranged from 0 to 49.93 units of total product generated (TPG). A correlation was found between telomerase activity and differentiation grade (p = 0.03). The only significant independent marker of response to treatment was clinical stage. We found differences between the frequency of expression of ERalpha (88%) and ERbeta (36%) (p = 0.007); bcl-2 was expressed in 79.5% of invasive breast carcinomas. We also found a significant correlation between low levels of telomerase activity and a lack of ERbeta expression (p = 0.03). CONCLUSION: Lower telomerase activity was found among tumors that did not express estrogen receptor beta. This is the first published study demonstrating that the absence of expression of ERbeta is associated with low levels of telomerase activity.
