Myelodysplastic syndromes (MDS) comprise a heterogeneous group of
hematologic malignancies characterized by clonal hematopoiesis, one or
more cytopenias such as anemia, neutropenia, or thrombocytopenia,
abnormal cellular maturation, and a high risk of progression to acute myeloid
leukemia. The bone marrow microenvironment (BMME) in general and
mesenchymal stromal cells (MSCs) in particular contribute to both the
initiation and progression of MDS. However, little is known about the role of
MSC-derived extracellularmatrix (ECM) in this context. Therefore, we performed
a comparative analysis of in vitro deposited MSC-derived ECM of different MDS
subtypes and healthy controls. Atomic force microscopy analyses demonstrated
that MDS ECM was significantly thicker and more compliant than those from
healthy MSCs. Scanning electron microscopy showed a dense meshwork of
fibrillar bundles connected by numerous smaller structures that span the
distance between fibers in MDS ECM. Glycosaminoglycan (GAG) structures
were detectable at high abundance in MDS ECM as white, sponge-like arrays
on top of the fibrillar network. Quantification by Blyscan assay confirmed these
observations, with higher concentrations of sulfated GAGs in MDS ECM.
Fluorescent lectin staining with wheat germ agglutinin and peanut agglutinin
demonstrated increased deposition of N-acetyl-glucosamine GAGs (hyaluronan
(HA) and heparan sulfate) in low risk (LR) MDS ECM. Differential expression of Nacetyl-
galactosamine GAGs (chondroitin sulfate, dermatan sulfate) was observed
between LR- and high risk (HR)-MDS. Moreover, increased amounts of HA in the
matrix of MSCs from LR-MDS patients were found to correlate with enhanced
HA synthase 1 mRNA expression in these cells. Stimulation of mononuclear cells
from healthy donors with low molecular weight HA resulted in an increased
expression of various pro-inflammatory cytokines suggesting a contribution of
the ECM to the inflammatory BMME typical of LR-MDS. CD34+ hematopoietic
stem and progenitor cells (HSPCs) displayed an impaired differentiation potential
after cultivation on MDS ECM and modified morphology accompanied by
decreased integrin expression which mediate cell-matrix interaction. In
summary, we provide evidence for structural alterations of the MSC-derived
ECM in both LR- and HR-MDS. GAGs may play an important role in this
remodeling processes during the malignant transformation which leads to the
observed disturbance in the support of normal hematopoiesis.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:88255 |
| Date | 24 November 2023 |
| Creators | Bains, Amanpreet Kaur, Behrens Wu, Lena, Rivière, Jennifer, Rother, Sandra, Magno, Valentina, Friedrichs, Jens, Werner, Carsten, Bornhäuser, Martin, Götze, Katharina S., Cross, Michael, Platzbecker, Uwe, Wobus, Manja |
| Publisher | Frontiers Media S.A. |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 10.3389/fonc.2022.961473 |
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