engleski

Microenvironment in MDS

Haematopoietic stem cells (HSCs) are multipotent, self-renewing progenitors that generate all mature blood cells. HCS function is tightly controled to maintain hematopoietic homeostasis and this regulation relies on specialised cells and factors that constitute haematopietic „niche“ or microenvironment.. The concept of the niche includes specifice cell types, anatomical location, soluble molecules, signaling cascades and gradients, as well as physcial factors, such as shear stress, oxygen tension and temperature.. There are two types of niches: the endosteal niche and vascular niche. Bone-forming osteoblast interactes with HSCs at the interface betwen the bone and the marrow space in what has been termed the endosteal niche. Osteoblast secrete cytokines, such as granulocyte colony-stimulating factor (G-CSF), granulocyte –macrophage CSF (GM-CSF) and interleukin-6. Osteoblast also express factors that regulate HSC numbers, including angiopoietin, thrombopoietin, WNT, Notch, N-cadhedrin and osteopontin. Several cell type within perivascular space, including perivascular mesenchimal stromal cell (MSC), CXC12 abundant reticular cellls (CAR cells) and neural cells, have been reported to act independently to regulate HSC as vascular niche. In light of identification of many distinct perivascular stomal cells that are capable of affecting haematopoiesis, and the new knowledge that HSC are frequently positioned in close proxyimity to both osteoblast and vascular structures, a more holistic model of the niche is reqquired, in wich HSCs may simultaneosly interact with, and respond to multiple different cell inputs. Also accumulating evidence supports the critical role of marrow inervationwere HCS activity seems to be regulated by both sympathetic and parasympathetic system. Although most haematopoietic malignancies are likely ton arise from mutations that inappropiately activate haematopietic cell proliferation and survival pathways recent data demonstrates that haematopoiesis can also be dysregulated by alteration in the niche, with defects in HSCs themselves arising secondarily. Concerning MDS the most compelling recent example comes from work in wich miRNA processing was disrupted in osteoblast precursors and mice developed myelodysolasiia. HSCs transplanted from mice into wild-type recipients did not transfer myeloydisplasia, indicating that the HSCs were not intrisucally competent to produce pathologyc changes. These study indicating that malignancy and premalignancy can arise from microinvironment defects or from cooperation between haematopietic and niche cells. Also numerous studies have adresses the quantitative and qualitative inbalance in cytokin and chemokin levels within MDS microenvironment. Recent evidence has implicated adhesion protein CD44 in hominig and adhesion of haematopietic precursor cells (HPCs) to mesenhimal stromal cells by CD44v7 isoform and by CD44v10 ligand that they express. Funcional assays revealed that t MSCs from MDS are intrinsically pathological, showing continuous decline of proloferation and reduced clonogenig capacity in the absens from hematopietic cells. The MCS growth defects were significantly correlated with decereses in CD44 adhesion and CD49e (α5-intregrin). In our investigation we analise role of extracelularv matrix proteins and CD44 in MDS. It was found significant correlation between type of MDS and CD44 expresion, were RAEB 1 and RAEB2 show stronger expresion of CD44. Also it was found corelation between laminin expression that can be conected with higher angiogenesis in more agresive types of MDS.

bone marrow microenvironment; myelodisplasia

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