Aging- and Senescence-associated Changes of Mesenchymal Stromal Cells in Myelodysplastic Syndromes

Abstract

Hematopoietic stem and progenitor cells reside within the bone marrow (BM) microenvironment. By a well-balanced interplay between self-renewal and differentiation, they ensure a lifelong supply of mature blood cells. Physiologically, multiple different cell types contribute to the regulation of stem and progenitor cells in the BM microenvironment by cell-extrinsic and cell-intrinsic mechanisms. During the last decades, mesenchymal stromal cells (MSCs) have been identified as one of the main cellular components of the BM microenvironment holding an indispensable role for normal hematopoiesis. During aging, MSCs diminish their functional and regenerative capacities and in some cases encounter replicative senescence, promoting inflammation and cancer progression. It is now evident that alterations in specific stromal cells that comprise the BM microenvironment can contribute to hematologic malignancies, and there is growing interest regarding the contribution of MSCs to the pathogenesis of myelodysplastic syndromes (MDSs), a clonal hematological disorder, occurring mostly in the elderly, characterized by ineffective hematopoiesis and increased tendency to acute myeloid leukemia evolution. The pathogenesis of MDS has been associated with specific genetic and epigenetic events occurring both in hematopoietic stem cells (HSCs) and in the whole BM microenvironment with an aberrant cross talk between hematopoietic elements and stromal compartment. This review highlights the role of MSCs in MDS showing functional and molecular alterations such as altered cell-cycle regulation with impaired proliferative potential, dysregulated cytokine secretion, and an abnormal gene expression profile. Here, the current knowledge of impaired functional properties of both aged MSCs and MSCs in MDS have been described with a special focus on inflammation and senescence induced changes in the BM microenvironment. Furthermore, a better understanding of aberrant BM microenvironment could improve future potential therapies.

Keywords: aging; inflammation; mesenchymal stromal cell; microenvironment; myelodysplastic syndrome; senescence.

Fig. 1.

Aged bone marrow microenvironment. Oxidative stress and the increment of reactive oxygen species during aging stimulate the secretion of inflammatory cytokines by mesenchymal stromal cells (MSCs) through Nuclear factor Kappa-light-chain-enhancer of activated B cells (NFkB) pathway. Increased levels of inflammatory cytokines lead to infiltration of immune cells like T cells and macrophages. Altogether, these changes in the composition of bone marrow microenvironment result in an osteoblast-to-adipocyte shift in MSC differentiation potential which through secreted inflammatory cytokines and adipokines keep maintaining this inflammatory circle.