Abstract
Mesenchymal stem cells (MSC) constitute an important cell population of the bone marrow hematopoietic niche that supports normally hematopoietic stem cells (HSC) but eventually also leukemic cells. The alterations that occur in the MSC under leukemic stress are not well known. To deepen on this topic, we have used an in vitro model of the leukemic niche (LN) by coculturing MSC with an acute lymphocytic leukemia cell line (REH) and proceeded to evaluate MSC characteristics and functions. We found that leukemic cells induced in MSC a significant increase both in senescence-associated β-galactosidase activity and in p53 gene expression. MSC in the LN also showed a persistent production of cytoplasmic reactive oxygen species (ROS) and a G2/M phase arrest of the cell cycle. Another acute leukemic cell line (SUP-B15) produced almost the same effects on MSC. REH cells adhere strongly to MSC possibly as a result of an increased expression of the adhesion molecules VCAM-1, ICAM-1, and CD49e in MSC and of CD49d in REH cells. Although mesensphere formation was normal or even increased, multipotent differentiation capacity was impaired in MSC from the LN. A REH-conditioned medium was only partially (about 50%) capable of inducing the same changes in MSC, suggesting that cell-to-cell contact is more efficient in inducing these changes. Despite these important effects on MSC in the LN, REH cells increased their cell adhesion, proliferation rate, and directed-migration capacity. In conclusion, in this in vitro LN model, leukemic cells affect importantly the MSC, inducing a senescence process that seems to favour leukemic cell growth.
Highlights
The bone marrow (BM) niche [1, 2] is an important compartment for the maintenance and regulation of hematopoietic stem cell (HSC) function, i.e., self-renewal, differentiation capacity, and cell migration [3, 4]
We have previously established an in vitro leukemic niche (LN) model to study HSC functions under leukemic stress [14, 24]. This in vitro system showed that HSC are affected in a similar way as HSC and hematopoietic progenitor cells (HPC) do in leukemic patients; we envisaged that this LN could be a useful tool for studying the phenotypic and functional alterations of mesenchymal stem cells (MSC) during leukemic cell growth
We have previously demonstrated that three days of coculture of MSC with REH cells are sufficient to detect HSC phenotypic and functional alterations [14]; we assumed that three days would be appropriate to evaluate MSC in the LN
Summary
The bone marrow (BM) niche [1, 2] is an important compartment for the maintenance and regulation of hematopoietic stem cell (HSC) function, i.e., self-renewal, differentiation capacity, and cell migration [3, 4]. Niche cues are essential for ensuing a functional hematopoiesis during homeostasis and in stressful conditions. This niche encompasses different cell types, including stromal cells of mesenchymal or hematopoietic origin (including immune cells and their progenitors), extracellular matrix components, soluble factors, and sympathetic nerve fibers [3]. Many studies have shown that during leukemia proliferation, the hematopoietic niche is remodeled, altering its properties by mechanisms that are only partially understood, but may include abnormal expression of cell adhesion molecules, aberrant migration capacity, and secretion of soluble factors, among others [9,10,11,12].
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