Blood Res.  2016 Dec;51(4):225-232. 10.5045/br.2016.51.4.225.

Mesenchymal stromal cells in myeloid malignancies

• Schroeder
• Geyh S
• Germing U
• Haas R

• KMID: 2364312
• DOI: http://doi.org/10.5045/br.2016.51.4.225

Abstract

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal myeloid disorders characterized by hematopoietic insufficiency. As MDS and AML are considered to originate from genetic and molecular defects of hematopoietic stem and progenitor cells (HSPC), the main focus of research in this field has focused on the characterization of these cells. Recently, the contribution of BM microenvironment to the pathogenesis of myeloid malignancies, in particular MDS and AML has gained more interest. This is based on a better understanding of its physiological role in the regulation of hematopoiesis. Additionally, it was demonstrated as a "˜proof of principle' that genetic disruption of cells of the mesenchymal or osteoblastic lineage can induce MDS, MPS or AML in mice. In this review, we summarize the current knowledge about the contribution of the BM microenvironment, in particular mesenchymal stromal cells (MSC) to the pathogenesis of AML and MDS. Furthermore, potential models integrating the BM microenvironment into the pathophysiology of these myeloid disorders are discussed. Finally, strategies to therapeutically exploit this knowledge and to interfere with the crosstalk between clonal hematopoietic cells and altered stem cell niches are introduced.

Keyword

Myelodysplastic syndromes; Acute myeloid leukemia; Mesenchymal stromal cells; Hematopoiesis; Niche

MeSH Terms

Animals
Hematopoiesis
Leukemia, Myeloid, Acute
Mesenchymal Stromal Cells*
Mice
Myelodysplastic Syndromes
Osteoblasts
Stem Cell Niche
Stem Cells

Figure

• 

  Fig. 1 BM microenvironment presenting the HSC niche. The HSC niche is composed mainly of perivascular MSPCs and endothelial cells. They are producing CXCL12 and SCF required for HSC maintenance and retention in BM. BM endothelial cells expressing specific adhesion molecules (e.g. E-selectin) assist homing and engraftment of HSCs. CAR cells regulate both lymphoid progenitor maturation and myeloid progenitor retention. Sympathetic neuronal cells that innervate arterioles regulates HSC mobilization through circadian release of noradrenaline, which modulates CXCL12 expression. ECMs and other cells including macrophage, megakaryocyte, and osteoprogenitor cells are also participating in this landscape. Abbreviations: BM, bone marrow; ECM, extracellular matrix; HSC, hematopoietic stem cell; MSCP, mesenchymal stem and progenitor cell; SCF, stem cell factor; TGF-β1, transforming growth factor beta-1; CAR cell, CXCL12-abundant reticular cells; ECM, extracellular matrix; Nes, nestin; NG2, neuron/glial antigen 2.

• 

  Fig. 2 Potential pathophysiological models. (A) In this model, AML and MDS originate from a primary stromal defect. Functional alterations of MSPCs result in genotoxic stress and dysregulated crosstalk with HSPC favouring the acquisition of genetic and molecular aberrations. This supports the establishment and expansion of clonal hematopoiesis. (B) In this model, AML and MDS originate from primary alterations of the HSPC compartment. In a second step these clonal hematopoietic cells induce phenotypic and functional changes in the BM microenvironment turning it into a self-reinforcing niche, which supports malignant cells at the expense of healthy hematopoiesis.Abbreviations: CCL3, Chemokine (C-C motif) ligand 3; ECM, extracellular matrix; G-CSF, Granulocyte-colony stimulating factor; HSC, hematopoietic stem and progenitor cells; MSCP, mesenchymal stem and progenitor cell; ROS, reactive oxygen species; TGF-β, transforming growth factor-beta; TPO, thrombopoietin.

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