Abstract
Emerging evidence indicates that in myelodysplastic syndromes (MDS), the bone marrow (BM) microenvironment may also contribute to the ineffective, malignant haematopoiesis in addition to the intrinsic abnormalities of haematopoietic stem precursor cells (HSPCs). The BM microenvironment influences malignant haematopoiesis through indirect mechanisms, but the processes by which the BM microenvironment directly contributes to MDS initiation and progression have not yet been elucidated. Our previous data showed that BM-derived stromal cells (BMSCs) from MDS patients have an abnormal expression of focal adhesion kinase (FAK). In this study, we characterise the morpho-phenotypic features and the functional alterations of BMSCs from MDS patients and in FAK knock-downed HS-5 cells. The decreased expression of FAK or its phosphorylated form in BMSCs from low-risk (LR) MDS directly correlates with BMSCs’ functional deficiency and is associated with a reduced level of haemoglobin. The downregulation of FAK in HS-5 cells alters their morphology, proliferation, and differentiation capabilities and impairs the expression of several adhesion molecules. In addition, we examine the CD34+ healthy donor (HD)-derived HSPCs’ properties when co-cultured with FAK-deficient BMSCs. Both abnormal proliferation and the impaired erythroid differentiation capacity of HD-HSPCs were observed. Together, these results demonstrate that stromal adhesion mechanisms mediated by FAK are crucial for regulating HSPCs’ homeostasis.
Highlights
Myelodysplastic syndromes (MDS) are considered a heterogeneous group of clonal haematopoietic disorders in which spliceosome mutations cooperate with specific epigenetic modifiers in haematopoietic stem precursor cells (HSPCs) to raise the myelodysplastic syndromes (MDS) phenotype
We showed that Focal Adhesion Kinase (FAK) in bone marrow stromal cells (BMSCs) is an important regulator of HSPCs’ homeostasis
Focal Adhesion Kinase (FAK) Deficiency in Bone Marrow Stromal Cells Derived from Patients with
Summary
Myelodysplastic syndromes (MDS) are considered a heterogeneous group of clonal haematopoietic disorders in which spliceosome mutations cooperate with specific epigenetic modifiers in HSPCs to raise the MDS phenotype. Cells 2020, 9, 646 the microenvironment in MDS pathogenesis has largely been accepted. The mechanism by which MDS arises remains unknown, and it is not clear whether the intrinsic abnormalities of haematopoietic stem precursor cells (HSPCs) or the bone marrow (BM) microenvironment trigger the initial pathological process. In support of the ‘HSPC-first’ concept, Meydouf et al have shown that MDS HSPCs reprogram the bone marrow stromal cells (BMSCs) to favour MDS haematopoiesis [1]. Runx downregulation in HSPCs impairs osteogenic differentiation of bone marrow stromal cells (BMSCs) in MDS through the
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