Laboratoire d'Hématologie, CHU de Saint-Etienne, 42055 Saint-Etienne Cedex, France.
UMR 5239, Laboratoire de Biologie et Modélisation de la Cellule, 69364 Lyon, France.
Cells. 2020 Mar 6;9(3):646. doi: 10.3390/cells9030646.
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.
新出现的证据表明，在骨髓增生异常综合征（MDS）中，骨髓（BM）微环境除了造血干细胞前体细胞（HSPCs）的内在异常外，还可能导致无效的恶性造血。BM 微环境通过间接机制影响恶性造血，但 BM 微环境如何直接导致 MDS 的发生和进展尚不清楚。我们之前的数据表明，MDS 患者的 BM 基质细胞（BMSCs）中黏着斑激酶（FAK）的表达异常。在这项研究中，我们对 MDS 患者和 FAK 敲低的 HS-5 细胞中的 BMSCs 的形态表型特征和功能改变进行了研究。低危（LR）MDS 患者的 BMSCs 中 FAK 或其磷酸化形式的表达降低与 BMSCs 的功能缺陷直接相关，并与血红蛋白水平降低相关。在 HS-5 细胞中下调 FAK 会改变其形态、增殖和分化能力，并损害几种黏附分子的表达。此外，我们还研究了当与 FAK 缺陷的 BMSCs 共培养时，来自健康供体（HD）的 CD34+ HSPCs 的特性。观察到 HD-HSPCs 的异常增殖和红系分化能力受损。总之，这些结果表明，由 FAK 介导的基质黏附机制对调节 HSPCs 的稳态至关重要。
