Abbas Salar, Kini Archana, Srivastava Vivi M, M Marie Therese, Nair Sukesh C, Abraham Aby, Mathews Vikram, George Biju, Kumar Sanjay, Venkatraman Aparna, Srivastava Alok
Centre for Stem Cell Research, A Unit of inStem Bengaluru, Christian Medical College Campus, Bagayam, Vellore, Tamil Nadu, India.
Cytogenetics Unit, Christian Medical College, Vellore, Tamil Nadu, India; Department of General Pathology, Christian Medical College, Vellore, Tamil Nadu, India.
Blood Cells Mol Dis. 2017 Jul;66:37-46. doi: 10.1016/j.bcmd.2017.08.004. Epub 2017 Aug 9.
Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders related to hematopoietic stem and progenitor cell dysfunction. Several studies have shown the role of the bone marrow microenvironment in regulating hematopoietic stem, and progenitor function and their individual abnormalities have been associated with disease pathogenesis. In this study, we simultaneously evaluated hematopoietic stem cells (HSC), hematopoietic stem progenitor cells (HSPCs) and different stromal elements in a cohort of patients with MDS-refractory cytopenia with multilineage dysplasia (RCMD). Karyotyping of these patients revealed variable chromosomal abnormalities in 73.33% of patients. Long-term HSC and lineage-negative CD34+CD38- cells were reduced while among the HPCs, there was an expansion of common myeloid progenitor and loss of granulocyte-monocyte progenitors. Interestingly, loss of HSCs was accompanied by aberrant frequencies of endothelial (ECs) (CD31+CD45-CD71-) and mesenchymal stem cells (MSCs) (CD31-CD45-71-) and its subsets associated with HSC niche. We further demonstrate down-regulation of HSC maintenance genes such as Cxcl12, VEGF in mesenchymal cells and a parallel upregulation in endothelial cells. Altogether we report for the first time quantitative and qualitative de novo changes in hematopoietic stem and its associated niche in a cohort of MDS-RCMD patients. These findings further reinforce the role of different components of the bone marrow microenvironment in MDS pathogenesis and emphasize the need for comprehensive simultaneous evaluation of all niche elements in such studies.
骨髓增生异常综合征（MDS）是一组与造血干细胞和祖细胞功能障碍相关的克隆性造血疾病。多项研究表明骨髓微环境在调节造血干细胞和祖细胞功能中所起的作用，并且它们各自的异常与疾病发病机制相关。在本研究中，我们同时评估了一组骨髓增生异常综合征-多系发育异常难治性血细胞减少症（RCMD）患者的造血干细胞（HSC）、造血干祖细胞（HSPC）和不同的基质成分。这些患者的核型分析显示73.33%的患者存在多种染色体异常。长期造血干细胞和谱系阴性CD34+CD38-细胞减少，而在造血祖细胞中，常见髓系祖细胞扩增，粒细胞-单核细胞祖细胞减少。有趣的是，造血干细胞的减少伴随着与造血干细胞龛相关的内皮细胞（ECs）（CD31+CD45-CD71-）和间充质干细胞（MSCs）（CD31-CD45-71-）及其亚群频率的异常。我们进一步证明了间充质细胞中造血干细胞维持基因如Cxcl12、VEGF的下调以及内皮细胞中的平行上调。我们首次全面报告了一组MDS-RCMD患者造血干细胞及其相关龛的定量和定性新生变化。这些发现进一步强化了骨髓微环境不同成分在MDS发病机制中的作用，并强调了在此类研究中对所有龛元素进行全面同步评估的必要性。
