State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China.
National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guizhou Medical University, Guiyang, 550004, China.
Stem Cell Res Ther. 2021 Jun 26;12(1):365. doi: 10.1186/s13287-021-02444-0.
State-of-the-art advances have indicated the pivotal characteristics of bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) in hematopoietic microenvironment as well as coordinate contribution to hematological malignancies. However, the panoramic view and detailed dissection of BM-MSCs in patients with acute myeloid leukemia (AML-MSCs) remain obscure.
For the purpose, we isolated and identified AML-MSCs together with healthy donor-derived HD-MSCs from the bone marrow mononuclear cells (BM-MNCs) by using the standard density gradient centrifugation based on clinical diagnosis and cellular phenotypic analysis. Subsequently, we systematically compared the potential similarities and discrepancy both at the cellular and molecular levels via flow cytometry, multilineage differentiation, chromosome karyotyping, cytokine quantification, and transcriptome sequencing and bioinformatic analysis including single-nucleotide polymorphism (SNP), gene ontology (GO), HeatMap, principal component analysis (PCA), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA).
On the one hand, AML-MSCs exhibited undistinguishable signatures in cytomorphology, surface biomarker expression pattern, stemness, chromosome karyotype, and chondrogenesis as HD-MSCs, whereas with impaired adipogenesis, enhanced osteogenesis, and variations in cytokine expression pattern. On the other hand, with the aid of genomic and bioinformatic analyses, we verified that AML-MSCs displayed multidimensional discrepancy with HD-MSCs both in genome-wide gene expression profiling and genetic variation spectrum. Simultaneously, the deficiency of cellular vitality including proliferation and apoptosis in AML-MSCs was largely rescued by JAK-STAT signaling inhibition.
Overall, our findings elucidated that AML-MSCs manifested multifaceted alterations in biological signatures and molecular genetics, and in particular, the deficiency of cellular vitality ascribed to over-activation of JAK-STAT signal, which collectively provided systematic and overwhelming new evidence for decoding the pathogenesis of AML and exploring therapeutic strategies in future.
最先进的进展表明骨髓间充质干细胞（BM-MSCs）在造血微环境中的关键特征，以及对血液恶性肿瘤的协调贡献。然而，急性髓系白血病（AML-MSCs）患者的 BM-MSCs 的全景和详细剖析仍然不清楚。
为此，我们根据临床诊断和细胞表型分析，使用基于标准密度梯度离心的方法，从骨髓单核细胞（BM-MNCs）中分离和鉴定 AML-MSCs 以及健康供体来源的 HD-MSCs。随后，我们通过流式细胞术、多系分化、染色体核型分析、细胞因子定量和转录组测序以及包括单核苷酸多态性（SNP）、基因本体论（GO）、热图、主成分分析（PCA）、京都基因与基因组百科全书（KEGG）和基因集富集分析（GSEA）在内的生物信息学分析，系统比较了细胞和分子水平上的潜在相似性和差异。
一方面，AML-MSCs 在细胞形态学、表面标志物表达模式、干性、染色体核型和软骨生成方面与 HD-MSCs 表现出相似的特征，但脂肪生成受损、成骨增强和细胞因子表达模式的变化。另一方面，借助基因组和生物信息学分析，我们验证了 AML-MSCs 在全基因组基因表达谱和遗传变异谱上与 HD-MSCs 表现出多维差异。同时，AML-MSCs 的细胞活力缺陷，包括增殖和凋亡，在 JAK-STAT 信号抑制后得到了很大的恢复。
总的来说，我们的研究结果表明，AML-MSCs 在生物学特征和分子遗传学方面表现出多方面的改变，特别是细胞活力的缺陷归因于 JAK-STAT 信号的过度激活，这为解析 AML 的发病机制和未来探索治疗策略提供了系统而压倒性的新证据。
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