Bone marrow-derived mesenchymal stem/stromal cells in patients with acute myeloid leukemia reveal transcriptome alterations and deficiency in cellular vitality.
Bone marrow-derived mesenchymal stem/stromal cells in patients with acute myeloid leukemia reveal transcriptome alterations and deficiency in cellular vitality.
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急性髓系白血病患者的骨髓来源间充质干细胞/基质细胞揭示转录组改变和细胞活力缺陷
DOI：
10.1186/s13287-021-02444-0
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发表时间：
2021-06-26
影响因子：
7.5
通讯作者：
Han Z
中科院分区：
文献类型：
--
作者：
Zhang L;Chi Y;Wei Y;Zhang W;Wang F;Zhang L;Zou L;Song B;Zhao X;Han Z
骨髓间充质干细胞/基质细胞（BM-MSCs）在造血微环境中的重要特性以及对血液系统恶性肿瘤的协同作用已被广泛研究。然而，急性髓系白血病（AML-MSCs）患者BM-MSCs的全景和详细解剖仍不清楚。为此，我们在临床诊断和细胞表型分析的基础上，采用标准密度梯度离心法从骨髓单个核细胞（BM-MNCs）中分离并鉴定AML-MSCs和健康供体来源的HD-MSCs。随后，我们通过流式细胞术、多谱系分化、染色体核型分析、细胞因子定量、转录组测序和生物信息学分析（包括单核苷酸多态性（SNP）、基因本体（GO）、HeatMap、主成分分析（PCA）、京都基因和基因组百科全书（KEGG）、和基因集富集分析（GSEA）。一方面，AML-MSCs在细胞形态学、表面生物标志物表达模式、干性、染色体核型和软骨形成方面与HD-MSCs表现出不可区分的特征，而脂肪形成受损、骨形成增强和细胞因子表达模式的变化。另一方面，借助基因组学和生物信息学分析，我们证实AML-MSCs与HD-MSCs在全基因组基因表达谱和遗传变异谱方面存在多维差异。同时，JAK-STAT信号抑制在很大程度上挽救了AML-MSCs中细胞活力的不足，包括增殖和凋亡。总之，我们的研究结果阐明了AML-MSCs在生物学特征和分子遗传学上表现出多方面的改变，特别是JAK-STAT信号过度激活导致的细胞活力不足，这些都为破解AML的发病机制和探索未来的治疗策略提供了系统和压倒性的新证据。在线版本包含补充材料，可通过10.1186/s13287-021-02444-0获得。
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. The online version contains supplementary material available at 10.1186/s13287-021-02444-0.
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影响因子：
3.6
作者：
Cai SF;Levine RL
通讯作者：
Levine RL
影响因子：
3.2
作者：
Rebelatto, C. K.;Aguiar, A. M.;Correa, A.
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Correa, A.
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影响因子：
44.1
作者：
Wu, Qingqing;Zhang, Leisheng;Zhou, Jiaxi
通讯作者：
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影响因子：
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作者：
Fathi, Ezzatollah;Charoudeh, Hojjatollah Nozad;Farahzadi, Raheleh
通讯作者：
Farahzadi, Raheleh
影响因子：
3.1
作者：
Kayser S;Levis MJ
通讯作者：
Levis MJ