Bone marrow-derived mesenchymal stem/stromal cells in patients with acute myeloid leukemia reveal transcriptome alterations and deficiency in cellular vitality

Stem Cell Research & Therapy

Fuxu Wang¹  Wenxia Zhang¹  Linglin Zou²  Baoquan Song³  Xing Zhao⁴  Lei Zhang⁵  Ying Chi⁵  Yimeng Wei⁵  Leisheng Zhang⁶  Zhongchao Han⁷ 

[1] Department of Hematology, The Second Hospital of Hebei Medical University, 050000, Shijiazhuang, China;Department of oncology, Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China;National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, 215006, Suzhou, 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, 550004, Guiyang, China;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, 300020, Tianjin, China;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, 300020, Tianjin, 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, 550004, Guiyang, China;Precision Medicine Division, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., 301700, Tianjin, China;Department of Neurosurgery, The First Affiliated Hospital & Qianfoshan Hospital of Shandong First Medical University, 250014, Ji-nan, China;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, 300020, Tianjin, China;Precision Medicine Division, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., 301700, Tianjin, China;

关键词: Acute myeloid leukemia (AML);    BM-MSCs;    Cellular vitality;    Genomic variation;    JAK-STAT signaling;   

DOI  :  10.1186/s13287-021-02444-0

来源: Springer

【 摘 要 】

BackgroundState-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.MethodsFor 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).ResultsOn 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.ConclusionsOverall, 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.

【 授权许可】

CC BY