Integrated Single-cell Bioinformatics Analysis Reveals Intrinsic and Extrinsic Biological Characteristics of Hematopoietic Stem Cell Aging

Abstract Hematopoietic stem cell (HSC) aging, which is accompanied by loss of self-renewal capacity, myeloid-biased differentiation and increased risks of hematopoietic malignancies, is an important focus in stem cell research. However, the mechanisms underlying HSC aging have not been fully elucidated. In the present study, we integrated 3 independent single-cell transcriptome datasets of HSCs together and identified Il10ra and Tnfsf14 as two markers of inflammatory and apoptosis-biased aged HSCs. Besides, common differentially expressed genes (DEGs) between young and aged HSCs were identified and further validated by quantitative RT-PCR. Functional enrichment analysis revealed that these DEGs were predominantly involved in the cell cycle and the tumor necrosis factor (TNF) signaling pathway. We further found that the Skp2-induced signaling pathway (Skp2→Cip1→CycA/CDK2→DP-1) contributed to a rapid transition through G1 phase in aged HSCs. In addition, analysis of the extrinsic alterations on HSC aging revealed the increased expression levels of inflammation genes in bone marrow microenvironment. Colony formation unit assays showed that inflammatory cytokines promoted cellular senescence and that blockade of inflammatory pathway markedly rejuvenated aged HSC functions and increased B cell output. Collectively, our study elucidated the biological characteristics of HSC aging, and the genes and pathways we identified could be potential biomarkers and targets for the identification and rejuvenation of aged HSCs.

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Crosstalk between NOTCH and AKT signaling during murine megakaryocyte lineage specification

Blood ◽

10.1182/blood-2011-01-328567 ◽

2011 ◽

Vol 118 (5) ◽

pp. 1264-1273 ◽

Cited By ~ 47

Author(s):

Melanie G. Cornejo ◽

Vinciane Mabialah ◽

Stephen M. Sykes ◽

Tulasi Khandan ◽

Cristina Lo Celso ◽

...

Keyword(s):

Stem Cell ◽

Notch Signaling ◽

Signaling Pathway ◽

Hematopoietic Stem Cell ◽

Stem Cell Differentiation ◽

Notch Signaling Pathway ◽

Developmental Pathways ◽

Lineage Specification ◽

Hematopoietic Stem

Abstract The NOTCH signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. However, the molecular basis for its role at the different steps of stem cell lineage commitment is unclear. We recently identified the NOTCH signaling pathway as a positive regulator of megakaryocyte lineage specification during hematopoiesis, but the developmental pathways that allow hematopoietic stem cell differentiation into the erythro-megakaryocytic lineages remain controversial. Here, we investigated the role of downstream mediators of NOTCH during megakaryopoiesis and report crosstalk between the NOTCH and PI3K/AKT pathways. We demonstrate the inhibitory role of phosphatase with tensin homolog and Forkhead Box class O factors on megakaryopoiesis in vivo. Finally, our data annotate developmental mechanisms in the hematopoietic system that enable a decision to be made either at the hematopoietic stem cell or the committed progenitor level to commit to the megakaryocyte lineage, supporting the existence of 2 distinct developmental pathways.

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A Stochastic Single Cell Based Model of BrdU Measured Hematopoietic Stem Cell Kinetics

Computational Methods in Systems Biology - Lecture Notes in Computer Science ◽

10.1007/978-3-540-88562-7_26 ◽

2008 ◽

pp. 387-401 ◽

Cited By ~ 2

Author(s):

Richard C. van der Wath ◽

Pietro Lio’

Keyword(s):

Stem Cell ◽

Single Cell ◽

Hematopoietic Stem Cell ◽

Cell Kinetics ◽

Hematopoietic Stem

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The Role of Circular RNA CDR1as/ciRS-7 in Regulating Tumor Microenvironment: A Pan-Cancer Analysis

Biomolecules ◽

10.3390/biom9090429 ◽

2019 ◽

Vol 9 (9) ◽

pp. 429 ◽

Cited By ~ 24

Author(s):

Zou ◽

Zheng ◽

Deng ◽

Yang ◽

Xie ◽

...

Keyword(s):

Tumor Microenvironment ◽

Signaling Pathway ◽

Malignant Tumors ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Circular Rna ◽

Gene Set Enrichment Analysis ◽

Functional Enrichment ◽

Receptor Interaction

Circular RNA CDR1as/ciRS-7 functions as an oncogenic regulator in various cancers. However, there has been a lack of systematic and comprehensive analysis to further elucidate its underlying role in cancer. In the current study, we firstly performed a bioinformatics analysis of CDR1as among 868 cancer samples by using RNA-seq datasets of the MiOncoCirc database. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), CIBERSORT, Estimating the Proportion of Immune and Cancer cells (EPIC), and the MAlignant Tumors using Expression data (ESTIMATE) algorithm were applied to investigate the underlying functions and pathways. Functional enrichment analysis suggested that CDR1as has roles associated with angiogenesis, extracellular matrix (ECM) organization, integrin binding, and collagen binding. Moreover, pathway analysis indicated that it may regulate the TGF-β signaling pathway and ECM-receptor interaction. Therefore, we used CIBERSORT, EPIC, and the ESTIMATE algorithm to investigate the association between CDR1as expression and the tumor microenvironment. Our data strongly suggest that CDR1as may play a specific role in immune and stromal cell infiltration in tumor tissue, especially those of CD8+ T cells, activated NK cells, M2 macrophages, cancer-associated fibroblasts (CAFs) and endothelial cells. Generally, systematic and comprehensive analyses of CDR1as were conducted to shed light on its underlying pro-cancerous mechanism. CDR1as regulates the TGF-β signaling pathway and ECM-receptor interaction to serve as a mediator in alteration of the tumor microenvironment.

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Identification of PKP 2/3 as potential biomarkers of ovarian cancer based on bioinformatics and experiments

Cancer Cell International ◽

10.1186/s12935-020-01602-3 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Lingling Gao ◽

Xiao Li ◽

Qian Guo ◽

Xin Nie ◽

Yingying Hao ◽

...

Keyword(s):

Ovarian Cancer ◽

Signaling Pathway ◽

Poor Prognosis ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Functional Enrichment ◽

Biological Behavior ◽

Cell Junction ◽

Immune Infiltration ◽

Potential Biomarker

Abstract Background Plakophilins (PKPs) are widely involved in gene transcription, translation, and signal transduction, playing a crucial role in tumorigenesis and progression. However, the function and potential mechanism of PKP1/2/3 in ovarian cancer (OC) remains unclear. It’s of great value to explore the expression and prognostic values of PKP1/2/3 and their potential mechanisms, immune infiltration in OC. Methods The expression levels, prognostic values and genetic variations of PKP1/2/3 in OC were explored by various bioinformatics tools and databases, and PKP2/3 were selected for further analyzing their regulation network and immune infiltration. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) enrichment were also conducted. Finally, the expression and prognosis of PKP2 were validated by immunohistochemistry. Results The expression level and prognosis of PKP1 showed little significance in ovarian cancer, and the expression of PKP2/3 mRNA and protein were upregulated in OC, showing significant correlations with poor prognosis of OC. Functional enrichment analysis showed that PKP2/3 and their correlated genes were significantly enriched in adaptive immune response, cytokine receptor activity, organization of cell–cell junction and extracellular matrix; KEGG analysis showed that PKP2/3 and their significantly correlated genes were involved in signaling pathways including cytokine-mediated signaling pathway, receptor signaling pathway and pathways in cancer. Moreover, PKP2/3 were correlated with lymphocytes and immunomodulators. We confirmed that high expression of PKP2 was significantly associated with advanced stage, poor differentiation and poor prognosis of OC patients. Conclusion Members of plakophilins family showed various degrees of abnormal expressions and prognostic values in ovarian cancer. PKP2/3 played crucial roles in tumorigenesis, aggressiveness, malignant biological behavior and immune infiltration of OC, and can be regarded as potential biomarker for early diagnosis and prognosis evaluation in OC.

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Human and Murine Hematopoietic Stem Cell Aging Is Associated with Functional Impairments and Intrinsic Megakaryocytic/Erythroid Bias

PLoS ONE ◽

10.1371/journal.pone.0158369 ◽

2016 ◽

Vol 11 (7) ◽

pp. e0158369 ◽

Cited By ~ 40

Author(s):

Alexandra Rundberg Nilsson ◽

Shamit Soneji ◽

Sofia Adolfsson ◽

David Bryder ◽

Cornelis Jan Pronk

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Cell Aging ◽

Functional Impairments ◽

Hematopoietic Stem ◽

Stem Cell Aging ◽

Murine Hematopoietic Stem Cell

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Hematopoietic Stem Cell Aging and Fate Decision

Molecular Mechanisms of Adult Stem Cell Aging - Else Kröner-Fresenius-Symposia ◽

10.1159/000312645 ◽

2010 ◽

pp. 17-37

Author(s):

Anett Illing ◽

Zhenyu Ju

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Cell Aging ◽

Hematopoietic Stem ◽

Stem Cell Aging ◽

Fate Decision

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Noncoding RNA and Epigenetic Change in Hematopoietic Stem Cell Aging

Handbook of Immunosenescence ◽

10.1007/978-3-319-64597-1_99-1 ◽

2017 ◽

pp. 1-29

Author(s):

David Garrick ◽

Antoine David ◽

Christelle Freitas ◽

Dounia Djeghloul ◽

Michele Goodhardt

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Noncoding Rna ◽

Cell Aging ◽

Epigenetic Change ◽

Hematopoietic Stem ◽

Stem Cell Aging

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PDGFB-expressing mesenchymal stem cells improve human hematopoietic stem cell engraftment in immunodeficient mice

Bone Marrow Transplantation ◽

10.1038/s41409-019-0766-z ◽

2019 ◽

Vol 55 (6) ◽

pp. 1029-1040 ◽

Cited By ~ 4

Author(s):

Xiuxiu Yin ◽

Linping Hu ◽

Yawen Zhang ◽

Caiying Zhu ◽

Hui Cheng ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Hematopoietic Stem Cell ◽

Human Mesenchymal Stem Cells ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Hematopoietic Stem ◽

Immunodeficient Mice ◽

Bm Niche

AbstractThe bone marrow (BM) niche regulates multiple hematopoietic stem cell (HSC) processes. Clinical treatment for hematological malignancies by HSC transplantation often requires preconditioning via total body irradiation, which severely and irreversibly impairs the BM niche and HSC regeneration. Novel strategies are needed to enhance HSC regeneration in irradiated BM. We compared the effects of EGF, FGF2, and PDGFB on HSC regeneration using human mesenchymal stem cells (MSCs) that were transduced with these factors via lentiviral vectors. Among the above niche factors tested, MSCs transduced with PDGFB (PDGFB-MSCs) most significantly improved human HSC engraftment in immunodeficient mice. PDGFB-MSC-treated BM enhanced transplanted human HSC self-renewal in secondary transplantations more efficiently than GFP-transduced MSCs (GFP-MSCs). Gene set enrichment analysis showed increased antiapoptotic signaling in PDGFB-MSCs compared with GFP-MSCs. PDGFB-MSCs exhibited enhanced survival and expansion after transplantation, resulting in an enlarged humanized niche cell pool that provide a better humanized microenvironment to facilitate superior engraftment and proliferation of human hematopoietic cells. Our studies demonstrate the efficacy of PDGFB-MSCs in supporting human HSC engraftment.

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