Dataset Information

Diabetes Induces a Transcriptional Signature in Bone Marrow-Derived CD34⁺ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction.

ABSTRACT: Hematopoietic stem/progenitor cells (HSPCs) participate in cardiovascular (CV) homeostasis and generate different types of blood cells including lymphoid and myeloid cells. Diabetes mellitus (DM) is characterized by chronic increase of pro-inflammatory mediators, which play an important role in the development of CV disease, and increased susceptibility to infections. Here, we aimed to evaluate the impact of DM on the transcriptional profile of HSPCs derived from bone marrow (BM). Total RNA of BM-derived CD34⁺ stem cells purified from sternal biopsies of patients undergoing coronary bypass surgery with or without DM (CAD and CAD-DM patients) was sequenced. The results evidenced 10566 expressed genes whose 79% were protein-coding genes, and 21% non-coding RNA. We identified 139 differentially expressed genes (p-value < 0.05 and |log2 FC| > 0.5) between the two comparing groups of CAD and CAD-DM patients. Gene Set Enrichment Analysis (GSEA), based on Gene Ontology biological processes (GO-BP) terms, led to the identification of fourteen overrepresented biological categories in CAD-DM samples. Most of the biological processes were related to lymphocyte activation, chemotaxis, peptidase activity, and innate immune response. Specifically, HSPCs from CAD-DM patients displayed reduced expression of genes coding for proteins regulating antibacterial and antivirus host defense as well as macrophage differentiation and lymphocyte emigration, proliferation, and differentiation. However, within the same biological processes, a consistent number of inflammatory genes coding for chemokines and cytokines were up-regulated. Our findings suggest that DM induces transcriptional alterations in HSPCs, which are potentially responsible of progeny dysfunction.

SUBMITTER: D'Alessandra Y

PROVIDER: S-EPMC7866997 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Diabetes Induces a Transcriptional Signature in Bone Marrow-Derived CD34<sup>+</sup> Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction.

D'Alessandra Yuri Y Chiesa Mattia M Vigorelli Vera V Ricci Veronica V Rurali Erica E Raucci Angela A Colombo Gualtiero Ivanoe GI Pompilio Giulio G Vinci Maria Cristina MC

International journal of molecular sciences 20210131 3

Hematopoietic stem/progenitor cells (HSPCs) participate in cardiovascular (CV) homeostasis and generate different types of blood cells including lymphoid and myeloid cells. Diabetes mellitus (DM) is characterized by chronic increase of pro-inflammatory mediators, which play an important role in the development of CV disease, and increased susceptibility to infections. Here, we aimed to evaluate the impact of DM on the transcriptional profile of HSPCs derived from bone marrow (BM). Total RNA of B ...[more]

PMID: 33572602

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Project description:BackgroundWe assessed the mechanism of hematopoietic stem cell (HSC) mobilization using etoposide with granulocyte-colony stimulating factor (G-CSF), and determined how this mechanism differs from that induced by cyclophosphamide with G-CSF or G-CSF alone.MethodsWe compared the clinical features of 173 non-Hodgkin's lymphoma patients who underwent autologous peripheral blood stem cell transplantation (auto-PBSCT). Additionally, we performed in vitro experiments to assess the changes in human bone marrow stromal cells (hBMSCs), which support the HSCs in the bone marrow (BM) niche, following cyclophosphamide or etoposide exposure. We also performed animal studies under standardized conditions to ensure the following: exclude confounding factors, mimic the conditions in clinical practice, and identify the changes in the BM niche caused by etoposide-induced chemo-mobilization or other mobilization methods.ResultsRetrospective analysis of the clinical data revealed that the etoposide with G-CSF mobilization group showed the highest yield of CD34+ cells and the lowest change in white blood cell counts during mobilization. In in vitro experiments, etoposide triggered interleukin (IL)-8 secretion from the BMSCs and caused long-term BMSC toxicity. To investigate the manner in which the hBMSC-released IL-8 affects hHSCs in the BM niche, we cultured hHSCs with or without IL-8, and found that the number of total, CD34+, and CD34+/CD45- cells in IL-8-treated cells was significantly higher than the respective number in hHSCs cultured without IL-8 (p = 0.014, 0.020, and 0.039, respectively). Additionally, the relative expression of CXCR2 (an IL-8 receptor), and mTOR and c-MYC (components of IL-8-related signaling pathways) increased 1 h after IL-8 treatment. In animal studies, the etoposide with G-CSF mobilization group presented higher IL-8-related cytokine and MMP9 expression and lower SDF-1 expression in the BM, compared to the groups not treated with etoposide.ConclusionCollectively, the unique mechanism of etoposide with G-CSF-induced mobilization is associated with IL-8 secretion from the BMSCs, which is responsible for the enhanced proliferation and mobilization of HSCs in the bone marrow; this was not observed with mobilization using cyclophosphamide with G-CSF or G-CSF alone. However, the long-term toxicity of etoposide toward BMSCs emphasizes the need for the development of more efficient and safe chemo-mobilization strategies.

Dataset Information

Diabetes Induces a Transcriptional Signature in Bone Marrow-Derived CD34⁺ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction.

Publications

Diabetes Induces a Transcriptional Signature in Bone Marrow-Derived CD34<sup>+</sup> Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction.

Similar Datasets

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Dataset Information

Diabetes Induces a Transcriptional Signature in Bone Marrow-Derived CD34+ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction.

Publications

Diabetes Induces a Transcriptional Signature in Bone Marrow-Derived CD34<sup>+</sup> Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Diabetes Induces a Transcriptional Signature in Bone Marrow-Derived CD34⁺ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction.