Diabetes Induces a Transcriptional Signature in Bone Marrow–Derived CD34+ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction
Abstract
:1. Introduction
2. Results
2.1. Experimental Design
2.2. Gene Expression Biotype in HSPCs of CAD and CAD-DM Patients
2.3. DM Induces a Distinct Transcriptome Profile in BM-Derived HSPCs
2.4. Functional Genomics Analysis Reveals a Disease-Specific Genomic Signature in HSPCs of CAD-DM Patients
2.5. Validation of Sequencing Data with qPCR
3. Discussion
4. Materials and Methods
4.1. Study Participants
4.2. Sternal Bone Marrow Biopsy and CD34+ Stem Cell Isolation
4.3. Total RNA Extraction
4.4. MinION Nanopore Sequencing
4.5. Bioinformatics and Statistical Analysis
4.6. Functional Analysis
4.7. qPCR Validation
4.8. Flow Cytometric Assay
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
BM | Bone marrow |
CABG | Coronary artery bypass surgery |
CAD | Coronary artery disease |
CV | Cardiovascular |
DM | Diabetes mellitus |
FDR | False discovery rate |
GO-BP | Gene Ontology-biological processes |
GSEA | Gene set enrichment analysis |
HPSCs | Hematopoietic stem/progenitor cells |
MNC | Mononuclear cell |
NGS | Next generation sequencing |
T1DM | Type 1 diabetes mellitus |
T2DM | Type 2 diabetes mellitus |
VSN | Variance-stabilizing normalization |
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CAD | CAD-DM | p-Value | |
---|---|---|---|
N | 11 | 12 | |
Gender (male) | 91% | 92% | 1.000 |
Age (years) | 70 [57–77] | 70 [65–74] | 0.916 |
BMI (Kg/mq) | 28.05 ± 4.04 | 27.01 ± 3.87 | 0.536 |
Glycemia (mg/dL) | 111 ± 14 | 155 ± 49 ° | 0.015 |
LDL (mg/dL) | 136 [93–157] # | 75 [72–89] ° | 0.018 |
HDL (mg/dL) | 44.3 ± 9.2 # | 47.3 ± 12.0 ° | 0.536 |
Total cholesterol (mg/dL) | 190.2 ± 43.2 # | 156.1 ± 34.2 ° | 0.058 |
Creatinine (mg/dL) | 0.92 [0.88–1.05] | 1.03 [0.85–1.24] | 0.338 |
Other CV Risk Factors | |||
Hypertension | 82% | 100% | 0.217 |
Dyslipidemia | 73% | 67% | 1.000 |
Smoke | 18% | 42% | 0.370 |
DM Therapies | |||
Oral antidiabetic agents | 0 | 83% | |
Insulin | 0 | 8.5% | |
Oral antidiabetic agents + insulin | 0 | 8.5% | |
Other Therapies | |||
Antihypertensive drugs | 100% | 92% ° | 1.000 |
Lipid-lowering drugs | 45% | 75%° | 0.214 |
CAD | CAD-DM | p-Value | |
---|---|---|---|
N | 6 | 8 | |
Gender (male) | 100% | 100% | 1.000 |
Age (years) | 66.3 ± 11.6 | 70.1 ± 5.36 | 0.427 |
BMI (Kg/mq) | 26.80 ± 3.26 | 26.31 ± 3.10 | 0.782 |
Glycemia (mg/dL) | 120 ± 15 # | 162 ± 44 ° | 0.049 |
LDL (mg/dL) | 134 [70–146] # | 75 [70–85] ° | 0.287 |
HDL (mg/dL) | 43.0 ± 10.4 # | 48.7 ± 12.5 ° | 0.424 |
Total cholesterol (mg/dL) | 176.8 ± 48.5 # | 151.6 ± 39.8 ° | 0.345 |
Creatinine (mg/dL) | 0.94 [0.90–1.06] | 0.98 [0.85–1.24] | 0.880 |
Other CV Risk Factors | |||
Hypertension | 83% | 100% | 0.429 |
Dyslipidemia | 67% | 63% | 1.000 |
Smoke | 0% | 50% | 0.085 |
DM Therapies | |||
Oral antidiabetic agents | 0 | 87.5% | |
Insulin | 0 | 0 | |
Oral antidiabetic agents + insulin | 0 | 12.5% | |
Other Therapies | |||
Antihypertensive drugs | 100% | 88% | 1.000 |
Lipid-lowering drugs | 50% | 75% | 0.580 |
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D’Alessandra, Y.; Chiesa, M.; Vigorelli, V.; Ricci, V.; Rurali, E.; Raucci, A.; Colombo, G.I.; Pompilio, G.; Vinci, M.C. Diabetes Induces a Transcriptional Signature in Bone Marrow–Derived CD34+ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction. Int. J. Mol. Sci. 2021, 22, 1423. https://doi.org/10.3390/ijms22031423
D’Alessandra Y, Chiesa M, Vigorelli V, Ricci V, Rurali E, Raucci A, Colombo GI, Pompilio G, Vinci MC. Diabetes Induces a Transcriptional Signature in Bone Marrow–Derived CD34+ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction. International Journal of Molecular Sciences. 2021; 22(3):1423. https://doi.org/10.3390/ijms22031423
Chicago/Turabian StyleD’Alessandra, Yuri, Mattia Chiesa, Vera Vigorelli, Veronica Ricci, Erica Rurali, Angela Raucci, Gualtiero Ivanoe Colombo, Giulio Pompilio, and Maria Cristina Vinci. 2021. "Diabetes Induces a Transcriptional Signature in Bone Marrow–Derived CD34+ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction" International Journal of Molecular Sciences 22, no. 3: 1423. https://doi.org/10.3390/ijms22031423