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Pan-myeloid Differentiation of Human Cord Blood Derived CD34+ Hematopoietic Stem and Progenitor Cells
Published on: August 9, 2019
LDL cholesterol modulates human CD34+ HSPCs through effects on proliferation and the IL-17 G-CSF axis
Thomas R Cimato1, Beth A Palka, Jennifer K Lang
1Department of Medicine/Division of Cardiovascular Medicine, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Clinical and Translational Research Center, Buffalo, New York, USA. tcimato@buffalo.edu
Insights
High LDL cholesterol increases hematopoietic stem/progenitor cells (HSPCs) in humans. This occurs through IL-17/G-CSF mobilization and direct effects on HSPC proliferation, suggesting a link to cardiovascular disease.
Area of Science:
- Cardiovascular Science
- Hematology
- Immunology
Background:
- Hypercholesterolemia is a key factor in atherosclerosis development.
- Inflammatory cells implicated in atherosclerosis originate from CD34+ CD45dim Lineage- hematopoietic stem/progenitor cells (HSPCs).
- High cholesterol in mice mobilizes HSPCs and promotes their differentiation into monocytes and granulocytes.
Purpose of the Study:
- To investigate the impact of cholesterol levels on human HSPC quantity.
- To elucidate the mechanisms by which cholesterol influences HSPCs.
Main Methods:
- A blinded, randomized study involving 12 human subjects treated with statins to modulate lipid levels.
- Measurement of CD34+ HSPC levels in blood via flow cytometry.
- Hematopoietic colony-forming assays to confirm HSPC multilineage potential and ELISA for cytokine analysis.
Main Results:
- A positive correlation was observed between CD34+ HSPC levels and total/LDL cholesterol.
- LDL cholesterol enhanced HSPC proliferation and cell surface expression of CXCR4, G-CSFR, and CD47.
- HSPC-mobilizing cytokine G-CSF and its regulator IL-17 positively correlated with LDL cholesterol.
Conclusions:
- LDL cholesterol positively correlates with human CD34+ HSPC levels.
- Mechanisms include IL-17-mediated G-CSF mobilization and direct effects on HSPC proliferation.
- Findings suggest a potential link between HSPCs, cholesterol levels, and cardiovascular disease events.
Background:
Hypercholesterolemia plays a critical role in atherosclerosis. CD34+ CD45dim Lineage- hematopoietic stem/progenitor cells (HSPCs) give rise to the inflammatory cells linked to atherosclerosis. In mice, high cholesterol levels mobilize HSPCs into the bloodstream, and promote their differentiation to granulocytes and monocytes. The objective of our study was to determine how cholesterol levels affect HSPC quantity in humans.
Methods:
We performed a blinded, randomized hypothesis generating study in human subjects (n=12) treated sequentially with statins of differing potencies to vary lipid levels. CD34+ HSPC levels in blood were measured by flow cytometry. Hematopoietic colony forming assays confirmed the CD34+ population studied as HSPCs with multlineage differentiation potential. Mobilizing cytokine levels were measured by ELISA.
Results:
The quantity of HSPCs was 0.15 ± 0.1% of buffy coat leukocytes. We found a weak, positive correlation between CD34+ HSPCs and both total and LDL cholesterol levels (r(2)=0.096, p < 0.025). Additionally, we tested whether cholesterol modulates CD34+ HSPCs through direct effects or on the levels of mobilizing cytokines. LDL cholesterol increased cell surface expression of CXCR4, G-CSFR affecting HSPC migration, and CD47 mediating protection from phagocytosis by immune cells. LDL cholesterol also increased proliferation of CD34+ HSPCs (28 ± 5.7%, n=6, p < 0.03). Finally, the HSPC mobilizing cytokine G-CSF (r(2)=0.0683, p < 0.05), and its upstream regulator IL-17 (r(2)=0.0891, p < 0.05) both correlated positively with LDL cholesterol, while SDF-1 levels were not significantly affected.
Conclusions:
Our findings support a model where LDL cholesterol levels positively correlate with CD34+ HSPC levels in humans through effects on the levels of G-CSF via IL-17 promoting mobilization of HSPCs, and by direct effects of LDL cholesterol on HSPC proliferation. The findings are provocative of further study to determine if HSPCs, like cholesterol levels, are linked to CVD events.
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