Lotte C. Stiekema, Netherlands
Amsterdam UMC Vascular MedicinePresenter of 1 Presentation
Hypercholesterolemia disrupts the metabolic regulation of hematopoietic stem cell behavior, favoring the production of pro-inflammatory monocytes in patients with familial hypercholesterolemia
Abstract
Background and Aims
We hypothesize that hypercholesterolemia-induced priming of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM), results in enhanced production of pro-inflammatory monocytes in patients with familial hypercholesterolemia (FH).
Methods
10 FH patients with an indication for lipid lowering treatment (LLT) (statin, PCSK9-antibody or both) as primary prevention were included. Transcriptomic and functional analyses of BM HSPCs and peripheral monocytes were performed at baseline and after 12 weeks of LLT. Results were compared to healthy controls matched for age, sex and BMI.
Results
Untreated FH patients have more CD34+ HSPCs with decreased expression of homing marker CXCR4, and more CCR2+ monocytes in the bone marrow compared to healthy controls. Transcriptomic analyses of untreated FH patients versus controls showed increased expression of genes involved in the migration and proliferation of HSPCs. Expression of genes involved in these pathways were partly reduced after LLT, with concomitant functional reduction in myeloid progenitor capacity. This reduction coincided with increased oxidative phosphorylation in CD34+ HSPCs measured on gene expression level, as well as with functional Seahorse analyses. Interestingly, these changes on bone marrow level did not result in a reduction of CCR2 expression measured by flow cytometry in circulating monocytes.
Conclusions
Hypercholesterolemia in untreated FH patients results in functional alterations of HSPC behavior, favoring the production of pro-inflammatory monocytes. This effect was only partly reduced after 12 weeks of lipid lowering treatment. Altered metabolic regulation of stem cell behavior could explain this persistent effect post-treatment.