Apolipoprotein A1 deficiency in mice primes bone marrow stem cells for T cell lymphopoiesis.

Amber B Ouweneel,Esther Lutgens,Miranda Van Eck,Menno Hoekstra,Robbert Wever,Frank H Schaftenaar,Olga S C Snip,Soňa Kauerova,Myrthe E Reiche,Ezra J Van Der Wel

doi:10.1242/jcs.258901

Abstract

ABSTRACTThe bone marrow has emerged as a potentially important target in cardiovascular disease as it generates all leukocytes involved in atherogenesis. In the current study, we evaluated whether a change in bone marrow functionality underlies the increased atherosclerosis susceptibility associated with high-density lipoprotein (HDL) deficiency. We found that HDL deficiency in mice due to the genetic lack of hepatocyte-derived apolipoprotein A1 (APOA1) was associated with an increase in the Lin−Sca-1+Kit+ (LSK) bone marrow stem cell population and lymphoid-primed multipotent progenitor numbers, which translated into a higher production and systemic flux of T cell subsets. In accordance with APOA1 deficiency-associated priming of stem cells to increase T lymphocyte production, atherogenic diet-fed low-density lipoprotein receptor knockout mice transplanted with bone marrow from APOA1-knockout mice displayed marked lymphocytosis as compared to wild-type bone marrow recipients. However, atherosclerotic lesion sizes and collagen contents were similar in the two groups of bone marrow recipients. In conclusion, systemic lack of APOA1 primes bone marrow stem cells for T cell lymphopoiesis. Our data provide novel evidence for a regulatory role of HDL in bone marrow functioning in normolipidemic mice.

Highlights

Atherosclerosis, narrowing of the vessel lumen due to arterial cholesterol deposition in response to chronic hypercholesterolemia, represents the primary cause of cardiovascular pathologies such as coronary artery disease, myocardial infarction, and stroke
In the current study we evaluated whether a change in bone marrow functionality underlies the increased atherosclerosis susceptibility associated with high-density lipoprotein (HDL) deficiency
HDL deficiency in mice due to the genetic lack of hepatocyte-derived apolipoprotein A1 (APOA1) was associated with an increase in the Lin(-)Sca-1(+)Kit(+) bone marrow stem cell population and lymphoid primed multipotent progenitor numbers, which translated into a higher production and systemic flux of T cell subsets

Summary

Introduction

Atherosclerosis, narrowing of the vessel lumen due to arterial cholesterol deposition in response to chronic hypercholesterolemia, represents the primary cause of cardiovascular pathologies such as coronary artery disease, myocardial infarction, and stroke. Culminating evidence supports the hypothesis that beneficially impacting the number or activation state of leukocytes may constitute a valuable therapeutic approach to treat atherosclerotic cardiovascular disease. SahBandar et al (2020) found that a shift in the circulating monocyte population towards the intermediate / inflammatory subtype, i.e. expressing CD16 and high levels of CD14 at their surface, is correlated with a higher carotid intima-media thickness - a surrogate marker of atherosclerosis burden – in the human general population. Höpfner et al (2019) and Rogacev et al (2012) have shown that absolute blood counts of CD14/CD16 double positive monocytes can predict major adverse cardiac events in coronary artery disease patients. In further support, Depuydt et al (2020) have recently shown that human atherosclerotic lesions are rich in activated T cells that express multiple granzyme species

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