Hetty de Boer

Research Spotlights
The vascular system permits blood to circulate and transports nutrients, oxygen, hormones and blood cells to fight diseases, stabilize blood pressure and maintain homeostasis. My research focusses on the influence of systemic factors on the maintenance and repair of the vascular system under physiological (wound healing) and pathophysiological circumstances, such as diabetes, chronic kidney disease, diabetic nephropathy and atrial fibrillation.
In wound healing, hematopoietic stem cells (HSCs) contribute to vascular regeneration, a process called vasculogenesis. I have studied the role of blood platelets in the homing of HSCs to an injury and in the differentiation of HSCs towards a more endothelial phenotype. Furthermore, a direct correlation between in vivo platelet activation and the number of circulating HSCs was proposed in patients with acute and chronic disease conditions. In the circulation of patients with atrial fibrillation, systemic activation of platelets coincides with hypercoagulability. The heart tissue of AF patients exhibit more fibrosis than heart tissue with normal sinus rhythm, which coincides with a loss of microvessels. Therefore, we study a possible causal relationship between the activation of platelets and coagulation and vascular integrity. Additionally, systemic factors associated with diabetes and diabetic nephropathy affect circulating monocytic cells, which are key components of the innate immune system and potential precursors of tissue macrophages. The knowledge obtained in my research provides insight in how systemic factors may influence circulating cells, which in turn may affect the vascular system.

My main topics involve:

A) The role of blood platelets in vasculogenesis.

The aim of this research is to study how platelets contribute to the escape of circulating HSCs from flow, and the role of platelets and/or platelet-secretion products in the differentiation of the stem cells towards a more endothelial cell phenotype. Our previous work has shown that under physiological conditions, activated platelets guide circulating HSCs to the site of a vascular injury, where aggregated platelets offer the HSCs a landing site to decelerate on and escape from flow. Subsequently, the immobilized HSCs become subject to shear stress and to local injury-associated cues (“fertile soil”), predominantly delivered by the activated platelets, consisting of adhesion molecules, cytokines, chemokines and growth factors. The combined shear stress and the local “fertile soil” lead to reprogramming of the stem cells towards a more endothelial cell phenotype.

B) The effect of activation of coagulation factors and platelets on the barrier function of endothelial cells in the context of atrial fibrillation (AF)

In the CVON consortium RACE V (sponsored by the Dutch Heart Foundation), we study the hypothesis that coagulation activation and platelets are causal factors in vascular leakage and ultimately the loss of the microvasculature in the atria of AF-patients, thereby leading to progression of the disease.

C) Identification of Quaking-isoforms at thrombus-architecture specific locations.

During platelet aggregation, the forming thrombus develops a very distinctive architecture, with a core of densely packed platelets, overlaid by a shell of loosely packed, adherent platelets. The core of the thrombus is consolidated with filamentous actin (F-Actin) which gives the thrombus its strength to withstand blood flow. Although platelets are anucleate cells, they contain the full machinery to perform alternative splicing of proteins. We have started to characterize the expression of alternative spliced isoforms of the protein Quaking, which may play a direct or indirect role in the polymerization of F-Actin. This study may give more insight into post-transcriptional processes in thrombus formation.

D) Monocyte conversion under pathophysiological conditions

Over the years we have devised a dedicated FACS protocol that enables the monitoring of  the conversion of the classical monocyte subset to a more inflammatory monocyte subtype in different patient cohorts, such as chronic kidney disease (CKD) and diabetic nephropathy (DN). In patients with DN, monocyte conversion was enhanced, which was positively correlated to the vascular injury marker angiopoetin II. Additionally, since cellular phenotype switching is intimately intertwined with physiological function, monocyte subsets were isolated and functionally tested for phagocytosis, differentiation towards dendritic cells, adhesion to endothelial cells and ROS production. Furthermore, we monitored monocyte conversion upon different treatments of the DN- or CKD-patients, such as administration of Alemtuzumab and Belatacept versus Calceineurin inhibitors. This research may give more insight in the correlation between the conversion of circulating monocyte subtypes and vascular injury.

Key Publications

  1. 1. de Boer HC, Hovens MM, van Oeveren-Rietdijk AM, Snoep JD, de Koning EJ, Tamsma JT, Huisman MV, Rabelink AJ, van Zonneveld AJ. Human CD34+/KDR+ cells are generated from circulating CD34+ cells after immobilization on activated platelets. Arterioscler Thromb Vasc Biol. 2011.
  2. 2. van Solingen C, de Boer HC, Bijkerk R, Monge M, van Oeveren-Rietdijk AM, Seghers L, de Vries MR, van der Veer EP, Quax PH, Rabelink TJ, van Zonneveld AJ. MicroRNA-126 modulates endothelial SDF-1 expression and mobilization of Sca-1(+)/Lin(-) progenitor cells in ischaemia. Cardiovasc Res. 2011.
  3. 3. de Boer HC, van Oeveren-Rietdijk AM, Rotmans JI, Dekkers OM, Rabelink TJ, van Zonneveld AJ. Activated platelets correlate with mobilization of naïve CD34(+) cells and generation of CD34(+) /KDR(+) cells in the circulation. A meta-regression analysis. J Thromb Haemost. 2013.
  4. 4. Spronk HM, De Jong AM, Verheule S, De Boer HC, Maass AH, Lau DH, Rienstra M, van Hunnik A, Kuiper M, Lumeij S, Zeemering S, Linz D, Kamphuisen PW, Ten Cate H, Crijns HJ, Van Gelder IC, van Zonneveld AJ, Schotten U. Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation. Eur Heart J. 2017.
  5. 5. de Boer HC, van Solingen C, Prins J, Duijs JM, Huisman MV, Rabelink TJ, van Zonneveld AJ. Aspirin treatment hampers the use of plasma microRNA-126 as a biomarker for the progression of vascular disease. Eur Heart J. 2013.

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