Person:

Nahrendorf, Matthias

Ischemic heart disease evokes a complex immune response. However, tools to noninvasively track leukocytes’ systemic behaviour and dynamics in vivo are lacking. Here, we present a multimodal hot spot imaging approach using an innovative high-density lipoprotein-derived nanotracer with a perfluoro-crown ether payload (19F-HDL) to allow myeloid cell tracking by 19F magnetic resonance imaging (MRI). The 19F-HDL nanotracer is additionally labelable with 89Zr and fluorophores to respectively detect myeloid cells by in vivo positron emission tomography (PET) imaging and optical modalities. Using our nanotracer in atherosclerotic mice with myocardial infarction, we observed rapid myeloid cell egress from the spleen and bone marrow by in vivo 19F-HDL-MRI. Concurrently, using ex vivo techniques, we were able to show that circulating pro-inflammatory myeloid cells accumulated in atherosclerotic plaques and the myocardial infarct site. Our multimodality imaging approach is a valuable addition to the immunology toolbox enabling the study of complex myeloid cell behaviour dynamically.

Ischemic heart disease evokes a complex immune response. However, tools to noninvasively track leukocytes’ systemic behaviour and dynamics in vivo are lacking. Here, we present a multimodal hot spot imaging approach using an innovative high-density lipoprotein-derived nanotracer with a perfluoro-crown ether payload (19F-HDL) to allow myeloid cell tracking by 19F magnetic resonance imaging (MRI). The 19F-HDL nanotracer is additionally labelable with 89Zr and fluorophores to respectively detect myeloid cells by in vivo positron emission tomography (PET) imaging and optical modalities. Using our nanotracer in atherosclerotic mice with myocardial infarction, we observed rapid myeloid cell egress from the spleen and bone marrow by in vivo 19F-HDL-MRI. Concurrently, using ex vivo techniques, we were able to show that circulating pro-inflammatory myeloid cells accumulated in atherosclerotic plaques and the myocardial infarct site. Our multimodality imaging approach is a valuable addition to the immunology toolbox enabling the study of complex myeloid cell behaviour dynamically.

Bone marrow hematopoietic stem and progenitor cells (HSPC) give rise to billions of blood cells every day. Bone marrow endothelial cells (BMECs) form a network of blood vessels that regulates HSC maintenance and blood cell traffic. Here we report the design of a lipid/polymer nanoparticle that delivers siRNA to the hematopoietic stem cell niche in vivo. Newly identified nanoparticles induced potent gene silencing in BMECs. We demonstrate RNAi control of cellular release from the hematopoietic niche by silencing the proteins Sdf1 and Mcp1, which enhanced and inhibited bone marrow HSPC and leukocyte release, respectively. In mice with myocardial infarction, nanoparticle-mediated inhibition of cell release from the hematopoietic niche reduced leukocytes in the diseased heart, improved infarct healing and reduced heart failure. These nanoparticles target the hematopoietic niche in vivo and may be utilized to probe fundamental hematopoietic processes for therapeutic applications in cancer, infection and cardiovascular disease.