Biology subjects

Fleischmann, B. K.

Publications and source records attributed to Fleischmann, B. K..

3 recordsLinked to original sources

bioRxiv2024

Efficient targeting of heart lesions with cardiac myofibroblasts: Combined gene and cell therapy enhanced by magnetic steering

1The cardiac scar is a collagen-rich area, which is populated by myofibroblasts and has proven little amenable for therapeutic interventions. Herein, we have established an efficient targeting strategy for cardiac lesions by genetically manipulating embryonic cardiac myofibroblasts (mFB) in vitro, load the cells with magnetic nanoparticles and inject these into infarcted mouse hearts using magnetic steering. This yields strongly increased numbers ([~]4 fold compared to other cell types) of engrafted mFB. The injected mFB and endogenous myofibroblast (endoFB) population remain separate in the scar, but grafted mFB enhance the proliferation rate of endoFB by [~]4 fold. We also tested the functional impact of this approach by grafting lentiviral (LV)-transduced Connexin43 (Cx43) overexpressing mFB into the cardiac lesion. Prominent engraftment of Cx43+ mFB provides strong protection against post-infarct ventricular tachycardia (VT) in vivo, as VT incidence is reduced by [~]50 % at two and eight weeks after cell injection. Thus, ex vivo gene and subsequent in vivo cell therapy combined with magnetic steering of cardiac mFB enable efficient functional targeting of the cardiac scar.

physiology↗

bioRxiv2022

Deficiency in hyaluronan synthase 3 attenuates ruptures in a murine model of abdominal aortic aneurysms by reduced aortic monocyte infiltration

Abdominal aortic aneurysms (AAA) are a common vascular disorder with a high mortality due to the prevalence of aortic ruptures. The underlying pathomechanisms are complex and involve immune cell infiltration and degradation of the vascular extracellular matrix (ECM). Hyaluronan (HA), synthesized at the plasma membrane by three HA synthase isoenzymes (HAS1-3), is not only a major constituent of the ECM but also known to directly affect the phenotype of vascular smooth muscle cells as well as immunological responses. Specifically, the HAS3 isoenzyme has been reported to play a major role in various inflammatory conditions. Therefore, the aim of the present study was to elucidate the role of HAS3-derived HA in the pathogenesis of abdominal aortic aneurysm. To this end, we used a murine model of Angiotensin II (AngII)-induced abdominal aortic aneurysms and dissections (AAAs/AADs) and could demonstrate that genetic depletion of Has3 improves survival in Apoe/Has3 double deficient (Apoe/Has3-DKO) mice via the reduced occurrence of aortic ruptures. Mechanistically, fewer elastica breaks were observed in Apoe/Has3-DKO mice compared to Apoe-KO littermates. This was associated with a decreased infiltration of myeloid immune cells into the vessel wall of Has3-deficient mice while in parallel elevated numbers of circulating leukocytes were detected. RNA seq analysis from aortic tissue pointed towards a disturbed endothelial-myeloid cell communication as a cause for the diminished recruitment of immune cells to the aortic wall. While endothelial cells were unaffected, upregulation of adhesion receptors as well as the HA receptor CD44, known to mediate leukocyte adhesion to the endothelium, was blunted in monocytes from Apoe/Has3-DKO mice in response to AngII treatment. These findings underline the pivotal detrimental role of monocytes HAS3-dependent pericellular HA matrix for an exaggerated immune cell recruitment to inflammatory foci giving here rise for an increased incidence of ruptured aortic aneurysms.

immunology↗

bioRxiv2022

Inhibition of myeloperoxidase prevents thoracic aortic aneurysm formation in Marfan mice

Marfan syndrome (MFS) is the most prevalent inherited connective tissue disorder, still remains uncurable, and is characterized by high mortality at early age driven by dissection and rupture of thoracic aortic aneurysms. MFS is caused by mutations in the fibrillin-1 gene and aberrant TGF{beta} signaling. Here we addressed whether myeloperoxidase (MPO), a leukocyte derived enzyme with potent matrix modulating properties also influences the aortic phenotype in MFS. MFS patients displayed increased circulating MPO levels compared to controls as well as marked aortic MPO deposition. In an MFS mouse model, MPO induced inflammatory endothelial activation and endothelial to mesenchymal transition which triggered aortic leukocyte recruitment. Moreover, MPO directly contributed to adverse extracellular matrix remodeling by promoting oxidative stress and nitration of proteins within the vascular wall. Genetic MPO deficiency and pharmacological MPO inhibition attenuated MFS-related aneurysm formation. We herein identify MPO as a critical mediator of MFS-related thoracic aortic aneurysm formation and - in the absence of any pharmacological treatment so far in this disease - a first anti-inflammatory target to modulate disease progression.

immunology↗