Biology subjects

Sattler, S.

Publications and source records attributed to Sattler, S..

4 recordsLinked to original sources

bioRxiv2026

Early immune cell development precedes gastrulation in annual killifish

During embryogenesis, cell types arise in a predictable order because developmental regulators act sequentially. But how evolutionary changes in morphogenesis reshape the signaling environments that activate these regulators remains unknown. Across vertebrates, primitive myeloid cells emerge from bone morphogenetic protein (BMP)-patterned ventral mesoderm through a conserved regulatory program. Here we show that in the annual killifish, Nothobranchius furzeri, a vertebrate with highly derived embryogenesis, neutrophils emerge prior to gastrulation, before ventral mesoderm has formed. Vascular progenitors arise later from ventral mesoderm, whereas myeloid progenitors are largely absent from this tissue. BMP inhibition abolishes pre-gastrula neutrophil specification, while disruption of Nodal-dependent mesendoderm formation does not. These findings reveal that conserved cell type programs can be redeployed within an altered embryonic architecture.

Developmental Biology↗

bioRxiv2020

Myocardial damage induced by a single high dose of isoproterenol in C57Bl/6J mice triggers a persistent adaptive immune response against the heart.

Heart failure is the common final pathway of a range of conditions resulting in myocardial damage and a major cause of morbidity and mortality worldwide. Strategies to improve tissue repair and prevent heart failure thus remain an urgent clinical need. Recent studies have documented activation of the adaptive immune system in response to myocardial damage and have implicated anti-heart autoimmunity in the development of heart failure. In an attempt to target anti-heart autoimmune responses as new therapeutic avenue, the number of experimental studies using in vivo models of myocardial damage to study the ensuing immune response has surged. The beta-adrenergic agonist isoproterenol-hydrochloride has been used for its cardiac effects in a variety of different dosing and administration regimes. Most prominently, low doses (<10mg/kg sc) over an extended time period induce cardiac hypertrophy and fibrosis. In addition, single injections of high doses (>100mg/kg) induce cardiomyocyte necrosis and have been used to mimic acute myocardial necrotic lesions as seen in myocardial infarction (MI). However, despite significant resource and animal welfare advantages, concerns about off-target effects and clinical relevance have so far limited uptake in the cardiovascular research community. To assess suitability of the isoproterenol model for the analysis of chronic post-MI immunological readouts, we treated C57BL/6J mice with a single intra-peritoneal bolus injection of 160mg/kg isoproterenol. Our results confirm the presence of necrotic lesions in the myocardium with significant resemblance of the histopathology of Type 2 MI. Kidneys develop mild fibrosis secondary to early cardiac damage, while other organs remain unaffected. Most importantly, we showed that isoproterenol treatment causes myocardial inflammation and fibrosis, activation of T cells in the heart-draining mediastinal lymph nodes, deposition of mature antibodies in the myocardium and the presence of auto-antibodies against the heart in the serum 12 weeks after the initial injury. In summary, this simple and cost-effective experimental model with significant animal welfare benefits induces myocardial damage reminiscent of human Type 2 MI, which is followed by a persistent adaptive immune response against the heart. This makes it a suitable and high-throughput model to study pathological mechanisms of anti-heart autoimmunity as well as to test potential immunomodulatory therapeutic approaches.

immunology↗

bioRxiv2019

Persistent anti-heart autoimmunity causes cardiomyocyte damage in chronic heart failure.

Although clinicians and researchers have long appreciated the detrimental effects of excessive acute inflammation after myocardial infarction (MI), less is known about the role of the adaptive immune system in MI complications including heart failure. Yet, abundant cardiac self-antigens released from necrotic cardiomyocytes in a highly inflammatory environment are likely to overwhelm peripheral mechanisms of immunological self-tolerance and adaptive auto-reactivity against the heart may cause ongoing tissue destruction and exacerbate progression to chronic heart failure (CHF). Here, we confirm that the adaptive immune system is indeed persistently active in CHF due to ischemic heart disease triggered by MI in rats. Heart draining mediastinal lymph nodes contain active secondary follicles with mature class-switched IgG2a positive cells, and mature anti-heart auto-antibodies binding to cardiac epitopes are still present in serum as late as 16 weeks after MI. When applied to healthy cardiomyocytes in vitro, humoral factors present in CHF serum promoted apoptosis, cytotoxicity and signs of hypertrophy. These findings directly implicate post-MI autoimmunity as an integral feature of CHF progression, constituting a roadblock to effective regeneration and a promising target for therapeutic intervention.

immunology↗

bioRxiv2018

Detection of acute TLR-7 agonist-induced hemorrhagic myocarditis in mice by refined multi-parametric quantitative cardiac MRI.

BACKGROUNDHemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Cardiac magnetic resonance (CMR) imaging is the current gold standard for non-invasive detection of suspected inflammatory damage to the heart and changes in T1 and T2 relaxation times are commonly used to detect edema associated with immune cell infiltration and fibrosis. These measurements also form the basis of the Lake Louise Criteria, which define a framework for the CMR-based diagnosis of myocarditis. However, they do not take into account the possibility of hemorrhage leading to tissue iron deposition which strongly influences T1 and T2 measurements and may complicate interpretation based on these two parameters only.\n\nMETHODSSystemic inflammation was induced in CFN mice by application of the TLR-7 agonist Resiquimod. Histopathology was performed on heart sections to assess immune cell infiltration (Hematoxylin & Eosin), fibrosis (PicoSirius Red) and tissue iron deposition (Perls Prussian Blue). A multi-parametric cardiac MRI tissue mapping approach measuring T1, T2, and T2* relaxation times was established to non-invasively identify these parameters in this small rodent model.\n\nRESULTSResiquimod-treated mice developed severe thrombocytopenia and hemorrhagic myocarditis. We identified patches of cardiac hemorrhage based on the presence of two major MRI phenotypes. Increased T2 with normal T1 and T2* values correlated with infiltration/edema only, while decreased T1, T2, and T2* values identify areas with infiltration/edema in the presence of iron indicating hemorrhagic myocarditis.\n\nCONCLUSIONWe show that over-activation of the TLR-7 pathway by Resiquimod treatment of CFN mice induces an early immune response reminiscent of excessive systemic inflammation due to viral infection. This causes internal bleeding which manifests most prominently as severe hemorrhagic myocarditis. We optimized a comprehensive noninvasive in vivo MRI approach based on quantitative measurement of T1, T2 and T2* to demonstrate the presence of diffuse myocardial edema, infiltration and iron deposition without the need of contrast agent administration. We propose that adding quantitative T2* mapping to CMR protocols for detection of myocarditis will improve diagnostic sensitivity and interpretation of disease mechanisms.

physiology↗