Publications by authors named "W Tom Stump"

23 Publications

Resident cardiac macrophages mediate adaptive myocardial remodeling.

Immunity 2021 09 27;54(9):2072-2088.e7. Epub 2021 Jul 27.

Departmental of Medicine, Washington University School of Medicine; Department of Pathology and Immunology, Washington University School of Medicine; Department of Developmental Biology, Washington University School of Medicine. Electronic address:

Cardiac macrophages represent a heterogeneous cell population with distinct origins, dynamics, and functions. Recent studies have revealed that C-C Chemokine Receptor 2 positive (CCR2) macrophages derived from infiltrating monocytes regulate myocardial inflammation and heart failure pathogenesis. Comparatively little is known about the functions of tissue resident (CCR2) macrophages. Herein, we identified an essential role for CCR2 macrophages in the chronically failing heart. Depletion of CCR2 macrophages in mice with dilated cardiomyopathy accelerated mortality and impaired ventricular remodeling and coronary angiogenesis, adaptive changes necessary to maintain cardiac output in the setting of reduced cardiac contractility. Mechanistically, CCR2 macrophages interacted with neighboring cardiomyocytes via focal adhesion complexes and were activated in response to mechanical stretch through a transient receptor potential vanilloid 4 (TRPV4)-dependent pathway that controlled growth factor expression. These findings establish a role for tissue-resident macrophages in adaptive cardiac remodeling and implicate mechanical sensing in cardiac macrophage activation.
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http://dx.doi.org/10.1016/j.immuni.2021.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446343PMC
September 2021

Mechanical dysfunction of the sarcomere induced by a pathogenic mutation in troponin T drives cellular adaptation.

J Gen Physiol 2021 05;153(5)

Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO.

Familial hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death, is primarily caused by mutations in sarcomeric proteins. The pathogenesis of HCM is complex, with functional changes that span scales, from molecules to tissues. This makes it challenging to deconvolve the biophysical molecular defect that drives the disease pathogenesis from downstream changes in cellular function. In this study, we examine an HCM mutation in troponin T, R92Q, for which several models explaining its effects in disease have been put forward. We demonstrate that the primary molecular insult driving disease pathogenesis is mutation-induced alterations in tropomyosin positioning, which causes increased molecular and cellular force generation during calcium-based activation. Computational modeling shows that the increased cellular force is consistent with the molecular mechanism. These changes in cellular contractility cause downstream alterations in gene expression, calcium handling, and electrophysiology. Taken together, our results demonstrate that molecularly driven changes in mechanical tension drive the early disease pathogenesis of familial HCM, leading to activation of adaptive mechanobiological signaling pathways.
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http://dx.doi.org/10.1085/jgp.202012787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054178PMC
May 2021

SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis.

JACC Basic Transl Sci 2021 Apr 26;6(4):331-345. Epub 2021 Feb 26.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

There is ongoing debate as to whether cardiac complications of coronavirus disease-2019 (COVID-19) result from myocardial viral infection or are secondary to systemic inflammation and/or thrombosis. We provide evidence that cardiomyocytes are infected in patients with COVID-19 myocarditis and are susceptible to severe acute respiratory syndrome coronavirus 2. We establish an engineered heart tissue model of COVID-19 myocardial pathology, define mechanisms of viral pathogenesis, and demonstrate that cardiomyocyte severe acute respiratory syndrome coronavirus 2 infection results in contractile deficits, cytokine production, sarcomere disassembly, and cell death. These findings implicate direct infection of cardiomyocytes in the pathogenesis of COVID-19 myocardial pathology and provides a model system to study this emerging disease.
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http://dx.doi.org/10.1016/j.jacbts.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909907PMC
April 2021

Computational Tool for Ensemble Averaging of Single-Molecule Data.

Biophys J 2021 01 26;120(1):10-20. Epub 2020 Nov 26.

Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri. Electronic address:

Molecular motors couple chemical transitions to conformational changes that perform mechanical work in a wide variety of biological processes. Disruption of this coupling can lead to diseases, and therefore there is a need to accurately measure mechanochemical coupling in motors in both health and disease. Optical tweezers with nanometer spatial and millisecond temporal resolution have provided valuable insights into these processes. However, fluctuations due to Brownian motion can make it difficult to precisely resolve these conformational changes. One powerful analysis technique that has improved our ability to accurately measure mechanochemical coupling in motor proteins is ensemble averaging of individual trajectories. Here, we present a user-friendly computational tool, Software for Precise Analysis of Single Molecules (SPASM), for generating ensemble averages of single-molecule data. This tool utilizes several conceptual advances, including optimized procedures for identifying single-molecule interactions and the implementation of a change-point algorithm, to more precisely resolve molecular transitions. Using both simulated and experimental data, we demonstrate that these advances allow for accurate determination of the mechanics and kinetics of the myosin working stroke with a smaller set of data. Importantly, we provide our open-source MATLAB-based program with a graphical user interface that enables others to readily apply these advances to the analysis of their own data.
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http://dx.doi.org/10.1016/j.bpj.2020.10.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820714PMC
January 2021

SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis.

bioRxiv 2020 Nov 5. Epub 2020 Nov 5.

Epidemiological studies of the COVID-19 pandemic have revealed evidence of cardiac involvement and documented that myocardial injury and myocarditis are predictors of poor outcomes. Nonetheless, little is understood regarding SARS-CoV-2 tropism within the heart and whether cardiac complications result directly from myocardial infection. Here, we develop a human engineered heart tissue model and demonstrate that SARS-CoV-2 selectively infects cardiomyocytes. Viral infection is dependent on expression of angiotensin-I converting enzyme 2 (ACE2) and endosomal cysteine proteases, suggesting an endosomal mechanism of cell entry. After infection with SARS-CoV-2, engineered tissues display typical features of myocarditis, including cardiomyocyte cell death, impaired cardiac contractility, and innate immune cell activation. Consistent with these findings, autopsy tissue obtained from individuals with COVID-19 myocarditis demonstrated cardiomyocyte infection, cell death, and macrophage-predominate immune cell infiltrate. These findings establish human cardiomyocyte tropism for SARS-CoV-2 and provide an experimental platform for interrogating and mitigating cardiac complications of COVID-19.
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http://dx.doi.org/10.1101/2020.11.04.364315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654892PMC
November 2020
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