Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes

Abstract It has been reported that corticosteroid therapy was effective in the management of severe acute respiratory syndrome (SARS) and the Middle East Respiratory Syndrome (MERS), and recently in coronavirus disease 2019 (COVID-19). Corticosteroids are potent anti-inflammatory drugs that mitigate the risk of acute respiratory distress syndrome (ARDS) in COVID-19 and other viral pneumonia, despite a reduction of viral clearance; corticosteroids inhibit the development of cytokine storm and multi-organ damage. The risk–benefit ratio should be assessed for critical COVID-19 patients. In conclusion, corticosteroid therapy is an effective way in the management of COVID-19, it reduces the risk of complications primarily acute lung injury and the development of ARDS. Besides, corticosteroid therapy mainly dexamethasone and methylprednisolone are effective in reducing the severity of COVID-19 and associated comorbidities such as chronic obstructive pulmonary diseases (COPD), rheumatoid arthritis, and inflammatory bowel disease (IBD). 

/pdf/covid-19-and-corticosteroids-a-narrative-review-2tf88ln1.pdf

COVID-19 and corticosteroids: a narrative review

PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem-cell-derived cardiomyocytes.

COVID-19 affects multiple organs. Clinical data from the Mount Sinai Health System shows that substantial numbers of COVID-19 patients without prior heart disease develop cardiac dysfunction. How COVID-19 patients develop cardiac disease is not known. We integrate cell biological and physiological analyses of human cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs) infected with SARS-CoV-2 in the presence of interleukins, with clinical findings, to investigate plausible mechanisms of cardiac disease in COVID-19 patients. We infected hiPSC-derived cardiomyocytes, from healthy human subjects, with SARS-CoV-2 in the absence and presence of interleukins. We find that interleukin treatment and infection results in disorganization of myofibrils, extracellular release of troponin-I, and reduced and erratic beating. Although interleukins do not increase the extent, they increase the severity of viral infection of cardiomyocytes resulting in cessation of beating. Clinical data from hospitalized patients from the Mount Sinai Health system show that a significant portion of COVID-19 patients without prior history of heart disease, have elevated troponin and interleukin levels. A substantial subset of these patients showed reduced left ventricular function by echocardiography. Our laboratory observations, combined with the clinical data, indicate that direct effects on cardiomyocytes by interleukins and SARS-CoV-2 infection can underlie the heart disease in COVID-19 patients. One Sentence Summary Cardiomyocytes derived from human induced pluripotent stem cells treated with interleukins and infected with SARS- CoV- 2 in cultures, show increased release of troponin, disorganization of myofibrils, and changes in beating mirroring specific pathologies in some COVID-19 patients.

/pdf/physiology-of-cardiomyocyte-injury-in-covid-19-39mif0ozmj.pdf

Physiology of cardiomyocyte injury in COVID-19

COVID-19 affects multiple organs. Clinical data from the Mount Sinai Health System show that substantial numbers of COVID-19 patients without prior heart disease develop cardiac dysfunction. How COVID-19 patients develop cardiac disease is not known. We integrated cell biological and physiological analyses of human cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the presence of interleukins (ILs) with clinical findings related to laboratory values in COVID-19 patients to identify plausible mechanisms of cardiac disease in COVID-19 patients. We infected hiPSC-derived cardiomyocytes from healthy human subjects with SARS-CoV-2 in the absence and presence of IL-6 and IL-1β. Infection resulted in increased numbers of multinucleated cells. Interleukin treatment and infection resulted in disorganization of myofibrils, extracellular release of troponin I, and reduced and erratic beating. Infection resulted in decreased expression of mRNA encoding key proteins of the cardiomyocyte contractile apparatus. Although interleukins did not increase the extent of infection, they increased the contractile dysfunction associated with viral infection of cardiomyocytes, resulting in cessation of beating. Clinical data from hospitalized patients from the Mount Sinai Health System show that a significant portion of COVID-19 patients without history of heart disease have elevated troponin and interleukin levels. A substantial subset of these patients showed reduced left ventricular function by echocardiography. Our laboratory observations, combined with the clinical data, indicate that direct effects on cardiomyocytes by interleukins and SARS-CoV-2 infection might underlie heart disease in COVID-19 patients. IMPORTANCE SARS-CoV-2 infects multiple organs, including the heart. Analyses of hospitalized patients show that a substantial number without prior indication of heart disease or comorbidities show significant injury to heart tissue, assessed by increased levels of troponin in blood. We studied the cell biological and physiological effects of virus infection of healthy human iPSC-derived cardiomyocytes in culture. Virus infection with interleukins disorganizes myofibrils, increases cell size and the numbers of multinucleated cells, and suppresses the expression of proteins of the contractile apparatus. Viral infection of cardiomyocytes in culture triggers release of troponin similar to elevation in levels of COVID-19 patients with heart disease. Viral infection in the presence of interleukins slows down and desynchronizes the beating of cardiomyocytes in culture. The cell-level physiological changes are similar to decreases in left ventricular ejection seen in imaging of patients' hearts. These observations suggest that direct injury to heart tissue by virus can be one underlying cause of heart disease in COVID-19. 

Functional Effects of Cardiomyocyte Injury in COVID-19

Summary A library of well-characterized human induced pluripotent stem cell (hiPSC) lines from clinically healthy human subjects could serve as a useful resource of normal controls for in vitro human development, disease modeling, genotype-phenotype association studies, and drug response evaluation. We report generation and extensive characterization of a gender-balanced, racially/ethnically diverse library of hiPSC lines from 40 clinically healthy human individuals who range in age from 22-61. The hiPSCs match the karyotype and short tandem repeat identity of their parental fibroblasts, and have a transcription profile characteristic of pluripotent stem cells. We provide whole genome sequencing data for one hiPSC clone from each individual, genomic ancestry determination, and analysis of Mendelian disease genes and risks. We document similar transcriptomic profiles, single-cell RNA-seq derived cell clusters and physiology of cardiomyocytes differentiated from multiple independent hiPSC lines. This extensive characterization makes this hiPSC library a valuable resource for many studies on human biology.

/pdf/a-library-of-induced-pluripotent-stem-cells-from-clinically-2dg5ota75p.pdf

A Library of Induced Pluripotent Stem Cells from Clinically Well-Characterized, Diverse Healthy Human Individuals

Summary A library of well-characterized human induced pluripotent stem cell (hiPSC) lines from clinically healthy human subjects could serve as a useful resource of normal controls for in vitro human development, disease modeling, genotype-phenotype association studies, and drug response evaluation. We report generation and extensive characterization of a gender-balanced, racially/ethnically diverse library of hiPSC lines from 40 clinically healthy human individuals who range in age from 22 to 61 years. The hiPSCs match the karyotype and short tandem repeat identities of their parental fibroblasts, and have a transcription profile characteristic of pluripotent stem cells. We provide whole-genome sequencing data for one hiPSC clone from each individual, genomic ancestry determination, and analysis of mendelian disease genes and risks. We document similar transcriptomic profiles, single-cell RNA-sequencing-derived cell clusters, and physiology of cardiomyocytes differentiated from multiple independent hiPSC lines. This extensive characterization makes this hiPSC library a valuable resource for many studies on human biology.

A library of induced pluripotent stem cells from clinically well-characterized, diverse healthy human individuals

Regular use of inhaled corticosteroids (ICS) is the standard of care for patients with persistent asthma and chronic obstructive pulmonary disease (COPD). Adherence to ICS is measured using the 10-...

Validity of the Medication Adherence Rating Scale for Adherence to Inhaled Corticosteroids among Older Adults with Asthma or Chronic Obstructive Pulmonary Disease.

Neelima C. Tangirala

Papers

A Library of Induced Pluripotent Stem Cells from Clinically Well-Characterized, Diverse Healthy Human Individuals

A library of induced pluripotent stem cells from clinically well-characterized, diverse healthy human individuals

Validity of the Medication Adherence Rating Scale for Adherence to Inhaled Corticosteroids among Older Adults with Asthma or Chronic Obstructive Pulmonary Disease.