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Heart with Covid Cells

Helping to Identify New Therapeutic Targets for Covid-19

Lifeline Aortic Smooth Muscle Cells in Covid-19 Research

The emergence of SARS-CoV-2 or COVID-19 has dramatically changed the world we live in today. Considerable resources in the medical and scientific communities are being put into understanding its mechanism of action, which can provide insight into new treatments, diagnostic tests, and vaccine options. It is exciting to see Lifeline® cells being used in research to facilitate these goals.

In a recent paper published in June 2020, Bhattacharyya and colleagues used Lifeline’s human aortic smooth muscle cells to investigate the mechanisms by which the SARS-CoV-2 infection leads to hypoxia and respiratory failure to help identify new therapeutic targets. Angiotensin II receptor (ACE2) is expressed in arterial smooth muscle cells in all the organs studied thus far, making it a good in vitro model to study the interactions between the spike protein of SARS-CoV-2 and ACE2.

Recent research into the glycosylations on the spike protein of SARS-CoV-2 indicates that protein-carbohydrate and carbohydrate-carbohydrate interactions with cell receptors may be an initial step in viral entry.  Specifically, a galectin-like fold identified at the N-terminal domain of the SARS-CoV-2 spike protein suggests that binding with chondroitin sulfates on the surface of cells of the respiratory epithelium may be important.

To investigate the contribution of chondroitin sulfates, chondroitin sulfatases, and chondroitin sulfotransferases to the pathophysiology of Covid-19, the researchers used Lifeline’s human aortic smooth muscle cells, which they refer to as vascular smooth muscle cells, stimulated with Angiotensin (Ang) II. mRNA expression of two chondroitin sulfotransferases, CHST11 and CHST15, was increased at 3.5X and 2.5X above baseline with AngII treatment, respectively.

When the cells were co-treated with AngII and candesartan, an angiotensin (AT)-1 receptor blocker (ARB), the increases in CHST11, and CHST15 were reduced but not completely inhibited. These sulfotransferases are required for the synthesis of chondroitin sulfates chondroitin 4-sulfate (C4S) and chondroitin 4,6-disulfate (CSE). High levels of these sulfated glycosaminoglycans (GAGs) contribute to the adherence of SARS-CoV-2 virus to bronchioalveolar cells and the progression of respiratory disease in Covid-19.

Conversely, the enzyme arylsulfatase B (ARSB) is required for the degradation of chondroitin sulfates C4S and CSE. Previous studies using the bronchial epithelial cells of cystic fibrosis patients show that decreased ARSB enzyme levels resulted in increased expression of the cytokine IL-6 and contributed to inflammation and the pulmonary deficiencies caused by the disease. Since IL-6 is a key cytokine contributing to the cytokine storms observed in Covid-19, this finding is particularly relevant to the mechanism whereby ARSB decline can contribute to and can accelerate Covid-19 disease. ARSB activation requires oxygen for post-translational modification and activation, and its activity can be reduced in hypoxic conditions or by treatment with chloroquine or hydroxychloroquine.

Based on the results, the authors hypothesize that stimulation of the ACE2 receptor increases the expression of CHST11 and CHST15 leading to high levels of C4S and CSE, which impairs airflow and oxygenation in the respiratory tract. This low oxygen, hypoxic environment dramatically impairs ARSB activation, which causes C4S and CSE to accumulate further. A decline in ARSB also results in increased levels of IL-6, thereby contributing to a cytokine storm and exacerbating the respiratory distress caused by SARS-CoV-2 infection.

These findings also suggest that treatment with chloroquine/hydroxychloroquine, which inhibits ARSB and increases chondroitin 4-sulfation, may negatively impact clinical response to SARS-CoV-2 infection. This may enhance viral binding to respiratory tract cells caused by increases in C4S and CSE; impair responsiveness to oxygen treatment; and enhances IL-6 production contributing to the refractory hypoxia experienced by Covid-19 patients.

Recombinant human (rh) ARSB is used clinically to treat Mucopolysaccharidosis VI (MPS VI), the inherited genetic deficiency of ARSB. The authors suggest that rhARSB may be a useful, new approach to treating refractory hypoxia in Covid-19 patients while we await a vaccine and/or effective antiviral treatment of Covid-19.

Lifeline Skeletal Muscle Cells and Smooth Muscle Cells

Smooth muscle cells are responsible for the body’s involuntary movement, and are quite heterogeneous, depending on the organ system in which they are located, which makes them useful for a variety of research applications. ACE2 expression in arterial smooth muscle cells makes it a valuable in vitro model to study SARS-CoV-2, which is particularly relevant right now. Their major role is to control the diameter, wall movement, and wall stiffness of hollow organs like the vascular, bronchial, and gastrointestinal and uterine systems. Smooth muscles, along with skeletal muscle (found in muscles attached to the skeleton) and cardiac muscle (found in the heart) are the three types of muscle present in the body and their contractile nature is important for the movement of various body parts.

For more information on the Lifeline skeletal and smooth muscle cells, please click on the links below:

Here at Lifeline Cell Technology, we love to highlight research that uses our cells in different ways. Keep checking back to see what’s new!

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