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Luca Anna Bors Heart and Vascular Center, Semmelweis University, Budapest, Hungary

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Barbara Orsolits Heart and Vascular Center, Semmelweis University, Budapest, Hungary

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Norah Mahnoor Ahmed Heart and Vascular Center, Semmelweis University, Budapest, Hungary

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Hyunsoo Cho Heart and Vascular Center, Semmelweis University, Budapest, Hungary

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Béla Merkely Heart and Vascular Center, Semmelweis University, Budapest, Hungary

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Gábor Földes Heart and Vascular Center, Semmelweis University, Budapest, Hungary

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https://orcid.org/0000-0003-4415-352X
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Abstract

This review aims to summarise new approaches in SARS-CoV-2-related research in cardiology. We provide a head-to-head comparison of models, such as animal research and human pluripotent stem cells, to investigate the pathomechanisms of COVID-19 and find an efficient therapy. In vivo methods were useful for studying systemic processes of the disease; however, due to differences in animal and human biology, the clinical translation of the results remains a complex task. In vitro stem cell research makes cellular events more observable and effective for finding new drugs and therapies for COVID-19, including the use of stem cells. Furthermore, multicellular 3D organoids even make it possible to observe the effects of drugs to treat SARS-CoV-2 infection in human organ models.

Abstract

This review aims to summarise new approaches in SARS-CoV-2-related research in cardiology. We provide a head-to-head comparison of models, such as animal research and human pluripotent stem cells, to investigate the pathomechanisms of COVID-19 and find an efficient therapy. In vivo methods were useful for studying systemic processes of the disease; however, due to differences in animal and human biology, the clinical translation of the results remains a complex task. In vitro stem cell research makes cellular events more observable and effective for finding new drugs and therapies for COVID-19, including the use of stem cells. Furthermore, multicellular 3D organoids even make it possible to observe the effects of drugs to treat SARS-CoV-2 infection in human organ models.

Introduction

There are still many questions about the origin of SARS-CoV-2, but several theories have come to light since its outbreak. The epicentre of the infections was recognised as the Huanan marketplace in Wuhan back at the end of 2019. Most evidence shows that this coronavirus was originally a zoonotic pathogen that mutated and transmitted to its first human hosts from wild animals sold as goods on the market [1]. Since then, the virus has gone through multiple variants, such as the more severe delta or the mild but extremely infectious omicron variant.

It is a well-known fact that the main target of SARS-CoV-2 spike protein is the angiotensin-converting enzyme 2 (ACE2) receptor. Although it is disputed if the virus had this high affinity to ACE2 receptor as it thought from the beginning [1]. In most cases, COVID-19 affects the lungs and the cardiovascular system [2, 3] as these organs have the most dense ACE2 receptor expression [4].

Almost ten thousand publications recognise that patients with increased cardiovascular risk are disproportionately more affected by COVID-19 than healthy individuals. Clinical statistics currently identify cardiac arrhythmia, cardiomyopathy, myocarditis, and cardiac arrest are often terminal events in patients with SARS-CoV-2 infection [3]. On the other hand, a dilemma arises regarding the vaccination with messenger RNA-based vaccines against SARS-CoV-2. Rare adverse effects like vaccine-associated immune thrombosis and thrombocytopenia (VITT), which resemble heparin-induced thrombocytopenia (HIT) prothrombotic disorders and myocarditis, occurred short after vaccination [5, 6] The reason behind VITT cases that young women on hormonal contraception were more susceptible to thrombosis, however, in the case of myocarditis, a direct causal relationship cannot be established due to the lack of viral genomes or autoantibodies in the cardiovascular tissue samples. Nonetheless, studies showed that these symptoms are much more frequent and severe in unvaccinated people infected by SARS-CoV-2 than as an adverse effect of vaccination. After reviewing the published papers, multiple methods and models were collected from animal models to clinical therapies to show the available tools for COVID-19 research in cardiology.

Cardiovascular risks in SARS-CoV-2 infection

SARS-CoV-2 main targets in the cardiovascular system are Toll-like receptor 4 and ACE2. The virus binds to these proteins and often disrupts different signalling pathways in the cardiovascular and immune systems, for example, uncontrolled cytokine cascades and platelet activation, causing metabolic and coagulation abnormalities, arrhythmia, cardiomyopathy, ischemia and cytokine storm [7–12].

On the vascular side, it has been suggested that COVID-19, particularly in the chronic stages of the disease, may represent a primarily endothelial disease [2]. SARS-CoV-2-induced pneumonitis incorporates the notion of endothelial dysfunction, such as defective endothelial barrier function and disruption of vascular endothelial (VE)-cadherin responsible for the integrity of tight junctions [13]. In small vessels, like those in the alveoli of the lung, impaired barrier function leads to capillary leak and subsequent lower oxygenation of the blood. In addition to increased vascular permeability, endothelial damage is further characterised by vasodilation and leukocyte recruitment, culminating in pulmonary injury, hypoxemia, and cardiovascular stress. Indeed, endothelial dysfunction and thus a loss of the endothelial protective mechanism may contribute to multi-organ failure in the advanced stages of infection. This is particularly dominant in a cytokine storm, where cytokines affect the homeostatic function of endothelial cells, contributing to thrombosis and local tissue injury and thereby in numerous complications of COVID-19 [14]. The vascular component is not confined to the disease but also its prevention. A rare clinical constellation associated with vaccines against SARS-CoV-2 is cerebral venous thromboembolism and thrombocytopenia that has resulted in death [15]. Again, direct links between infection and abnormal clotting remain vague in patients with suspected vaccine-induced thrombosis and thrombocytopenia. Many clinical teams now share this interesting hypothesis that highlights the key underlying role of the vasculature; it provides hands-on guidance for effective therapeutic strategies against this still not particularly well-understood infection.

Animal models in COVID-19 research and their limitations

Animal models are widely used in SARS-CoV-2 research to understand systemic mechanisms of infection and pathogenesis. Several species have been used in various studies, such as hamsters, African green monkeys, rhesus macaques, minks, ferrets, cats, dogs and transgenic mice [16]. For example, mouse models showed the pathomechanism whereby the SARS-CoV-2 spike protein 1 (S1) interacting with Toll-like receptor 4 (TLR4), resulting in an innate immune response to the virus [17]. This increased inflammatory state leads to cardiac hypertrophy and heart damage. The limitation of animal models is that strict regulation is required to keep the 3R rule: replace, reduce and refine. Besides the general drawbacks of in vivo models, there is another problem that SARS-CoV-2 only infects cells with human-like angiotensin-converting enzyme 2 (ACE2) receptors. Three sequences of ACE2 receptors must be present for the virus to infiltrate host cells: the first α-helix of the protein containing Lys31 and Tyr41 and the amino-acid sequences between 82–84 and 353–357 [18]. This further narrows the applicable species and brings up ethical dilemmas about whether to use transgenic rodents or wild animals that were not kept in general for research purposes like bats, masked palm civets, ferrets, raccoon dogs, and minks [16, 19]. Arguments against in vitro and in vivo experiments are shown in Table 1.

Table 1.

Limitations of in vitro and in vivo in SARS-CoV-2 research [16, 20]

Arguments against Possible solution
IN VITRO It does not show whether or not the observed cells are major targets of SARS-CoV-2 Analysis of primary patient-derived samples
It does not show systemic reactions like immune response Include immune system components in the model
Only shows direct toxicity and damages Comparing results to primary patient-derived samples
IN VIVO Most model animals do not produce clinical symptoms of SARS-CoV-2 infection when infected Transgenic animals
In vitro is ethically more acceptable Follow the rule of 3R
Using appropriate species for the SARS-CoV-2 infection model can be problematic (wild species, time and resource consuming, hard to translate to human disease) Complementary in vitro studies

Disease modelling and personalised medicine using human pluripotent stem cells

Human cell lines can provide an additional platform to study pathomechanism. However, human cardiomyocytes and endothelial cells from the myocardium are difficult to culture, costly to obtain and limited in number. Furthermore, for drug discovery in COVID-19 therapies, alternatives for these cell types represent a great immediate need. In line with this, the concept of personalised medicine has been recently articulated, which calls for basing medical treatment on a patient's genetic makeup and specific disease characteristics to increase therapeutic benefits and decrease adverse effects [21]. The drug discovery also translates the concept even in SARS-CoV-2 into the related premise of “precision medicine”. Precision medicine aims to integrate both clinical and molecular information to understand the biological basis of disease better and select better disease targets. These new approaches or treatments focus on a particular subgroup of patients with certain genotypic and/or phenotypic characteristics that make them more likely to benefit or, conversely, to experience side effects. To address this need, immortalised human cells [16], embryonic stem cells (hESC) [22], induced pluripotent cell (hiPSC)-derived gut [1920, 23], brain [24], lung [25], cardiac [22, 26–29] and other cells and organoids [22, 26, 27, 29] have been proposed. These can be infected with the virus or treated with drugs that induce inflammation, which can help in understanding how SARS-CoV-2 works and causes diseases like cardiac dysfunctions [30], thrombosis [31] or cytokine storm [26]. A collection of different drug research on cardiovascular cell and organ models are shown in Table 2.

Table 2.

hiPSC and human embryonic stem cells derived cardiovascular cell cultures and organoids in COVID-19 drug research (Abbreviations: CM: Cardiomyocytes, EC: Endothelial cells, CF: Cardiac fibroblasts, FB: Fibroblasts, PC: Pericytes, SMC: Smooth muscle cells, ECC: epicardial cells, TLR: Toll-like receptor, ATR: ataxia telangiectasia and Rad3 related, BET: Bromodomain and extra-terminal motif)

Model Origin Cell types Drugs and treatments Mechanism of effect Efficiency against SARS-CoV-2 Ref
Human cardiomyocytes hiPSC CM Remdesivir Decrease viral RNA production Reduced spike protein expression (P < 0.05) [32]
N-acetyl-L-leucyl-L-leucyl-L methionine Potent inhibitor of cathepsin-L and B Reduced spike protein expression (P < 0.05)
Recombinant human ACE2 protein Inhibition of virus binding to host cells Reduced spike protein expression (P < 0.0001)
ACE2 neutralising antibody Inhibition of virus binding to host cells Reduced spike protein expression (P < 0.0001)
Human cardiac cells hiPSC CM, CF, EC ACE2 blocking antibody Inhibition of virus binding to host cells Reduced viral detection (P < 0.05) [27]
Apilimod Inhibition of phosphotransferase activity of TLR-4 regulator Reduced viral detection (P < 0.05)
Bafilomycin Autophagy inhibitor Reduced viral detection (P < 0.05)
Z-Phe-Tyr(tBu)-diazomethylketone Cathepsin-L inhibitor Reduced viral detection (P < 0.01)
Aprotinin Small protein bovine pancreatic trypsin inhibitor Not significant
CA-074 Cathepsin B inhibitor Not significant
Camostat Anti-inflammatory, antifibrotic, and potential antiviral Not significant
Remdesivir Decrease viral RNA production Reduced viral detection (P < 0.01)
Interferon (IFN)-β Modulate functions of the immune system (antiviral) Reduced viral detection (P < 0.01)
E-64d Cathepsin inhibitor; interferes with autolysosomal digestion Reduced viral detection (P < 0.01)
Human cardiomyocytes hiPSC CM Berzosertib Inhibitor of ATR enzyme Rescued beating, reduced inflammation, apoptosis and viral detection [28]
Remdesivir Decrease viral RNA production Rescued beating, reduced viral detection
Hydroxychloroquine Inhibits stimulation of the TLR 9 family receptors Rescued beating, reduced apoptosis and viral detection
Human cardiac organoids hESC and hiPSC CM, ECC, FB, PC, EC INCB054329 BET inhibitor Decreases hace2 expression and reduces SARS-CoV-2 detection [22]
Human blood vessel organoids hiPSC EC, PC Human recombinant soluble ACE2 Inhibition of virus binding to host cells Blocks early entry of SARS-CoV-2 infections in host cells [29]

Important details about viral inclusion can be understood by investigating molecular mechanisms, which is easier to observe in vitro. Studies have shown that in addition to ACE2, Transmembrane Serine Protease 2 (TMPRSS2), cathepsin-L (CTSL) and cathepsin-B (CTSB) can also be potential targets for COVID-19 treatment [27]. Regarding the cardiovascular system, the potential of stem cell-derived cardiomyocytes for disease modelling has been enhanced by realising that cardiomyocytes from human induced pluripotent stem cells (hiPSC-CM) can be obtained with disease-specific genotypes and phenotypes. These cells are suggested to have many of the properties of authentic cells, and their phenotypes provide validation that characteristics of the disease can be reproduced in vitro. An important development is to use these cells to model long-term disease processes. In this regard, the pluripotent stem cell-derived cells have the critical advantages of stability in culture over months and greater ease of genetic manipulation, providing immediate superiority over the classical rodent neonate preparation in addition to their human genotype. A game-changing advantage of the hiPSC-CM is their derivation from a wide range of patients and healthy subjects, allowing them to dissect genotype/phenotype relationships.

3D and multicellular models

The SARS-CoV-2 has a clear vasculature disrupting effect; thus, endothelial cells may play a key role in SARS-CoV-2 pathogenesis; however, the exact underlying mechanisms remain unknown. To support their participation, Schimmel et al. found endothelial cells actively replicating the virus in a monoculture [33]. Yet, the presence of epithelial cells in a co-culture setting inhibited the appearance of detectable viral proteins in the endothelial cells. Furthermore, the endothelium remains uninfected in vivo. These conflicting results confirm that a better understanding warrants complex, multicellular models; 3D models mimicking the in vivo-like tissue structure and cellular composition can offer such experimental tools. We and others have shown that endothelial cells from stem cell origin (hPSC-derived cells or endothelial colony-forming cells, ECFC) along with leukocytes can be used to screen drug toxicity. These improved bioassays are applied to cytokine storm modelling, detect cytokine storm-inducing drugs, biologics, and other viral triggers [34]. Also, using these cells in a dish reflects innate immune receptor-mediated viral responsiveness, such as those with NOD1 and the associated RIP2 signalling [35]. Understanding the mechanisms of these unwanted innate immune receptor (TLR or NOD)-mediated vascular inflammation may offer a potential therapeutic or preventive advantage. Our transcriptomic analysis of stem cell-derived endothelial cells also showed highly abundant expression of ACE2 (Foldes et al., unpublished observation). ACE and ACE2 ratios can also explain the heterogeneity of cases among COVID-19 patients. A study has shown that a higher ACE/ACE2 ratio might be a factor of the severity of COVID-19 [36]. An increased ACE/ACE2 ratio, more prevalent in stem cells derived from older patients [111], causes increased oxidative stress and inflammation leading to cytokine storm and ARDS. Therefore, stem cells from older donors have insufficient immunomodulatory and regenerative functions.

To identify small molecule inhibitors of infection and subsequent endocytosis, the combination of 3D cellular models with a quantitative automated high-content imaging and analysis system appears to be the most appropriate method (shown in Fig. 1). Traditionally, high-content analyses have been performed on two-dimensional images due to the prohibitively complex 3D high-content image processing. However, virus-induced cell death, endocytosis into endothelial cells, and overall infection quantitation may require 3D measurements. This can be facilitated by spinning disk confocal high content microscopy if equipped with optical sectioning and suitable subcellular resolution capability. We can explore the timing and severity of apoptosis, cellular integrity of primary (for example, human umbilical vein endothelial cells, HUVEC) or stem cell-derived endothelial cells and transcriptional and intracellular/membrane-bound factors involved in the inflammatory processes. Collection and image analysis of infection-related features can be derived from a preliminary workflow designed especially for hPSC-CM and hPSC-CM phenotype evaluations. For validation of clinical value for these in vitro findings from pluripotent stem cell-facilitated drug screening and 3D disease modelling, we can run a head-to-head comparison with ex vivo, cellular, histological and RNA samples from blood vessels affected by chronic/acute inflammation. This allows us to get a primary picture of vascular events and responsiveness during the inflammation in vitro and ex vivo.

Fig. 1.
Fig. 1.

Workflow of stem cell-based disease model and drug development assay using High Content Screening (HCS) analysis. This method can be personalised by collecting cells and tissues from patients or specific model animals. Primary cell culture or reprogramed induced pluripotent stem cells can then be used in assays to investigate the pathomechanism of the virus or cytokine storm or to find new treatments with the help of immunocytochemistry and High content imaging. At the end of the process, a vast amount of raw data goes through software analysis to create statistics

Citation: Physiology International 109, 3; 10.1556/2060.2022.00010

Clinical trials and stem cell therapies

Numerous drugs have been in the spotlight in the search for new treatments for SARS-CoV-2 infection, but the COVID-19 Treatment Guidelines Panel recommends against them for various reasons. For example, convalescent plasma therapy appears to be effective in severe cases but not significant in milder cases; furthermore, the plasma sources are limited and expensive. Additionally, most interferon treatments are ineffective in clinical studies. Some promising drugs have already been used as antiviral compounds to treat diseases such as malaria or HIV. The detailed list of ongoing clinical trials for different types of COVID-19 medications and vaccines is available on the website of Milken Institute [37]. Stem cells have been proposed not only for disease modelling but also as a logical measure to tackle virus-induced immune responses directly. For COVID-19 therapy, more than 130 stem cell-based clinical trials have been registered at clinicaltrials.gov to date. Mesenchymal stem cells have received major attention as potential cell therapy products. MSCs have also produced growth factors and other humoral factors for tissue repair. MSCs are safe and well-tolerated in clinical use, with limited or no adverse effects in systemic lupus erythematosus or graft-versus-host disease [38, 39]. Recent studies have aimed at leveraging their immunosuppressive activity, including the inhibition of adaptive immune cell activation and blockage of mononuclear inflammatory infiltration, dominated by lymphocytes at the damaged tissues. Intravenous administration of MSCs in moderate or severe COVID-19 patients was also safe and well-tolerated [40]. In a later phase 2 double-blind, randomised, controlled trials, their efficacy to control inflammation and pulmonary fibrosis and reduce mortality was also tested. Yet, the COVID-19 Treatment Guidelines Panel [41] recommends using MSC to treat COVID-19 only in clinical trial settings. In addition to MSC [42], other stem cell types, such as hESC-derived immunity- and matrix-regulatory cells (hESC-IMRCs), have also been utilised to treat COVID-19 patients in first-in-man studies [43].

Conclusion

SARS-CoV-2 showed us that we still have much to learn about viruses. We also need to push back the illegal trade of wild animals as pets and food to prevent future outbreaks like COVID-19. Poor cardiovascular health is a significant risk factor of severe COVID-19 cases as arrhythmia, cardiomyopathy, myocarditis, thrombosis, and cardiac arrest are the most frequent terminal events of COVID-19.

In vitro methods are important in COVID-19 research due to the species specificity of ACE2. Most popular animal models were unaffected by the virus or had different or less severe symptoms than humans. To create viable models for COVID-19, hiPSC derived cardiovascular cells were used, from monocultures to 3D organoids. Big data collected from assays using these in vitro models and high throughput methods can increase the potential to study cardiovascular diseases and find treatment.

Acknowledgements

This project was supported by grants from the National Research, Development and Innovation Office (NKFIH) of Hungary (K128444 and RRF-2.3.1-21-2022-00003). Projects NVKP_16-1–2016-0017 have been implemented with the support of the National Research, Development and Innovation Fund of Hungary, financed under the NVKP_16 funding scheme.

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    Reed DM , Paschalaki KE , Starke RD , Mohamed NA , Sharp G , Fox B , et al. An autologous endothelial cell: Peripheral blood mononuclear cell assay that detects cytokine storm responses to biologics. FASEB J 2015; 29(6): 25952602. https://doi.org/10.1096/fj.14-268144.

    • PubMed
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  • 35.

    Reed DM , Foldes G , Gatheral T , Paschalaki KE , Lendvai Z , Bagyura Z , et al. Pathogen sensing pathways in human embryonic stem cell derived-endothelial cells: Role of NOD1 receptors. PLoS One 2014; 9(4): e91119. https://doi.org/10.1371/journal.pone.0091119.

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    Pagliaro P , Penna C . ACE/ACE2 ratio: A key also in 2019 coronavirus disease (Covid-19)? Front Med (Lausanne) 2020; 7: 335. https://doi.org/10.3389/fmed.2020.00335.

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    COVID-19 treatment and vaccine tracker [Internet]. Milken Institute; 2022 [updated 2022 March 7; cited 2022 March 12]. Available from: https://covid-19tracker.milkeninstitute.org/.

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    Zhou T , Li HY , Liao C , Lin W , Lin S . Clinical efficacy and safety of mesenchymal stem cells for systemic lupus erythematosus. Stem Cells Int 2020; 2020: 6518508. https://doi.org/10.1155/2020/6518508.

    • PubMed
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    • Export Citation
  • 39.

    Hashmi S , Ahmed M , Murad MH , Litzow MR , Adams RH , Ball LM , et al. Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis. Lancet Haematol 2016; 3(1): e45e52. https://doi.org/10.1016/S2352-3026(15)00224-0.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Leng Z , Zhu R , Hou W , Feng Y , Yang Y , Han Q , et al. Transplantation of ACE2(-) mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis 2020; 11(2): 216228. https://doi.org/10.14336/AD.2020.0228.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    COVID-19 Treatment Guidelines Panel . Cell-based therapy under evaluation for the treatment of COVID-19 [Internet]. National Institutes of Health; 2021 [updated 2021 April 21; cited 2022 March 12]. Available from: https://www.covid19treatmentguidelines.nih.gov/therapies/cell-based-therapy/.

    • Search Google Scholar
    • Export Citation
  • 42.

    Zumla A , Wang FS , Ippolito G , Petrosillo N , Agrati C , Azhar EI , et al. Reducing mortality and morbidity in patients with severe COVID-19 disease by advancing ongoing trials of Mesenchymal Stromal (stem) Cell (MSC) therapy - achieving global consensus and visibility for cellular host-directed therapies. Int J Infect Dis 2020; 96: 431439. https://doi.org/10.1016/j.ijid.2020.05.040.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Wu J , Zhou X , Tan Y , Wang L , Li T , Li Z , et al. Phase 1 trial for treatment of COVID-19 patients with pulmonary fibrosis using hESC-IMRCs. Cell Prolif 2020; 53(12): e12944. https://doi.org/10.1111/cpr.12944.

    • PubMed
    • Search Google Scholar
    • Export Citation
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    Reed DM , Paschalaki KE , Starke RD , Mohamed NA , Sharp G , Fox B , et al. An autologous endothelial cell: Peripheral blood mononuclear cell assay that detects cytokine storm responses to biologics. FASEB J 2015; 29(6): 25952602. https://doi.org/10.1096/fj.14-268144.

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    Reed DM , Foldes G , Gatheral T , Paschalaki KE , Lendvai Z , Bagyura Z , et al. Pathogen sensing pathways in human embryonic stem cell derived-endothelial cells: Role of NOD1 receptors. PLoS One 2014; 9(4): e91119. https://doi.org/10.1371/journal.pone.0091119.

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    Pagliaro P , Penna C . ACE/ACE2 ratio: A key also in 2019 coronavirus disease (Covid-19)? Front Med (Lausanne) 2020; 7: 335. https://doi.org/10.3389/fmed.2020.00335.

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    • Export Citation
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    COVID-19 treatment and vaccine tracker [Internet]. Milken Institute; 2022 [updated 2022 March 7; cited 2022 March 12]. Available from: https://covid-19tracker.milkeninstitute.org/.

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    • Export Citation
  • 38.

    Zhou T , Li HY , Liao C , Lin W , Lin S . Clinical efficacy and safety of mesenchymal stem cells for systemic lupus erythematosus. Stem Cells Int 2020; 2020: 6518508. https://doi.org/10.1155/2020/6518508.

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    Hashmi S , Ahmed M , Murad MH , Litzow MR , Adams RH , Ball LM , et al. Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis. Lancet Haematol 2016; 3(1): e45e52. https://doi.org/10.1016/S2352-3026(15)00224-0.

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    Leng Z , Zhu R , Hou W , Feng Y , Yang Y , Han Q , et al. Transplantation of ACE2(-) mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis 2020; 11(2): 216228. https://doi.org/10.14336/AD.2020.0228.

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    COVID-19 Treatment Guidelines Panel . Cell-based therapy under evaluation for the treatment of COVID-19 [Internet]. National Institutes of Health; 2021 [updated 2021 April 21; cited 2022 March 12]. Available from: https://www.covid19treatmentguidelines.nih.gov/therapies/cell-based-therapy/.

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    Zumla A , Wang FS , Ippolito G , Petrosillo N , Agrati C , Azhar EI , et al. Reducing mortality and morbidity in patients with severe COVID-19 disease by advancing ongoing trials of Mesenchymal Stromal (stem) Cell (MSC) therapy - achieving global consensus and visibility for cellular host-directed therapies. Int J Infect Dis 2020; 96: 431439. https://doi.org/10.1016/j.ijid.2020.05.040.

    • PubMed
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    • Export Citation
  • 43.

    Wu J , Zhou X , Tan Y , Wang L , Li T , Li Z , et al. Phase 1 trial for treatment of COVID-19 patients with pulmonary fibrosis using hESC-IMRCs. Cell Prolif 2020; 53(12): e12944. https://doi.org/10.1111/cpr.12944.

    • PubMed
    • Search Google Scholar
    • Export Citation
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Editor-in-Chief

László ROSIVALL (Semmelweis University, Budapest, Hungary)

Managing Editor

Anna BERHIDI (Semmelweis University, Budapest, Hungary)

Co-Editors

  • Gábor SZÉNÁSI (Semmelweis University, Budapest, Hungary)
  • Ákos KOLLER (Semmelweis University, Budapest, Hungary)
  • Zsolt RADÁK (University of Physical Education, Budapest, Hungary)
  • László LÉNÁRD (University of Pécs, Hungary)
  • Zoltán UNGVÁRI (Semmelweis University, Budapest, Hungary)

Assistant Editors

  • Gabriella DÖRNYEI (Semmelweis University, Budapest, Hungary)
  • Zsuzsanna MIKLÓS (Semmelweis University, Budapest, Hungary)
  • György NÁDASY (Semmelweis University, Budapest, Hungary)

Hungarian Editorial Board

  • György BENEDEK (University of Szeged, Hungary)
  • Zoltán BENYÓ (Semmelweis University, Budapest, Hungary)
  • Mihály BOROS (University of Szeged, Hungary)
  • László CSERNOCH (University of Debrecen, Hungary)
  • Magdolna DANK (Semmelweis University, Budapest, Hungary)
  • László DÉTÁRI (Eötvös Loránd University, Budapest, Hungary)
  • Zoltán GIRICZ (Semmelweis University, Budapest, Hungary and Pharmahungary Group, Szeged, Hungary)
  • Zoltán HANTOS (Semmelweis University, Budapest and University of Szeged, Hungary)
  • Zoltán HEROLD (Semmelweis University, Budapest, Hungary) 
  • László HUNYADI (Semmelweis University, Budapest, Hungary)
  • Gábor JANCSÓ (University of Pécs, Hungary)
  • Zoltán KARÁDI (University of Pecs, Hungary)
  • Miklós PALKOVITS (Semmelweis University, Budapest, Hungary)
  • Gyula PAPP (University of Szeged, Hungary)
  • Gábor PAVLIK (University of Physical Education, Budapest, Hungary)
  • András SPÄT (Semmelweis University, Budapest, Hungary)
  • Gyula SZABÓ (University of Szeged, Hungary)
  • Zoltán SZELÉNYI (University of Pécs, Hungary)
  • Lajos SZOLLÁR (Semmelweis University, Budapest, Hungary)
  • Gyula TELEGDY (MTA-SZTE, Neuroscience Research Group and University of Szeged, Hungary)
  • József TOLDI (MTA-SZTE Neuroscience Research Group and University of Szeged, Hungary)
  • Árpád TÓSAKI (University of Debrecen, Hungary)

International Editorial Board

  • Dragan DJURIC (University of Belgrade, Serbia)
  • Christopher H.  FRY (University of Bristol, UK)
  • Stephen E. GREENWALD (Blizard Institute, Barts and Queen Mary University of London, UK)
  • Osmo Otto Päiviö HÄNNINEN (Finnish Institute for Health and Welfare, Kuopio, Finland)
  • Helmut G. HINGHOFER-SZALKAY (Medical University of Graz, Austria)
  • Tibor HORTOBÁGYI (University of Groningen, Netherlands)
  • George KUNOS (National Institutes of Health, Bethesda, USA)
  • Massoud MAHMOUDIAN (Iran University of Medical Sciences, Tehran, Iran)
  • Tadaaki MANO (Gifu University of Medical Science, Japan)
  • Luis Gabriel NAVAR (Tulane University School of Medicine, New Orleans, USA)
  • Hitoo NISHINO (Nagoya City University, Japan)
  • Ole H. PETERSEN (Cardiff University, UK)
  • Ulrich POHL (German Centre for Cardiovascular Research and Ludwig-Maximilians-University, Planegg, Germany)
  • Andrej A. ROMANOVSKY (University of Arizona, USA)
  • Anwar Ali SIDDIQUI (Aga Khan University, Karachi, Pakistan)
  • Csaba SZABÓ (University of Fribourg, Switzerland)
  • Eric VICAUT (Université de Paris, UMRS 942 INSERM, France)
  • Nico WESTERHOF (Vrije Universiteit Amsterdam, The Netherlands)

 

Editorial Correspondence:
Physiology International
Semmelweis University
Faculty of Medicine, Institute of Translational Medicine
Nagyvárad tér 4, H-1089 Budapest, Hungary
Phone/Fax: +36-1-2100-100
E-mail: pi@semmelweis-univ.hu

Indexing and Abstracting Services:

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  • Medline
  • Referativnyi Zhurnal
  • SCOPUS
  • WoS - Science Citation Index Expanded

 

2022  
Web of Science  
Total Cites
WoS
335
Journal Impact Factor 1.4
Rank by Impact Factor

Physiology (Q4)

Impact Factor
without
Journal Self Cites
1.4
5 Year
Impact Factor
1.6
Journal Citation Indicator 0.42
Rank by Journal Citation Indicator

Physiology (Q4)

Scimago  
Scimago
H-index
33
Scimago
Journal Rank
0.362
Scimago Quartile Score

Physiology (medical) (Q3)
Medicine (miscellaneous) (Q3)

Scopus  
Scopus
Cite Score
2.8
Scopus
CIte Score Rank
Physiology 68/102 (33rd PCTL)
Scopus
SNIP
0.508

2021  
Web of Science  
Total Cites
WoS
330
Journal Impact Factor 1,697
Rank by Impact Factor

Physiology 73/81

Impact Factor
without
Journal Self Cites
1,697
5 Year
Impact Factor
1,806
Journal Citation Indicator 0,47
Rank by Journal Citation Indicator

Physiology 69/86

Scimago  
Scimago
H-index
31
Scimago
Journal Rank
0,32
Scimago Quartile Score Medicine (miscellaneous) (Q3)
Physiology (medical) (Q3)
Scopus  
Scopus
Cite Score
2,7
Scopus
CIte Score Rank
Physiology (medical) 69/101 (Q3)
Scopus
SNIP
0,591

 

2020  
Total Cites 245
WoS
Journal
Impact Factor
2,090
Rank by Physiology 62/81 (Q4)
Impact Factor  
Impact Factor 1,866
without
Journal Self Cites
5 Year 1,703
Impact Factor
Journal  0,51
Citation Indicator  
Rank by Journal  Physiology 67/84 (Q4)
Citation Indicator   
Citable 42
Items
Total 42
Articles
Total 0
Reviews
Scimago 29
H-index
Scimago 0,417
Journal Rank
Scimago Physiology (medical) Q3
Quartile Score  
Scopus 270/1140=1,9
Scite Score  
Scopus Physiology (medical) 71/98 (Q3)
Scite Score Rank  
Scopus 0,528
SNIP  
Days from  172
submission  
to acceptance  
Days from  106
acceptance  
to publication  

2019  
Total Cites
WoS
137
Impact Factor 1,410
Impact Factor
without
Journal Self Cites
1,361
5 Year
Impact Factor
1,221
Immediacy
Index
0,294
Citable
Items
34
Total
Articles
33
Total
Reviews
1
Cited
Half-Life
2,1
Citing
Half-Life
9,3
Eigenfactor
Score
0,00028
Article Influence
Score
0,215
% Articles
in
Citable Items
97,06
Normalized
Eigenfactor
0,03445
Average
IF
Percentile
12,963
Scimago
H-index
27
Scimago
Journal Rank
0,267
Scopus
Scite Score
235/157=1,5
Scopus
Scite Score Rank
Physiology (medical) 73/99 (Q3)
Scopus
SNIP
0,38

 

Physiology International
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Physiology International
Language English
Size B5
Year of
Foundation
2006 (1950)
Volumes
per Year
1
Issues
per Year
4
Founder Magyar Tudományos Akadémia
Founder's
Address
H-1051 Budapest, Hungary, Széchenyi István tér 9.
Publisher Akadémiai Kiadó
Publisher's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Responsible
Publisher
Chief Executive Officer, Akadémiai Kiadó
ISSN 2498-602X (Print)
ISSN 2677-0164 (Online)

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