Mesenchymal Stem Cells: Case Report of an Adjuvant Ambulatory Therapy for a COVID-19 High-Risk and steroid-hypersensitive Patient.

INTRODUCTION: Due to the rapid progression of COVID-19 to severe and critical stages, thousands of patients have required the use of intensive care unit (ICU) treatment, placing an excessive strain on health systems. Immunomodulatory effects of Wharton's Jelly Mesenchymal Stem Cells (WJ-MSCs) have shown promising results on the treatment of patients with COVID-19. However, the effect of promptly applied cell therapy on ambulatory patient prognosis has not been described. This case report presents the clinical outcome of a multimorbid, steroid-hypersensitive, COVID-19 patient treated with WJ-MSCs transplantation. CASE PRESENTATION: A 67-year-old woman with Type 2 diabetes, overweight (82 kg, 168 cm, BMI = 29.053), hypertension (60/190 mmHg) and steroid-hypersensitivity, tested positive for COVID-19 after presenting typical symptoms such as fatigue, chest pain, myalgia, nasal congestion, dysgeusia, anosmia and oxygen saturation (SpO2) 94% - 96%, with normal body temperature (36°C). The patient received pharmacologic treatment but, when symptoms worsened, WJ-MSCs were transplanted to modulate the suspected onset of the cytokine release syndrome. Significant improvement of symptoms and clinical parameters (inflammatory markers and CT score) were observed, and the patient fully recovered within a short period of time. CONCLUSION: The present case report exhibits the favorable outcome of using Wharton's Jelly Mesenchymal Stem Cells (WJ-MSCs) as an ambulatory and adjuvant therapy for COVID-19. Prompt WJ-MSCs infusion can be a safe ambulatory adjuvant therapy in COVID-19 infection care, preventing disease progression to critical stages and avoiding hospital overcrowding.

The Anti-Viral Activity of Stem Cells: A Rational Explanation for their Use in Clinical Application.

It is well established the importance of stem cells (SCs) in tissue growth, regeneration and repair, given their ability to self-renew and differentiate into mature cells. Stem cells are present in all individuals and are potentially active to the end of life. However, less is known about their unique function within the immune system as immune regulators and their important task in viral protection. Antiviral resistance is a common mechanism in all cells though stem cells utilize an antiviral RNA interference (RNAi) mechanism, while adult cells react by using the interferondependent repression pathway via interferon-associated protein-based response to induce an antiviral response. Therefore, the idea behind this review is to highlight the mechanisms of viral evasion of host defense, which would then allow us to highlight the rationale use of autologous stem cells and their biochemical and immunological ability to reset the subverted immune responses. Recently, scientists have highlighted their use in the field of immune-therapy, establishing the possibilities of using them outside the conventional protocol with the advancement in manipulating these cells in such a way that specific body activity can be restored. This paper describes the remarkable SCs profile and discusses some ideas regarding their promising use in vivo.

The Emergence of Novel Coronavirus Disease, Global Treatment Update and its Containment Strategies in Overpopulated Countries: A Review

The ongoing pandemic of the novel coronavirus SARS-CoV-2 (COVID-19) has created a major challenge for the public health worldwide. The reported cases indicate that the outbreak is more widespread than initially assumed. Around 18 million people have been infected with 689,000 reported deaths (August 2020;the number is increasing daily);with a high mutation rate, this virus poses an even more serious threat worldwide. The actual source of COVID-19 is still un-clear;even if the initial reports link it to the Chinese seafood wet market in Wuhan, other animals such as birds, snakes, and many small mammals including bats are also linked with this novel coro-navirus. The structure of the COVID-19 shows distinctive proteins among which spike proteins have a pivotal role in host cell attachment and virus-cell membrane fusion in order to facilitate virus infection. Currently, no specific antiviral treatment or vaccine is available. Various drug can-didates, including SARS-CoV and MERS-CoV protease inhibitors, neuraminidase inhibitors, RNA synthesis inhibitors, ACE2 inhibitors and lungs supportive therapy, are under trials. Cell-based therapy also appeared with remarkable treatment possibilities. In this article, we endeavored to succinctly cover the current and available treatment options, including pharmaceuticals, cell-based therapy, and traditional medicine. We also focused on the extent of damages by this novel coron-avirus in India, Pakistan, and Bangladesh;the strategies adopted and the research activities initiat-ed so far by these densely populated countries (neighboring China) are explained in this review.Copyright © 2021 Bentham Science Publishers.

The promising approach of MSCs therapy for COVID-19 treatment.

Several ongoing investigations have been founded on the development of an optimized therapeutic strategy for the COVID-19 virus as an undeniable acute challenge for human life. Cell-based therapy and particularly, mesenchymal stem cells (MSCs) therapy has obtained desired outcomes in decreasing the mortality rate of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), mainly owing to its immunoregulatory impact that prevents the overactivation of the immune system. Also, these cells with their multipotent nature, are capable of repairing the damaged tissue of the lung which leads to reducing the probability of acute respiratory distress syndrome (ARDS). Although this cell-based method is not quite cost-effective for developing countries, regarding its promising results in order to treat SARS-COV-2, more economical evaluation as well as clinical trials should be performed for improving this therapeutic approach. Here in this article, the functional mechanism of MSCs therapy for the treatment of COVID-19 and the clinical trials based on this method will be reviewed. Moreover, its economic efficiency will be discussed.

Infection of Bone Marrow-Derived Mesenchymal Stem Cells with Virulent Newcastle Disease Virus Maximizes Cytokine Production: A Step Toward vNDV Immunotherapy

Newcastle Disease (ND) vaccines are being used for more than 7 decades, the disease is still a major challenge for poultry industry both locally and internationally. ND frequently emerges in highly vaccinated flocks causing high economic losses without specific treatment. Mesenchymal stem cells (MSCs) are a group of pluripotent cells with multiple biotechnology applications, including but not limited to tissue genesis, tissue repair, hematopoiesis, and immune modulation. Therapeutic strategies based on the usage of stem cells includes the cells either themselves or their secretions (secretome), which has recently shown ability to inhibit SARS-CoV2 replication in-vitro. In this study, MSCs were prepared from the bone marrow of native Egyptian Fayoumi chicken. The MSC with the surface marker CD105 (CD105+) were magnetically separated and infected with virulent Newcastle disease virus (vNDV). The virusinduced multiple changes at the cellular and ultrastructural level in the infected cells, and it was able to maximize the production of interferon-gamma (IFNγ) and interleukin 2 (IL2), interleukin 6 (IL6) and interleukin 12 (IL12). In conclusion, our data represent a preliminary step in vNDV immunotherapy where MSCs media could be used for the treatment of vNDV in infected flocks © 2022 by the authors. Licensee ResearchersLinks Ltd, England, UK

Immunomodulatory Mechanisms of Mesenchymal Stem Cells and Their Potential Clinical Applications.

Mesenchymal stem cells (MSCs) are multipotent stem cells with the capacity of self-renewal, homing, and low immunogenicity. These distinct biological characteristics have already shown immense potential in regenerative medicine. MSCs also possess immunomodulatory properties that can maintain immune homeostasis when the immune response is over-activated or under-activated. The secretome of MSCs consists of cytokines, chemokines, signaling molecules, and growth factors, which effectively contribute to the regulation of immune and inflammatory responses. The immunomodulatory effects of MSCs can also be achieved through direct cell contact with microenvironmental factors and immune cells. Furthermore, preconditioned and engineered MSCs can specifically improve the immunomodulation effects in diverse clinical applications. These multifunctional properties of MSCs enable them to be used as a prospective therapeutic strategy to treat immune disorders, including autoimmune diseases and incurable inflammatory diseases. Here we review the recent exploration of immunomodulatory mechanisms of MSCs and briefly discuss the promotion of the genetically engineered MSCs. Additionally, we review the potential clinical applications of MSC-mediated immunomodulation in four types of immune diseases, including systemic lupus erythematosus, Crohn's disease, graft-versus-host disease, and COVID-19.

Potential Cell-Based and Cell-Free Therapy for Patients with COVID-19.

Since it was first reported, the novel coronavirus disease 2019 (COVID-19) remains an unresolved puzzle for biomedical researchers in different fields. Various treatments, drugs, and interventions were explored as treatments for COVID. Nevertheless, there are no standard and effective therapeutic measures. Meanwhile, mesenchymal stem cell (MSC) therapy offers a new approach with minimal side effects. MSCs and MSC-based products possess several biological properties that potentially alleviate COVID-19 symptoms. Generally, there are three classifications of stem cell therapy: cell-based therapy, tissue engineering, and cell-free therapy. This review discusses the MSC-based and cell-free therapies for patients with COVID-19, their potential mechanisms of action, and clinical trials related to these therapies. Cell-based therapies involve the direct use and injection of MSCs into the target tissue or organ. On the other hand, cell-free therapy uses secreted products from cells as the primary material. Cell-free therapy materials can comprise cell secretomes and extracellular vesicles. Each therapeutic approach possesses different benefits and various risks. A better understanding of MSC-based and cell-free therapies is essential for supporting the development of safe and effective COVID-19 therapy.

Cellular Therapy: Shafts of Light Emerging for COVID-19.

The COVID-19 pandemic has presented with debilitating respiratory consequences especially more pronounced in high risk individuals. Individuals with underlying systemic diseases are more prone and vulnerable to suffer severe consequences of SARS-CoV-2 infectivity. The pathophysiological changes identified cytokine storm mechanism for out setting the series of adverse clinical conditions. Thereby, associating it with high mortality rates. This warrants urgent consideration of divergent modalities such as the cellular therapy. Cellular therapy (CT) is a new medical paradigm wherein cellular material is administered to patients for therapeutic purposes. In this regard, mesenchymal stem cells (MSCs) have yielded the most promising results among stromal vascular fraction (SVF); placental cells; natural killer (NK) cell and platelet lysate respectively. Following the administration of the CT as per preferred route, these play pivotal role in modifying the microenvironment of the lung tissue with their distinct sets of mechanism. Evidences have shown how their immunomodulatory action repairs and prevents lung injury which in turn improvise the compliance of lungs. In this review article we have discussed these emerging novel approaches and their target step serving as a ray of hope to combat severe form of COVID-19. Currently these aren't approved for preventing or treating COVID-19 cases, however clinical trials are afoot to dispense the utmost understanding in terms of efficacy and safety concerns.

Anti-inflammatory Effects of Mesenchymal Stem Cells and their Secretomes in Pneumonia.

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that play crucial roles in the microenvironment of injured tissues. The potential therapeutics of MSCs have attracted extensive attention for several diseases such as acute respiratory distress syndrome (ARDS) and novel coronavirus disease 2019 (COVID-19) pneumonia. MSC-extracellular vesicles have been isolated from MSC-conditioned media (MSC-CM) with similar functional effects as parent MSCs. The therapeutic role of MSCs can be achieved through the balance between the inflammatory and regenerative microenvironments. Clinical settings of MSCs and their extracellular vesicles remain promising for many diseases, such as ARDS and pneumonia. However, their clinical applications remain limited due to the cost of growing and storage facilities of MSCs with a lack of standardized MSC-CM. This review highlights the proposed role of MSCs in pulmonary diseases and discusses the recent advances of MSC application for pneumonia and other lung disorders.

A Role for Extracellular Vesicles in SARS-CoV-2 Therapeutics and Prevention.

Extracellular vesicles (EVs) are the common designation for ectosomes, microparticles and microvesicles serving dominant roles in intercellular communication. Both viable and dying cells release EVs to the extracellular environment for transfer of cell, immune and infectious materials. Defined morphologically as lipid bi-layered structures EVs show molecular, biochemical, distribution, and entry mechanisms similar to viruses within cells and tissues. In recent years their functional capacities have been harnessed to deliver biomolecules and drugs and immunological agents to specific cells and organs of interest or disease. Interest in EVs as putative vaccines or drug delivery vehicles are substantial. The vesicles have properties of receptors nanoassembly on their surface. EVs can interact with specific immunocytes that include antigen presenting cells (dendritic cells and other mononuclear phagocytes) to elicit immune responses or affect tissue and cellular homeostasis or disease. Due to potential advantages like biocompatibility, biodegradation and efficient immune activation, EVs have gained attraction for the development of treatment or a vaccine system against the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) infection. In this review efforts to use EVs to contain SARS CoV-2 and affect the current viral pandemic are discussed. An emphasis is made on mesenchymal stem cell derived EVs' as a vaccine candidate delivery system.

Mesenchymal stem cells in the fight against viruses: Face to face with the invisible enemy.

The relative ease of isolation of mesenchymal stem cells (MSCs) from different tissues coupled with their culture expansion in vitro and their differentiation capacity to mesodermal, endodermal and ectodermal lineages have made these cells attractive for a large number of therapeutic applications. In recent years, there has been remarkable progress in the utilization of MSCs in diverse clinical indications both in animal models and human clinical trials. However, the potential of MSCs to control or treat viral diseases is still in its infancy. In this study, we report quantitative data on the MSC-based clinical trials over the last ten years as they appear on the online database of clinical research studies from US National Institutes of Health. In particular, we provide comprehensive review of either completed or ongoing clinical trials using MSCs for virus-associated diseases focusing on HIV, hepatitis B virus and COVID-19 virus.

Stem Cells Therapy as a Possible Therapeutic Option in Treating COVID-19 Patients.

An unfortunate emergence of a new virus SARS-CoV-2, causing a disease known as COVID-19, has spread all around the globe and has caused a pandemic. It primarily affects the respiratory tract and lungs in some cases causing severe organ damage and pneumonia due to overwhelming immune responses. Clinical reports show that the most commons symptoms are fever, dry cough, and shortness of breath, along with several other symptoms. It is thought that an immense cytokine dysregulation in COVID-19 patients is caused following the virus infection. Notably, if patients present with pre-existing specific comorbidities like diabetes or high blood pressure, rates of COVID-19 induced complications and deaths are escalated. Mesenchymal stem cell (MSC) therapy has been shown to alleviate pneumonia and acute respiratory syndrome (ARDS) symptoms, through their immunomodulatory activities in COVID-19 patients. Although more research studies and clinical trial results are needed to elucidate the exact mechanism by which MSCs provide relief to COVID-19 infected patients. Results from clinical trials are encouraging as patients treated with MSCs, regain lung functions and have restored levels of cytokines and trophic factors underscoring the fact that stem cell therapy can be, at least, a complementary therapy to alleviate sufferings in COVID-19 patients. This review discusses the possible therapeutic uses of MSCs for treating COVID-19. Graphical Abstract.