Stem Cells and COVID-19

By Chandra P. Sharma

Stem Cells and COVID-19 presents up-to-date knowledge on the effect of hematopoietic and mesenchymal stem cells to combat SARS-CoV-2 infection in its diagnosis, treatment and prevention. In addition, the book critically discusses challenges, highlighting outstanding questions and future perspectives. Written by global experts in the field for both pre-clinical and clinical practitioners, this comprehensive book delves into how stem cells have a strong potential in developing better diagnostic, treatment and preventive strategies in SARS-CoV-2 infection.

Both hematopoietic and mesenchymal stem cells are critical to better understand the response of immune system to coronavirus infection in both healthy and co-morbid conditions in the development of effective vaccines and immunotherapies.

• Focuses on diagnosis, treatment and prevention
• Presents different aspects to enable researchers in the field to move toward designing novel therapeutics in the treatment of COVID-19
• Provides coverage of challenges and future perspectives in this fast-moving field

• Language: English
• Publisher: Academic Press
• Release date: Apr 21, 2022
• ISBN: 9780323886239

Book preview

Preface

Chandra P. Sharma; Devendra K. Agrawal; Finosh G. Thankam

The pandemic spread of COVID-19 infection throughout 190 countries and territories has created health crisis and huge economic burden across the globe. This is due to SARS-CoV-2 that induces aggravated and sustained inflammation with cytokine storm compared to other coronavirus strains, leading to multiorgan pathology. Tremendous efforts have been devoted to learn the underlying cellular and molecular mechanisms and developing effective vaccines.

Stem cells pose immense potential in developing better diagnostic, treatment, and preventive strategies in SARS-CoV-2 infection. Interestingly, hematopoietic and mesenchymal stem cells are critical to better understand the response of immune system to SARS-CoV-2 infection in both healthy and comorbid conditions, promising the development of effective vaccines and immunotherapies. Indeed, blood-forming type 1 dendritic cells and other antigen-presenting cells could present SARS-CoV-2 protein fragments to T-lymphocytes that undergo clonal expansion with the development of memory T cells to induce strong immune response and thus long-lasting immunity. Stem cells may also be helpful in disease modeling and drug screening to fight against viral infection.

In this book, our goal is to bring up-to-date knowledge on the effect of hematopoietic and mesenchymal stem cells to combat SARS-CoV-2 infection in its diagnosis, treatment, and prevention; critically discuss the challenges; and highlight outstanding questions and future perspectives for both preclinical and clinical practitioners. The book consists of 12 multiauthored chapters. All contributors are internationally recognized experts in their respective specialties and have reviewed the latest thoughts, concepts, and their implications.

We thank all the contributors for their excellent contributions, Ms. Elizabeth A. Brown for encouraging the project development at its initial stage, and Ms. Allard Samantha for her effective coordination.

We take this time to express our gratitude and thanks to our family members for sustained support during this project.

Chandra P. Sharma thanks and very much appreciates his wife Aruna Sharma for her continuous support during this entire project.

Finosh Thankam expresses his sincere gratitude for the continuous support and heartening from his wife Soumya and his son Rohin for the preparation of this book. Also, Finosh acknowledges the constant support from the editors and the excellent contribution by the authors and the perpetual blessings and inspiration from his parents, teachers, friends, and well-wishers for the successful completion of this project.

Devendra Agrawal expresses many thanks to his coeditors, Dr. Finosh G. Thankam and Prof. Chandra P. Sharma, the authors of the chapters for their exceptional contribution with the latest information in the field to complete this project, and the Elsevier editorial team for their patience and outstanding support.

1: Introduction

Finosh G. Thankama; Devendra K. Agrawala; Chandra P. Sharmab,c,d    a Department of Translational Research, Western University of Health Sciences, Pomona, CA, United States

b Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences & Technology (SCTIMST), Trivandrum, India

c Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India

d College of Biomedical Engineering and Applied Sciences, Purbanchal University, Kathmandu, Nepal

Pandemic outbreak of the novel coronavirus disease (COVID-19) infection caused by SARS-CoV-2 remains to be a serious threat to human population across the globe. As of July 22, 193,361,389 clinically confirmed cases with 4,150,618 deaths shook the world. The pandemic has globally impacted all dimensions of life, especially the health care system, economy, and education [1]. COVID-19 primarily infects respiratory system causing pneumonia-like clinical presentation; however, it affects heart, kidney, liver, and central nervous system leading to multiple organ failure and subsequent death in severe cases [2]. Indeed, the angiotensin-converting enzyme 2 (ACE2) receptor in the alveolar epithelial cells and macrophages is crucial for the viral entry to human system. The accelerated replication of COVID-19 in these cells leads to the activation of apoptosis, increasing the surge of proinflammatory cytokines potentially damaging the alveoli and reducing diffusion perfusion and ventilation leading to low level of oxygen in the blood [3]. Evidently, the severely infected patients displayed hypersecretion of interleukin (IL)-6 and tumor necrosis factor α (TNFα) along with decreased density of CD4   + and CD8   + T cells which significantly declined the recovery rate [4]. In addition, the compromised alveolar epithelium facilitates the influx of neutrophils and inflammatory macrophages contributing to the pool of proinflammatory cytokines resulting in cytokine burst sustaining the alveolar damage and potential development of multiorgan dysfunction [1].

Advancements in PCR and antibody technologies have made early detection of COVID-19 infection. Moreover, the diagnostic imaging (especially CT scan) coupled with artificial intelligence has proven to be advantageous [5]. Generally, the management of COVID-19 depends on the clinical symptoms where the patients with mild symptoms are treated without hospitalization. However, critical clinical care including oxygen support is required for patients with severe/aggravated COVID-19 infection. In addition, the commonly administered therapeutics include hydroxychloroquine, azithromycin, remdesivir, favipiravir, tocilizumab, and itolizumab and convalescent plasma. Despite the promising outcomes in the attenuation of symptoms, the overall clinical outcomes are minimally effective [6]. Also, a novel approach of binding the virus with soluble ACE2 receptor which neutralizes the S-protein of COVID-19 by preventing the entry to the cells and giving the opportunity for immune system to clear the virus has been attempted [7]. Currently, the global medical community is striving to tame the virus and to bring back the world as it was in pre-COVID-19 era.

As the world strives to control COVID-19, multiple approved vaccines are in clinical practice, and several are on the cusp of approval. Despite the concerns in the efficacy and safety, the COVID-19 vaccines are beneficial in preventing the pandemic spread [8]. However, potential concerns regarding the dose, effectiveness, efficiency, and duration of effect persist which warrant the next-generation vaccines with improved and long-lasting performance [8]. Multiple viral elements have been tried as target to vaccine development; however, the vaccines designed against S-protein have gained maximum significance owing to its crucial role in virus binding to the host cell. Interestingly, diverse strategies have been employed for the vaccines which include inactivated virus, viral-like nanoparticles, protein subunits, virus-vectored, DNA, mRNA, and live attenuated virus [9]. Unfortunately, the uncertainty in the performance of vaccines and the extent of tissue damage and comorbidities following the COVID-19 infection warrant effective regenerative/management strategies adjuvant to vaccine-based therapies.

Additionally, it is becoming extremely challenging because of constant mutation of the virus and the emergence and circulation of genetic variants of SARS-CoV2 around the globe during this COVID-19 pandemic. The major variants of COVID-19 that are circulating include B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and P.1 (Gamma). Among these, the cases of gamma variant (B.1.617.2) are surging in India, United States, and other countries, and appears to be 10–15 times more deadly than the earlier predominant strain (B.1.1.7-Alpha). In a very recent study, there was a modest difference in the effectiveness of the two vaccine doses between the delta variant and the alpha variant [10]. These findings support the effectiveness of the currently available vaccine against both alpha and delta variants. However, better therapies with longer duration of effect are warranted.

Several cell-based therapies have been attempted in the management of COVID-19 which revealed promising outcomes. Specifically, the contribution of stem cells in medicine and clinical practice is central which has been applied to COVID-19 as well. For instance, the intravenous administration of mesenchymal stromal cells (MSCs) in critically ill patients demonstrated the improvements in clinical symptoms, including the resolution of cough, fever, respiratory distress, and reversal of oxygen saturation within 2–4 days [7]. Importantly, MSCs have been an ideal choice for cell-based regenerative therapies owing to their lower immunogenicity, differentiation potential, immunomodulatory effects, and ease of harvest and manipulation. In addition, MSCs are abundant in most tissues and can be harvested using minimally invasive techniques. Owing to their potent immunomodulatory and prohealing effects, MSCs have been hailed to be promising for the management of COVID-19 as evident from the growing numbers of clinical trials [11]. Also, the MSCs harvested from adipose tissues, bone marrow, umbilical cord, blood, and other tissues offer flexibility in manipulation, in vitro expansion and storage which is further beneficial for COVID-19 management.

Since COVID-19 is associated with cytokine-driven multiple organ damage, MSC therapy has been innovative in the management of organ damage following COVID-19 infection. However, the potential healing mechanisms elicited by MSCs in COVID-19 mediated organ damage remain unanswered [12]. Route of administration, dose, biomarker definition of MSCs, and expansion status warrant further optimization. Despite these challenging questions, secretome from MSCs released as exosomes offers promising translational potential addressing the hurdles of MSC therapy [13]. The MSC-derived exosomes have been superior in preventing lung injury and lung fibrosis, offering the flexibility of injection, inhalation, and infusion suggesting their potential application in COVID-19 management. Interestingly, several clinical trials have been registered focusing on the application of exosomes in COVID-19 therapy [11,12]. In addition, the advantages of exosomes including safer than parent cells, easily diffusible nature, and ability to cross cellular/tissue barriers and the immunomodulatory contents (proteins, growth factors, miRNAs, and lncRNAs) upgrade the stem cell-derived exosomes to be the superior biological therapeutics for COVID-19 management.

The advancements in cell technologies and vesicle engineering have significantly contributed to clinical medicine and disease management. Apart from MSCs, induced pluripotent stem cells (iPSC) and programmed cells are ideal for the management of COVID-19 [1,14]. The combinatorial approaches employing stem cell technologies and advanced gene technologies including genome editing, CRISPR-cas9, and single cell genomics unveil the ideal stem cell population customized for COVID-19 management. Significant research commitment is required to translate the stem cells as a promising therapeutic for the management of COVID-19 infection and associated complications. Current knowledge regarding the prevention of COVID-19 virus entry and replication by stem cells in the respiratory and/or other tissues is limited; however, such possibility cannot be neglected owing to the healing effects of stem cells against viral infections. Taken together, stem cell biology leaves behind a promising opportunity as novel management strategy for COVID-19 and associated organ damage.

As the COVID-19 pandemic continues to challenge the global scientific community, the information presented in this book primarily focuses on the perspectives in the potential of stem cells in developing better diagnostic, treatment, and preventive strategies in COVID-19 infection. The 12 chapters contributed by highly qualified investigators critically review the therapeutic potential of stem cells in response of immune system to coronavirus infection in both healthy and comorbid conditions. In this book, our goal is to bring up-to-date knowledge on the effect of diverse stem cells and stem-cell derived entities to combat COVID-19 infection in its diagnosis, treatment, and prevention; critically discuss the challenges; and highlight outstanding questions and future perspectives for both preclinical and clinical practitioners.

References

[1] Djidrovski I., Georgiou M., Hughes G.L. SARS-CoV-2 infects an upper airway model derived from induced pluripotent stem cells. Stem Cells. 2021;doi:10.1002/stem.3422.

[2] Zhu N., Zhang D., Wang W. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727–733. doi:10.1056/NEJMoa2001017.

[3] Thankam F.G., Agrawal D.K. Molecular chronicles of cytokine burst in patients with coronavirus disease 2019 (COVID-19) with cardiovascular diseases. J Thorac Cardiovasc Surg. 2020;doi:10.1016/j.jtcvs.2020.05.083.

[4] Diao B., Wang C., Tan Y. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol. 2020;doi:10.3389/fimmu.2020.00827.

[5] Alsharif W., Qurashi A. Effectiveness of COVID-19 diagnosis and management tools: a review. Radiography (Lond, Engl: 1995). 2021;27:682–687. doi:10.1016/j.radi.2020.09.010.

[6] Mahendiratta S., Bansal S., Sarma P. Stem cell therapy in COVID-19: pooled evidence from SARS-CoV-2, SARS-CoV, MERS-CoV and ARDS: a systematic review. Biomed Pharmacother. 2021;137:111300doi:10.1016/j.biopha.2021.111300.

[7] Anka A.U., Tahir M.I., Abubakar S.D. Coronavirus disease 2019 (COVID‐19): An overview of the immunopathology, serological diagnosis and management. Scand J Immunol. 2020;e12998doi:10.1111/sji.12998.

[8] Soiza R.L., Scicluna C., Thomson E.C. Efficacy and safety of COVID-19 vaccines in older people. Age Ageing. 2020;afaa274. doi:10.1093/ageing/afaa274.

[9] Dai L., Gao G.F. Viral targets for vaccines against COVID-19. Nat Rev Immunol. 2020;1–10:doi:10.1038/s41577-020-00480-0.

[10] Lopez Bernal J., Andrews N., Gower C. Effectiveness of Covid-19 vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med. 2021;doi:10.1056/NEJMoa2108891.

[11] Riedel R.N., Pérez-Pérez A., Sánchez-Margalet V. Stem cells and COVID-19: are the human amniotic cells a new hope for therapies against the SARS-CoV-2 virus?. Stem Cell Res Ther. 2021;12:155. doi:10.1186/s13287-021-02216-w.

[12] Afarid M., Sanie-Jahromi F. Mesenchymal stem cells and COVID-19: cure, prevention, and vaccination. Stem Cells Int. 2021;2021:e6666370doi:10.1155/2021/6666370.

[13] Gennai S., Monsel A., Hao Q. Microvesicles derived from human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2015;15:2404–2412. doi:10.1111/ajt.13271.

[14] Fang W., Agrawal D.K., Thankam F.G. ‘Smart-exosomes’: a smart approach for tendon regeneration. Tissue Eng Part B Rev. 2021;doi:10.1089/ten.TEB.2021.0075.

2: Characteristics and immunobiology of COVID-19

Remya Kommeria; Finosh G. Thankamb; Devendra K. Agrawalb; Daniel R. Wilsona,b    a McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States

b Department of Translational Research, Western University of Health Sciences, Pomona, CA, United States

Abstract

COVID-19 (coronavirus disease-2019) has been identified as a serious respiratory infection by the SARS-CoV2 virus (severe acute respiratory syndrome coronavirus 2), was first reported in Wuhan, Hubei Province, China in December 2019. World Health Organization (WHO) declared COVID 19 as a pandemic on March 11, 2020 considering the exponential spread and unmanageable mortality. It continues currently as the utmost urgent/critical ailment of global public health. Moreover, the COVID-19 pandemic has not only affected global health scenarios but also has heavily burdened the economic, financial, political, educational, and other dimensions of humanity across the world. Monitoring the COVID 19 pathology reveals a potential respiratory infection followed by severe pneumonia like clinical observations with greater chances of microvascular injuries and multiorgan failures in worse scenario. The preexisting comorbidities including type II diabetes, cardiovascular diseases, hypertension, and older age are other major aggravating factors. Rather than other flu viruses, the intricate interplay of SARS-CoV2 virus with the immune system underlies the pathological manifestations in both symptomatic and asymptomatic patients. This chapter highlights the role of heterogenous immune cell population, cytokine storm, immune cell activation, and potential signaling pathways associated with COVID 19 infection that are greatly appreciated to evolve novel translational therapeutic interventions.

Keywords

COVID-19; Etiology; SARS-CoV2 virus; ARDS; Cytokine storm

Acknowledgments

This work was supported by the research funds of Western University of Health Sciences to FGT, and research grants R01 HL144125 and R01HL147662 to DKA from the National Institutes of Health, USA. The contents of this chapter are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. RK acknowledges the United States-India Educational Foundation (USIEF) for Fulbright-Nehru postdoctoral fellowship.

Conflict of Interests

All authors have read the Elsevier’s policy on disclosure of potential conflicts of interest. Author C (DKA) has received grants from the National Institutes of Health. Author B (FGT) received start-up funds from Western University of Health Sciences. Author D (DRW) has no relevant affiliations or financial or nonfinancial involvement with any organization or entity with financial or nonfinancial interest or conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Author A (RK), Author B (FGT), Author C (DKA, and Author D (DRW), declare that they have no conflict of interest. No writing assistance was utilized in the production of this manuscript.

Introduction

COVID-19 (coronavirus disease-2019) has been identified as a serious respiratory infection by the SARS-CoV2 virus (severe acute respiratory syndrome coronavirus 2), was first reported in Wuhan, Hubei Province, China in December 2019. Since then, COVID-19 has exponentially spread worldwide as a pandemic eventually declared by WHO on March 11, 2020. It continues currently as the utmost urgent/critical ailment of global public health [1]. Moreover, the COVID-19 pandemic has not only affected global health scenarios but also has heavily burdened the economic, financial, political, educational, and other dimensions of humanity across the world. As of June 20, 2021, according to Worldometer, 179,245,386 cases with 3,881,890 deaths and 163,798,559 recovered cases were reported globally. Data collection varies across nations, but officially the USA has reported the most cases (34,406,001 cases), followed by India (29,934,361 cases), and Brazil (17,927,928 cases; [2]). That these statistics continue to gather rapidly reflects how this severe global health challenge requires effective strategies for the diagnosis, prevention, and management of COVID-19. These, in turn, rely on understanding the vector structures, modes of infection, molecular pathologies, and optimal translational targets.

Generally, COVID-19 infection is characterized by lung dysfunction and respiratory difficulties leading to pneumonia-like clinical presentation causing death in severe cases. The major pathological mechanism for aggravated respiratory pathology in COVID-19 infection has been attributed to increased pro-inflammatory milieu due to cytokine storm [3]. Cytokine storm severely impairs gas exchange, induces edema and trauma in the lungs, elicits acute respiratory distress, and increases susceptibility to secondary infections. In addition, preexisting comorbidities including type II diabetes, cardiovascular diseases, hypertension, and older age are major aggravating factors in COVID-19 infection. Unfortunately, failure of proper management and lack of effective treatment modalities further complicate clinical presentations resulting in increased mortality [4]. Generally, postinfection manifestations and symptoms arise within 14 days, with a mean incubation time of 5 days. Despite the multiple clinical presentations, fever, cough, difficulty in breathing, loss of smell and taste, and fatigue are the typical initial symptoms of COVID‐19 infection [5]. Alarmingly, asymptomatic presentations, extremely higher infectivity, and lack of effective drugs or vaccines are major impediments to management and prevention of disease [6]. Hence, understanding the basic biology of COVID-19 and molecular mechanisms underlying the cytokine burst are crucial to develop effective management strategies. With this as background, the focus of this chapter is to delineate current knowledge regarding the basic immunobiology of COVID-19 with a decidedly translational perspective.

Structure and etiology

International Committee on Taxonomy of Viruses has classified coronaviruses under the family Coronaviridae, subfamily Coronavirinae, and further classified into four genera such as Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. In the family, 6 types of viruses infect humans, of which four cause the common cold, whereas the remaining two lead to fatal diseases. The fatal strains are SARS-CoV and MERS-CoV, identified in 2003 and 2012, respectively [7]. That the new variant, SARS-CoV2, has sequence similarities to bat coronavirus and human SARS-CoV indicates homology to the betacoronavirus family (Ref. [8], p. 2). SARS-CoV2 has a single-stranded positive-sense RNA genome of approximately 29.9 kb [9] packed in a nucleocapsid (N) and further surrounded by an envelope composed of three major structural proteins: membrane protein (M), spike protein (S), and envelope protein (E) [10]. Rather than structural proteins, 16 nonstructural proteins (NSP) are identified in SARS-CoV2 as essential for modulation and survival of the virus [11]. The spike protein is one of the decisive components for viral entry to host cells. Spike protein is composed of two subunits—an external S1 subunit with receptor-binding domain to bind with the angiotensin-converting enzyme 2 receptors on the human cells, and an S2 subunit comprised of transmembrane and internal domains that facilitate fusion of viral membrane with host cells [12]. Being an inevitable structural protein, S proteins are mostly targeted in therapeutic approaches [13], as well as easily recognized by the host immune system to develop antiviral immunity. The major functions of the identified structural and nonstructural proteins are presented in Table