**Abstract**

In the pandemic of COVID-19, while living normals have been changing, there have been a huge effort globally to find out effective and safe treatment agents and vaccines. As of now, the advances show the progress in vaccine development, however the treatment of the COVID-19 is yet not fully specified. The drugs, i.e. antibiotics, antivirals, antimalarians, even anti-HIV agents which have been known already were taken out of the shelves and brought into use in different combinations. On the other hand, the cellular treatment, more specifically the mesenchymal stem cell therapy has been encouraged, resulting in various evidence published all over the world. This chapter aims to compile the published information, in means of methods, disease manifestations, results and limitations, about the stem cell treatment of the COVID-19 and to provide a source of harmonized reference for scientific society.

**Keywords:** mesenchymal stem cell, cellular therapy, regenerative, restorative, personalised medicine

## **1. Introduction**

Since the global living routine have been dramatically changed by a novel virus called SARS-CoV-2, scientific community has been working hard on the understanding of the pathophysiology of the COVID-19 infection caused by this virus, and the methods of preventing and treating the disease. The spectrum of clinical manifestations of COVID-19 varies from asymptomatic or somewhat mild-disease (81%) to severe clinical conditions characterized by respiratory failure requiring mechanical ventilation (14%) and to critical systemic presentations with multiple organ dysfunction syndromes or failures (5%) [1, 2].

There is a huge effort to develop vaccines, some are developed and received the accelerated access at the moment, however, there is no specific antiviral treatment recommended or appreved for COVID-19, yet. Current therapeutic strategies are only supportive and oxygen therapy represents the primary treatment intervention for patients with severe pneumonia. The medications that have already been known such as anti-viral, anti-malarial, and anti-inflammatory agents have been taken from the shelves and began to be used as the emergency state action to improve the recovery of the patients and increase the survival. Whilst these treatments can improve patient's recovery and survival to some extend, these therapeutic strategies do not lead to unequivocal restoration of the lung damage inflicted by this disease [3]. The outcome so far shows that the antibiotics are ineffective; although systemic

corticosteroids seem be effective, they also reduce the immune system activity and thus its ability to fight against the infection. It is of crucial importance to save the patients with severe COVID-19 pneumonia, to prevent and even reverse the cytokine storm along with inhibiting the viral replication [4].

The cellular therapies with mesenchymal stem cells (MSCs) are attracting attention as they could offer a new therapeutic approach in this context. These stem cells have broad pharmacological effects, including anti-inflammatory, immunomodulatory, regenerative, pro-angiogenic and even anti-fibrotic properties [5].

Stem cells, in particular MSCs, exert their immunomodulatory, anti-oxidant, and reparative therapeutic effects likely through secreted extracellular vesicles (EVs), and therefore, could be beneficial, alone or in combination with other therapeutic agents, in patients diagnosed with COVID-19 [3, 6]. They are are emerging as new promising treatments, since they could not only attenuate the inflammation but also regenerate the lung damage caused by COVID-19 [7, 8].

In this chapter, we outline the information about this novel virus, and the pathophysiology of the COVID-19 infection, the mechanisms of cytokine storm and lung damage caused by SARS-CoV-2 virus and how mesenchymal stem cells (MSCs) can be utilized to hamper this damage by harnessing their regenerative properties. The potential of these ancestor cells in the enhanced clinical utility in treating the COVID-19 patients along with the opportunuties major roadblocks to progressing these promising curative therapies toward mainstream treatment for COVID-19 have also been evaluated.

### **2. SARS-CoV-2 infection: what to focus**

#### **2.1 SARS-CoV-2 virus**

Belonging to the β Coronavirus family, SARS-CoV2 is a single-stranded RNA, enveloped virus of 50-200 nm diameter [9]. Spike Glycoprotein (S) is the vital protein consisting of three S1-S2 heterodimers that bind to angiotensin-converting enzyme 2 (ACE2) receptor on type II pneumocyte in the lung tissue [3, 9, 10]. Besides S protein, enetically SARS-CoV-2 is constructed on structural proteins of membrane (M), envelope (E), and nucleocapsid (N) proteins. Spread of the virus is managed by the high affinity of S proteins to ACE2 receptors that are expressed in human organs, principally in lung alveolar epithelial cells and enterocytes of the small intestine [11, 12].

Once the SARS-CoV-2 virus enters into the type II pneumocyte and capillary endothelium by endocytosis, it increases in the cytoplasm. Apoptosis is induced by yhe stress in the pneumocytes. Besides, the viral RNA acts as a pathogen-associated molecular pattern and is recognized by the pattern recognition receptor or tolllike receptors. Subsequent chemokine attraction causes neutrophil migration and activation. Then the destruction of the alveolar-capillary walls occur. This leads to the lost interface between the intra-alveolar space and the stroma. Therefore, fluid leaks through and fills into the alveolar spaces [13, 14].

One of the prominent features of SARS-CoV-2 is its being more inclinable to infect the human lung and higher, 3.20-fold faster, duplication time than SARS-CoV [15].

#### **2.2 The development of the SARS-CoV-2 infection**

#### *2.2.1 In the society*

Modes of transmission occurs through droplet transmission, fecal-oral route, conjunctiva and fomites [13, 14]. Also, the local transmission can be traced back to

#### *Cellular Therapy as Promising Choice of Treatment for COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.96900*

the patient's body fluids such as respiratory droplets, saliva, feces, and urine [15]. The virion is stabilized at lower temperatures, i.e., 4 °C has higher survival than 22 °C [16, 17].

Before the clinical symptoms presentation, during the symptomatic stage and even during the recovery period, the patients with COVID-19 can spread the infection, because SARS-CoV-2 virions are shed throughout the clinical course.

When it comes to the residence time of the SARS-CoV-2 virion on surfaces, it has been known that the viable residence time of SARS-CoV-1 in aerosols, copper, cardboard, stainless steel, and plastic are 3 h, 4 h, 24 h, 48 h, and 72 h, respectively [18].

## *2.2.2 In the clinics*

## *2.2.2.1 Clinical presentation of COVID-19*

The symptoms and relevant clinical presentations of COVID-19 was deeply elaborated in WHO-China joint report [19]. Cases of 85%, present with pyrexia in but only 45% are febrile on early presentation [20]. Cough is seen in 67.7% of patients and sputum is seen in 33.4%. Cases show respiratory symptoms such as dyspnea (18.6%), sore throat (13.9%), and nasal congestion (4.8%) [20]. General symptoms such as muscle or bone aches (14.8%), chills (11.4%), and headache (13.6%) are also seen [20]. Gastrointestinal symptoms including nausea/vomiting and diarrhea are observed in 5% and 3.7% of the cases, respectively. These clinical presentations of COVID-19 were consistent in similar studies on COVID-19 cases in China [21–24].

In SARSCoV- 2 infected severe cases, fatal acute respiratory distress syndrome (ARDS), associated with monocyte and macrophage infiltration, diffuse alveolar damage, and cellular fibromyxoid exudates have been confirmed [25, 26] with mortality reported as high as 52.4% [27]. At the 7th–10th days of the manifestations of immune dysregulation, including cytokine release syndrome with elevated cytokine levels (IL-6, IL-8, IL-1, IL2R, IL-10, and TNF-α), lymphopenia (in CD4+ and CD8+ T cells), and decreases in IFN-γ expression in CD4<sup>+</sup> T cells [26–28]. It is suggested that the cytokine storm or response may weaken the adaptive immunity against COVID-19 infection, [29] which is associated with atrophy of the secondary lymphoid tissues [25]. The risk of the success of the anti-inflammatory treatment comes from the secondary infections [30].

In severely damaged the lung tissue the ARDS develops which can further turns to septic shock. These two complications are the major issues in intensive care unit (ICU) care. The mortality from COVID-19 in patients older than 60 years, with smoking history, and comorbid medical conditions including but not limited to hypertension, cardiovascular and cerebrovascular disease, and diabetes also occurs from these complications. Notably, smoking and older age group patients tend to have a higher density of ACE2 receptors [13].

Asymptomatic or presymptomatic infection takes its naming from the patients which are the most majority of the all cases have no symptoms although they test positive for SARS-Cov-2 by reverse-transcriptase polymerase chain reaction (RT-PCR). The rest of the cases demonstrate the symptoms of fever (98%), cough (76%), dyspnoea (55%) and myalgia or fatigue (44%). Other signs, such as sputum production (28%), headache (8%), haemoptysis (5%) and diarrhoea (3%), may also be present [31]. On the other hand, the severe cases are seen in the clinics and are typically characterised by pneumonia and usually accompanied by the complications of ARDS [31, 32], acute cardiac injury [33], and secondary infections [34].

ARDS is the most significant complication in severe cases of COVID-19, and it affects 20–41% of hospitalized patients [31, 35] besides, heart failure, renal failure, liver damage, shock and multi-organ failure have also been observed as complications.

Clinical manifestation severity has been seen in a stratification which depends on symptomatology [36] (**Figure 1**). Adult COVID-19 cases may be grouped as follows [37, 38]:


As the RNA expression is detectable across a wide range of human tissues [39], it is thought that the multi-organ dysfunction is probably linked to the expression pattern of ACE2 gene. The cells, tissues and organs most affected are those with high ACE2 expression, the entry receptor or opening doors for SARS-Cov-2. The research has shown that ACE2 is abundantly expressed in the epithelia of the lung and small intestine in humans, for possible routes of the SARS-Cov-2 [40]. Since the recent data suggest that cell-surface expression on the lungs is below the detection limit [41], it has been proposed that the COVID-19 disease pathology would not be directly correlate with ACE2 cell-surface protein expression [41]. As reported for the heart and kidneys, the said disparity may be linked to the selective, transient expression of ACE2 [42, 43].

Health condition of the patients suddenly detoriates in the later stages of diseases progression. Death comes right after the fast multiple organs' failure and ARDS. Cytokine storm has been indicated as the causal factor for ARDS and multiple organ failure [44, 45]. WHO has announced the case fatality rate of

**Figure 1.** *Clinical stages and the manifestations of COVID-19 disease.*

COVID-19 as ranging from 0.3 to 1%, higher than that of influenza A which is 0.1%. The epidemiological studies reported from the countries implementing COVID-19 mitigation strategies revealed that almost 80% of patients of COVID-19 had no symptoms or mild disease, whereas 14% of the patients had severe symptoms, and 6% of them were in critical condition [46].

#### *2.2.2.2 COVID-19 disease management*

The management of viral pneumonia is supportive in absence of specific treatment. The most dominating symptoms are fever and dry cough, therefore the firstline antipyretic agent antitussive medications [47]. Oxygen supplementation at 5 L/ min must be administered for patients requiring ARDS treatment and the oxygen saturation target must be ≥92–95% in pregnant cases, ≥90% in other cases [48].

Conventionally, the complications of septic shock and acute kidney injury should be managed with relevant sepsis and renal replacement therapies [49]. In the middle to later course of COVID-19, some of the cases may develop overlapping bacterial and/or fungal infection. In these cases, the empiric antimicrobial treatment should be provided.

The WHO has been recommending the usage of extracorporeal membrane oxygenation in the patients who sustain hypoxia refractory to supplementary oxygen [49]. Or else, the convalescent plasma and IgG are used as rescue therapy in critical cases, without any solid evidence for the benefit of this practice. Most of the cases demonstrate vital health measures to control COVID-19 spreading. If the public health measures are not taken properly, there will be a patient burden that exceeding the volume of ICU beds and mechanical ventilation, as seen in the crisis in Italy. Hence, the objective of the COVID-19 management lies on the maintenance of social distancing to suppress the rapid emergence inflow of new cases. This epidemiological approach is called as flattening of the curve. The public health interest should be for identifying and isolating the infective cases, attain and maintain contact tracing and isolation [50].
