1. Introduction

Coronavirus disease of 2019 (COVID-19) outbreak has been a popular subject of research since its emergence in December 2019 in Wuhan, China. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly, and the disease it causes was declared by the World Health Organization (WHO) an international health emergency on 30 January 2020 [1]. The spread rate of this virus is extremely high, and the reported mortality rate is variable in different regions [2]. Infected patients show a spectrum of symptoms, ranging from asymptomatic infections to acute respiratory distress syndrome (ARDS) [3]. SARS-CoV-2, the etiologic agent responsible for COVID-19, is a virion with single-stranded RNA and belongs to the beta-coronavirus (CoV) genus. To enter the host cells, the virus utilizes its spike glycoprotein (S protein) to recognize the angiotensin-converting enzyme-2 (ACE-2) receptor on the host and the transmembrane serine protease 2 (TMPRSS2), a priming enzyme required for processing the S proteins of SARS -CoV-2 ^[4][5][4,5]. It seems that the first host cells for SARS-CoV-2 are the ciliated cells of the airway and then the type-2 alveolar (AT-2) epithelial cells of the lung [6]. However, the cells of other tissues, particularly, nasal, intestinal, and corneal cells, are also shown to be easily targeted by SARS-CoV-2, which could be attributed to the high expression of ACE2 and TMPRSS2 on these cells [7]. Virus-infected cells produce a wide range of cytokines, including interferons β, γ, and CXCL10 (C-X-C motif chemokine 10), igniting a cytokine storm ^[8][9][8,9]. About 80% of patients will develop a mild disease at this stage, which is self-controlled and does not require hospitalization or intensive medical care [10]. Unfortunately, the disease progresses to a very severe condition in about 20% of the patients (including severe lung alveolar cell damage, excessive inflammation, and difficulty in breathing and oxygen delivery). Antiviral and anti-inflammatory therapies along with supportive care are the main treatments for COVID-19 [11]. Additionally, biological interventions such as mesenchymal stem cell (MSC) therapy have found a special place in COVID-19 therapeutic research [12]. MSCs are undifferentiated multipotent cells and are the most ubiquitous types of adult stem cells. After birth, MSCs are found in various tissues including bone, fat, cartilage, umbilical cord, skin, teeth, and many other tissues. MSCs function to grow, repair, and replace damaged cells and heal injuries [13]. MSCs have unique properties that make them a promising candidate for cell therapy of COVID-19 [14]. These cells can secrete a wide range of immunomodulatory cytokines and growth factors, such as keratinocyte growth factor (KGF), angiopoietin-1 (Ang1), hepatic growth factor (HGF), nitric oxide (NO), transforming growth factor- β (TGF- β ), prostaglandin E2 (PGE2), and indoleamine2,3-dioxygenase (IDO) ^{[14][15][16][17]}[14,15,16,17]. In this way, MSCs can prevent ARDS-induced apoptosis of alveolar epithelial and endothelial cells, inhibit SARS-CoV-19-associated inflammation, and regenerate the damaged lung tissue ^{[15][16][17][18][19][20]}[15,16,17,18,19,20]. MSCs interestingly express the major histocompatibility complex (MHC) at a very low level, which makes these stem cells non-immunogenic in host patients [21]. Moreover, the ACE2 receptor and the TMPRSS2 enzyme are also expressed in MSCs at very low levels, and previous studies indicated that the SARS-CoV-2 virus cannot infect these cells ^[22][23][24][22,23,24]. Positive therapeutic results have been reported when utilizing MSCs in the treatment of respiratory complications ^{[25][26][27][28][29]}[25,26,27,28,29]. MSCs are thought to use both juxtacrine (i.e., direct cell–cell interaction) and paracrine (secretion of extracellular vesicles and exosomes) paths [30]. MSCs help regenerate tissues and reduce cell-based and humoral immune responses through immunomodulating factors such as FGF, HGF, EGF, VEGF [31]. For instance, secretion of HFG by MSCs helps to induce dendritic cell immune tolerance and ease acute lung injury (ALI) [32]. MSCs are shown to reduce the inflammation of epithelial lung cells by transporting miR21-5p and increasing the polarization of alveolar macrophages from the pro-inflammatory to the anti-inflammatory phenotype [33]. Pro-inflammatory factors produced by M1 macrophages at the site of injury activate resting MSCs, whose induced immunosuppressive characteristics, in turn, lower the overall immune response [34]. MSCs further suppress the proliferation of lung Th1 and Th17 helper T lymphocytes through a plethora of secreted cytokines including TGF-β and HGF [35]. MSCs similarly suppress the cell cycle of B lymphocytes, resulting in a diminished expression of a series of chemokine receptors (such as CXCR4 and CXCR5) and immunoglobulins (IgM, IgG, IgA) [36]. Alongside the anti-inflammatory actions of MSCs, they further facilitate the restoration of tissues damaged by ARDS, ALI, and other repertory inflammatory complications through their angiomodulation [37]. Their support for the generation of blood vessels, through the production of a spectrum of proangiogenic factors such as VEGF, HGF, TGF-β, MCP-1, angiopoietin-1, etc., reinforces the recovery process of injured pulmonary tissues by addressing the oxygen supply [38]. Therapeutic applications of MSCs have been considered in several autoimmune disorders in the last decade, and the effectiveness and safety of this treatment have been proven [39]. Recently, Afarid et al. discussed clinical trials evaluating MSCs application for the treatment of COVID-19 infection, demonstrating the unique features of stem cells in the immunomodulation of the COVID-19-induced cytokine storm, the regeneration of alveolar epithelial and endothelial cells, and the secretion of factors that could prevent lung fibrosis and severe COVID-19 manifestations [14]. Given the above, along with the universal presence of MSCs in the human organism, from infants to the elderly, it is not farfetched to expect an important protective role of MSCs against COVID-19. However, a look at the COVID-19 prevalence, severity, and mortality rate in relation to different age brackets shows that MSCs probably act differently in different age groups of the population.

The mortality rate of COVID-19 is about 2% and is strongly correlated to the age of patients [10]. The average age of patients confirmed as positive for COVID-19 is 49–56 years [40]. It seems that the susceptibility to the virus increases with age. Although cases of infection were reported in children, clinical observations indicate that COVID-19 manifests milder symptoms in the youth compared to adults ^[41][42][41,42]. In a study by Hun et al., 53 COVID-19 patients from different age groups were compared for their clinical manifestations. The study revealed that patients older than 40 years showed significantly more symptoms associated with disease exacerbation, including CT abnormalities, multiple lung lesions, and bilateral lung involvement. In addition, this group needed to receive more intensive antiviral drug regimens to control the disease [43]. Interestingly, the study of COVID-19 in pregnant women has shown that, similar to the youth, pregnant women have a lower infection rate and show milder symptoms of COVID-19. In the present study, we reviewed the reports of COVID-19 in children and pregnant women. In relation to the lower incidence and severity of the disease in pregnant women and children, we highlight a common feature of these two groups, namely, the stem cell characteristics, that may lead to resistance to this disease. Finally, we suggest a significant role for actively proliferating stem cells in making pregnant women and children more tolerant to COVID-19.

2. COVID-19 in Children

Pediatric COVID-19 has been investigated in several studies around the world. A survey by the China Centers for Disease Control and Prevention on 72,314 COVID-19 patients showed that children below 10 years of age account for less than 1% of COVID-19 cases [44]. In another study in China, 1391 children (mean age of 6.7 years) were assessed, from which 171 cases were confirmed to be COVID-19-positive. This survey reported a range of disease exacerbation in children with COVID-19 from asymptomatic to severe cases (27 patients with symptomatic infection, 33 patients with upper respiratory tract infection, 111 pneumonia patients). Just 3 of 171 patients (all 3 with coexisting conditions) required intensive medical care, and one death was reported [45]. This study showed that, unlike infected adults, most infected children manifest a milder clinical course; a large fraction of asymptomatic infections was also observed. Similar results on the prevalence and severity of pediatric COVID-19 were reported in a study of the early onslaught of COVID-19 in the United States. In this study, out of 149,082 COVID-19-positive cases, 2572 (1.7%) were children under 18 years of age The researchers also observed that, among these pediatric cases, infants under one year of age (particularly those with coexisting conditions) were the largest group in need of hospitalization [46]. Similar results on the lower rate of infection and mortality in COVID-19-infected children have been reported by other medical centers ^[47][48][49][47,48,49]. In a review of COVID-19-positive cases of children and infants in China, the USA, Korea, and Taiwan, Jeng et al. indicated that, although the incidence of SARS-CoV-2 infection is relatively low in children and their symptoms are less severe than those of adults, critical conditions were reported in some cases, particularly for those with preexisting conditions [50]. Overall, COVID-19 mortality is rare in children, and clinical intervention is needed almost exclusively in children with coexisting conditions ^[45][46][45,46]. Table 1 shows a summary of reports on COVID-19 in children from different medical agencies (see references ^{[10][45][46][47][51][52][53][54][55][56][57][58][59][60]}[10,45,46,47,51,52,53,54,55,56,57,58,59,60]). Hence, published studies have consistently shown that, in children, COVID-19 patients manifest milder symptoms, need less frequent hospitalization, and show a lower fatality rate.

3. COVID-19 in Pregnant Women

The early studies of COVID-19 cases suggested that pregnant women did not exhibit a higher susceptibility to infection with the novel coronavirus [40]. Chen et al. reported nine cases of COVID-19 in pregnant women, all of whom were in their third trimester. Their clinical features were the same as those of non-pregnant women, while none of the pregnant patients in this study required mechanical ventilation [61]. Della Gatta et al. examined 51 pregnant patients and suggested that COVID-19 prognosis for both mothers and neonates is more promising, when compared to that for the general public [62]. In a report by a WHO–China joint mission on COVID-19, an analysis of 147 pregnant women showed that pregnancy does not impose a higher risk of developing severe pneumonia due to COVID-19 [63]. Dashraath et al. reported a 0% mortality of COVID-19-infected mothers and asserted more encouraging COVID-19 outcomes for pregnant women in comparison with MERS and SARS [64]. Pierce-Williams et al. also described the clinical course of 64 COVID-19-infected pregnant women with no maternal mortality [65]. Hantoushzadeh et al., on the other hand, documented seven deaths out of nine severe cases of COVID-19-infected pregnant women [66]. Although common symptoms were observed in the COVID-19-positive pregnant women, the milder symptoms and few reported deaths in pregnant women is a significant observation [67]. These reports indicate that pregnant women are less susceptible to COVID-19 and can battle this infectious disease better than other groups. Early studies do not indicate that there is a drastic difference between the levels of infection resistance in pregnant women in different trimesters; however, more experimental data might be needed to confidently draw a conclusion on the subject ^[68][69][70][68,69,70]. The intrinsic immune tolerance of pregnancy in general, and all or part of its underlining molecular mechanisms, including the roles of hormones, can contribute to the curious resistance of pregnant women to COVID-19 ^[71][72][73][71,72,73]. Alongside reviewing COVID in children and pregnant women, the authors tried to highlight common factors between these two demographic groups which may explain COVID-19 tolerance in these populations.

4. What Makes Children and Pregnant Women More Tolerant to COVID-19?

Although children and pregnant women are usually considered to be high-risk populations for infections ^[74][75][74,75], they show remarkable resistance in the COVID-19 pandemic. The statistics of those suffering from the disease around the world demonstrate that COVID-19 takes most of its victims from the elderly population ^[76][77][76,77]. Noteworthy is that the immune system is commonly weaker in children and it is modulated during pregnancy, as a result of which, children and pregnant women are more susceptible to contagious diseases ^[78][79][78,79]. Given the above, the question that naturally arises is “what increases the resistance of pregnant women and children to this dangerous viral disease?”. In terms of cell biology, one of the common features of these two groups is their stem cell composition. Stem cells in children/pregnant women differ in many molecular features from their counterparts in the elderly. Here, we point out two main differences between stem cells in the body of children/pregnant women and those of adults, namely, “active versus quiescent stem cells” and the “ACE/ACE2 ratio”. We hypothesize that these two differences in stem cell composition are associated with the observed increased resistance to COVID-19.

Similar to children, pregnant women have active fetal-derived stem cells circulating in their bodies, that are able to combat illnesses and repair maternal injured tissues ^[80][88]. Fetal stem cells are multipotent stem cells derived from fetal blood and tissues. These cells are more limited in growth potential than pluripotent embryonic stem cells ^[81][89], although their proliferation rate and regenerative properties are higher than those of MSCs from adults ^[82][83][84][90,91,92]. Fetal-derived stem cells start circulating into the maternal bloodstream in the sixth week of gestation and increase in number by gestational age. It is estimated that 1–6 cells/mL of fetal cells are present in the maternal venous blood in the second trimester of pregnancy. Fetal cells decrease after delivery; however, a small fraction of fetal cells remain in the maternal blood for decades after delivery ^[80][88]. The fetal cells that transfer through the placenta are from specific cell types, including hematopoietic stem cells and MSCs ^[85][93]. Samara et al. recently suggested that fetal MSCs circulating in the maternal blood may have an immunosuppressive effect on mothers, causing COVID-19 in pregnant women to be often mild and even asymptomatic ^[86][94]. Pietras et al. have neatly characterized the cell cycle regulation in hematopoietic stem cells from fetal, adult, and aged sources. According to this characterization, only 0.02% of fetal hematopoietic stem cells are in the quiescent phase (G0), and almost all of them are actively dividing. This is not the case for hematopoietic stem cells in adults and the elderly, where approximately 95% of the hematopoietic stem cells are in the G0 phase ^[87][95].

Based on the aforementioned differences between quiescent and active stem cells, we herein hypothesize that active stem cells are more successful in resisting the COVID-19 infection. This hypothesis can explain the COVID-19 resistance of children and pregnant women both at the early infection stage and at the time of recovery.

The difference in the stem cell composition can explain the smaller rate of infection/hospitalization in infected children/pregnant women versus adults. In other words, it would follow that SARS-CoV-2 infects quiescent stem cells (G0 cells) and hinders their proper function. This hypothesis agrees with the findings regarding the malfunction of resident stem cells located in adult tissues after infection with SARS -CoV-2 ^[88][89][107,108], which subsequently induces an inflammatory response and fibrotic reactions ^[90][109]. This is probably why older adults, who have the majority of their stem cell pool in the G0 phase, are more prone to SARS-CoV-2 infection. However, children and pregnant women, who have more active stem cells in their body, show more success against SARS-CoV-2-induced inflammation and more quickly compensate for the damage to injured tissues.