Next Article in Journal
Tetraspanin 8 Subfamily Members Regulate Substrate-Specificity of a Disintegrin and Metalloprotease 17
Next Article in Special Issue
Deciphering the Antifibrotic Property of Metformin
Previous Article in Journal
Update on the Molecular Aspects and Methods Underlying the Complex Architecture of FSHD
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Potential Therapeutic Role of Mesenchymal-Derived Stem Cells as an Alternative Therapy to Combat COVID-19 through Cytokines Storm

Department of Biotechnology, Parul Institute of Applied Sciences and Animal Cell Culture and Immunobiochemistry Lab, Centre of Research for Development, Parul University, Vadodara 391760, India
Department of Biotechnology, Noida Institute of Engineering & Technology, Greater Noida 201306, India
Department of Plantation, Spices, Medicinal & Aromatic Crops, BCKV-Agricultural University, Mohanpur 741252, India
Department of Laboratory Oncology, All India Institute of Medical Sciences, New Delhi 110023, India
Department of Biology, College of Sciences, University of Hail, Hail 34464, Saudi Arabia
Department of Korean Medicine, Kyung Hee University, Seoul 05254, Korea
Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
Authors to whom correspondence should be addressed.
Cells 2022, 11(17), 2686;
Received: 4 August 2022 / Revised: 20 August 2022 / Accepted: 25 August 2022 / Published: 29 August 2022
(This article belongs to the Collection Advances in Epithelial-Mesenchymal Transition (EMT))


Medical health systems continue to be challenged due to newly emerging COVID-19, and there is an urgent need for alternative approaches for treatment. An increasing number of clinical observations indicate cytokine storms to be associated with COVID-19 severity and also to be a significant cause of death among COVID-19 patients. Cytokine storm involves the extensive proliferative and hyperactive activity of T and macrophage cells and the overproduction of pro-inflammatory cytokines. Stem cells are the type of cell having self-renewal properties and giving rise to differentiated cells. Currently, stem cell therapy is an exciting and promising therapeutic approach that can treat several diseases that were considered incurable in the past. It may be possible to develop novel methods to treat various diseases by identifying stem cells’ growth and differentiation factors. Treatment with mesenchymal stem cells (MSCs) in medicine is anticipated to be highly effective. The present review article is organized to put forward the positive arguments and implications in support of mesenchymal stem cell therapy as an alternative therapy to cytokine storms, to combat COVID-19. Using the immunomodulatory potential of the MSCs, it is possible to fight against COVID-19 and counterbalance the cytokine storm.

1. Introduction

COVID-19, caused by the SARS-CoV2 virus, is a perilous disease that threatens global public health. “COVID-19”stands for Coronavirus Disease of 2019 and was named by the WHO on 11 February 2020 [1]. SARS-CoV-2, the causative agent of this disease, is an enveloped, positive, single-stranded RNA virus belonging to the beta-coronaviruses subfamily.
The spread of coronavirus occurs mainly through the droplets generated through the sneezing and coughing of the infected person [2]. Incubation period for this virus after transmission is from 2 to 14 days. The SARS-CoV-2 virus resides in the lower respiratory tract and causes pneumonia in humans, eventually leading to fatality from chronic hyper-inflammation and respiratory distress [3]. It attaches with the help of spike proteins present on its membrane, and mRNA coding for this spike protein induces mutations, making it antigenically favorable. The lipid nanoparticles protect the non-replicating RNA from degradation and allow it to be delivered into host cells. Once inside the host cell, the mRNA is translated into the SARS-CoV-2 spike protein, which is generated on the cell’s surface [4].
SARS-CoV-2 is a beta coronavirus belongs to the family coronaviridae and is mainly responsible for COVID-19. However, some of their mutants that arise mostly due to mutations are also responsible for causing COVID-19. SARS-CoV-2 family of coronavirus is closely related to the variant of coronavirus found in the population of bats and SARS-CoV. Two more variants named RaTG13 and RmYN02 show approximately 96.2% and 93.3% sequence homology, respectively, with the SARS-CoV-2 virus family and these variants are also found in the bat population [5,6]. Some of the variants such as B.1.526, B.1.525, and P.2 arise due to a common mutation D614G in which aspartic acid is replaced by glycine at codon 614, changing its spike protein. These variants have properties to spread faster than many other variants and have many different properties than original SARS-CoV-2 [7]. Despite this, some more variants such as 501Y.V1 (B.1.1.7) and 501Y.V2 (B.1.351) emerged in UK and South Africa, respectively. These variants had a mutation at the receptor-binding domain of the spike protein that helped in the higher spread of this variant. The 501Y.V2 variant arose due to additional mutations E484K and K417N of the spike protein in the 501Y.V [8,9,10]. In Southern California, a new variant named CAL.20C was reported to derive from 20C cluster and had a mutation in ORF1a: I4205V, ORF1b: D1183Y, spike protein: S13I, W152C, and L452R [11].
In COVID-19 disease, acute respiratory distress syndrome (ARDS) is the leading cause of death. Its main feature is the cytokine storm, an uncontrolled inflammatory response triggered by immune cells releasing cytokines and chemokines [12,13]. After infection with COVID-19, lung epithelial and endothelial cell apoptosis and vascular leakage, alveolar edema, and hypoxia result from the abnormal release of pro-inflammatory factors. ARDS is caused by an uncontrolled release of pro-inflammatory factors, such as IL-6, IL-8, and IL-1. In most severe patients of COVID-19, improper function of the immune system results in enhanced production of cytokines (cytokine storm) such as IL-2, IL-6, colony-stimulating factor, and TNFs, ultimately leading to death [13]. Furthermore, it is also caused by the release of chemokines and reactive oxygen species, such as CCL-2, CCL-5, IP-10, and CCL-3 [14]. Entry of the coronavirus in host cells occurs from receptor-mediated endocytosis through the numb-associated kinases (NKA). The capability of coronavirus to cause the disease resides in the spike glycoproteins, which binds to the angiotensin-converting enzyme-2 (ACE-2) receptor present on the alveolar epithelial cells, endothelial cells, and cardiac and renal cells. After binding with the receptor, the virus enters the cell’s cytoplasm to release its genetic material. Genetic material (RNA) replicates and gives rise to new virus progeny, resulting in the spread of the virus to the other cells due to cell burst [13,15].
Even though most COVID-19 patients are asymptomatic, some develop pneumonia, and about 10% require ventilation. As the most common symptoms, patients can have fever, cough, breathing difficulty, headaches, muscle and bone pain, hemoptysis, diarrhea, and nausea [3]. In 10–20% of the total infection cases of SARS-CoV2 virus, it may cause interstitial pneumonia and acute respiratory distress syndrome (ARDS), especially in older age people [16]. For the entry in lungs after infection, SARS-CoV-2 virus recognizes angiotensin I converting enzyme 2 receptor with the help of its spike proteins. After recognition, its spike protein primed by cellular transmembrane protease, serine 2 (TMPRSS2) leads to its entry and further spread to other organs [17,18,19]. SARS-CoV2 virus does not remain confined to the respiratory tract but can invade the CNS and induce many neurological diseases, causing severe illness. Moreover, SARS-CoV2 can also invade many organs simultaneously, resulting in multi-organ failure. Mesenchymal stem cells (MSCs) are emerging as therapy against SARS-CoV2 due to their distinctive ability to improve immune functions to combat multiple and severe disease conditions. MSCs show immunomodulatory effects by the secretion of a variety of paracrine factors. These paracrine factors interact with immune cells that lead to the immunomodulation [20]. In a study, it was reported that the infusion of umbilical cord-derived stem cells into patients having ARDS and cytokine storm resulted in better functional outcomes [21]. In another study, MSCs were implanted in a patient with severe brain and multiple organ infection along with developing cardiac arrest by COVID-19. It was reported that MSCs incorporation had a healing effect on infected organs and severe infection [22].

2. Cytokines

Small polypeptides of glycoproteins known as cytokines elicit diverse responses in the body by interacting with their receptors via autocrine, paracrine, or endocrine signaling. Cytokines can stimulate cellular proliferation, differentiate cell communication, and regulate immune responses based on the target cell type. The receptors bind to cytokines and subsequently alter gene transcription by triggering intracellular signaling. Cytokines can be growth factors, chemokines, or interleukins formed by superfamilies having familiar and different gene structures. They are pleiotropic, and different cytokines can have the same effects [23,24]. One of the largest classes of cytokines is chemokines accounting for nearly 44 members that play various roles in regulating the immune system, such as recruitment and trafficking of leukocytes. Any dysregulation in the trafficking mechanism can lead to hyperinflammation [25]. Table 1 shows various cytokines and their secretary cells along with their mode of action.

3. COVID-19 and the Cytokine Storm

Hyperactive host immune responses result in an excessive inflammatory response to the SARS-CoV-2 virus, popularly known as the “cytokine storm”. As far as we know, there is no universally accepted definition for cytokine storms or cytokine release syndromes. A study found that an auto-amplifying cascade of cytokines triggered by an immune system unregulated by different triggers such as infection, malignancy, and arthritis, can be a “cytokine storm” [76]. Similarly, another study suggested that cytokine storms are caused by systemic inflammation caused by infections and drugs and often result in excessive activation of the immune system and the release of pro-inflammatory cytokines [77]. A cytokine storm occurs when cytokines are released to be harmful to host cells. Dysregulated cytokine production damages healthy cells of the lungs, further spreading to the heart, kidney, vessels, and other organs. Moreover, cytokine storm may also depend on entry and binding of SARS-CoV-2 spike protein with membrane serine proteases of the host [78]. Entry of SARS-CoV-2 into respiratory epithelial cells induces immune cells along with the production of inflammatory cytokines due to the weak response of interferon (IFN).Downregulation of some immune system-associated signaling pathways regulate the immune response of pathogenic Th1 cells and CD14+CD16+monocytes that results in infiltration of macrophages and neutrophils in lung tissues, leading to the cytokine storm [79].
Cytokine storms can be readily identified in disorders with elevated cytokine levels. A complex question is whether certain cytokines help control infections while at the same time harming the host. This is mostly due to the fact that some cytokines help control infections while being harmful at the same time [80]. Cytokine storm is a broad term including characterization of immune system dysfunction by symptoms of inflammation leading to multi-organs failure in the case of inadequate treatment. Cytokine concentration may vary according to the cause and treatments against it. C-reactive proteins (CRPs) are considered as the diagnostic marker for inflammation. These CRPs are non-specific, and their elevated level indicates the severity of the disease [81,82]. In patients with severe COVID-19, C-reactive protein (CRP) levels in the blood are markedly elevated [83]. CRP is synthesized and released by the liver in response to the stimulation of interleukin-6. Researchers have identified the presence of both pro-and anti-inflammatory CRP, which can be used for monitoring the extent of tissue damage associated with the pathogenesis of COVID-19 [84].In a study by McElvaney et al., it was found that severe COVID-19 patients show higher levels of IL-1β, IL-6, and sTNFR1, but lower levels of IL-10 than the patient with mildly infected COVID-19 patients [85]. Levels of IL-6 and TNF-α in the serum can be considered for the COVID-19 patient treatment and management for the clinical trials, to guide resource allocation and therapeutic options [86].
Various immune cells such as macrophages and mast cells are responsible for the secretion of pro-inflammatory cytokines IL-1, TNF-α, IL-6, GSCF, IL-7, MIP1A, IL-2, and IP10, and chemokines such as CCL-2, CCL-3, CCL-5, CXCL-8, CXCL-9, and CXCL-10, leading to the innate immune response in the body [87,88]. The more-than-usual secretion of these pro-inflammatory cytokines attracts T cells, neutrophils, and macrophages, including many more immune cells to the site of infection from the circulation. These immune cells, in bulk, destabilize endothelial cell-to-cell interaction, cause damage to the capillaries and alveoli, and damage the vascular barriers, resulting in severe lung injury [89]. Cytokine storms develop symptoms according to the increased cytokines. Unregulated secretion of TNF-α and IFN-γ may result in fever, fatigue, vascular leakage, and lung injury. Another essential cytokine, IL-6, can cause coagulation leakage, complement system activation, and cause vascular leakage [90,91,92]. Adding to the complexity, most mediators involved in cytokine storms manifest pleiotropic downstream effects, and their biological activities are often interdependent. There will neither be a linear nor a constant interaction of these mediators. However, measurements of their quantitative levels are not always indicative of pathogenicity. Understanding this complex interplay allow us to know the limitations of targeting single mediators and intervening in the acute inflammatory response [93].
Interferons (IFNs) are the main secretory immune response to provide the defense against viral infection. IFNs work as the first line of defense against viral infection and help in viral clearance through the modulation of innate and adoptive immune systems. In the case of SARS-CoV-2 infection, an elevated level of IFNs can regulate the cytokine storms by removing the SARS-CoV-2 virus. IFNs regulate various signaling pathways such as nuclear factor-κB (NF-κB), IFN regulatory factor 3/7 (IRF3/7), and activator protein-1 (AP-1). Activation of these pathways further activates Janus kinase 1 (JAK1)/tyrosine kinase 2–signal transducer and activator of transcription 1/2 (STAT1/2) pathway. These activated pathways promote the formation of STAT1/2/IRF9 complex, resulting in increased production of IFN-stimulated genes (ISGs) [94,95].

4. Stem Cells and Stem Cell Therapy

The stem cells are believed to be precursors of diverse tissues capable of self-renewal and provide replacement cells for a broad range of tissue types. The inner cell mass of the embryonal blastocyst is the primary source of embryonic stem cells. Stem cells can also be isolated from different sources such as the umbilical cord, fetal liver, adipose tissues, and bone marrow. Many cytokines are synthesized and secreted by stem cells that stimulate cell recruitment, angiogenesis, immunomodulation, neuroregeneration, and extracellular matrix remodeling. In addition to generating various cell types, stem cells can differentiate into other types of cells, such as endothelial cells, pericytes, myofibroblasts, and keratinocytes, which may play a role in wound healing [96,97,98,99]. Stem cells can essentially be of three types: embryonic stem cells (ESCs), adult stem cells, and mesenchymal stem cells (MSCs). Embryonic stem cells can be isolated from the inner cell mass of the early embryo, and these cells have high regenerative potential. Adult stem cells can be isolated from various sources such as cord blood, placenta, bone marrow, peripheral blood, adipose tissue, and menstrual blood. One of the types of adult stem cells, MSCs, is very efficient types of stem cells, having therapeutic, immunomodulatory, and regenerative properties [100].
Compared to other therapeutic strategies, MSCs are viewed as more attractive since they are multipotent, have a high proliferation rate, and are free from social or ethical issues [101]. MSCs have a similar morphology to fibroblasts. Hence, it is difficult to identify them morphologically. There are, however, cellular markers that can help identify MSCs [102]. Because of their immune-evasive nature, MSCs release factors that allow them to remain immune from rejection mechanisms for an extended period, allowing them to have the desired therapeutic effect [103]. MSCs can give rise to several cells, such as stromal cells, myoblasts, adipocytes, osteoblasts, endothelial cells, and chondrocytes [104]. MSCs exhibit anti-inflammatory and immunomodulatory benefits by expressing anti-inflammatory cytokines, inhibiting inflammatory T-cell proliferation, and inhibiting monocyte maturation as shown in Figure 1 [105,106,107,108]. MSCs are plastic-adherent stromal cells expressing biomarkers such as CD1025, CD73, and CD90, and devoid of a few biomarkers, including CD45, CD11b, CD19, and many more [109]. The properties of human mesenchymal stem cells, such as the production of paracrine factors VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor), and HGF (hepatocyte growth factor), which promotes angiogenesis, neovascularization, and cell survival, have made them a well-known candidate for cell-based therapies for many years [110]. Due to the potential use of mesenchymal stem cells (MSC) in autologous transplantation, these cells are of great clinical interest. MSCs have been used in several trials, including this one, and many others are undergoing testing. Recently, reports revealed that 2000 patients were treated with allogeneic or autologous MSCs for various diseases by autologous or culture-expanded MSCs [111].
In recent years, studies have emphasized the paracrine properties of MSC and the mechanism of release of extracellular vesicles containing mRNAs, regulatory molecules, bioactive molecules, and the production of regulatory substances overall, rather than on the direct differentiation and replacement of cells by MSC [112,113]. A new cellular therapy that uses mesenchymal stem cells from bone marrow is BM-MSCs. However, clinical implementation of these BM-MSCs still remains challenging. Although the first generation infusion of BM-MSCs was found to be safe according to meta-analysis, still many uncertainties exist, such as hemato-compatibility, side effects of large doses, and safety of adipose tissue and perinatal tissue-derived products [114,115,116,117,118,119]. Mesenchymal stem cells can be beneficial for generating many kinds of organs and treating various diseases. Genomic alterations in these MSCs can improve survival rate, growth factor secretion, and increased migration [120]. MSCs can modulate the immune system, leading to the varied responses of immune cells. They can inhibit T-cells’ cytotoxicity and proliferation, resulting in the inactivation of T-cells [121]. Table 2 shows the stem cells used as a therapy for various diseases and their mode of action.

5. Stem Cell Therapy for COVID-19 and Cytokine Storm

As infection of COVID-19 is increasing globally with its new variants Omicron and XE, this is high time to find a complete treatment apart from the vaccine to prevent COVID-19. The XE variant is a combination of BA.1 and BA.2 variant of omicron in which BA.2 is already spreading 10% faster thanBA.1 variant [144]. Many studies are going on to explore the role of stem cells in suppressing the cytokine storm during COVID-19, as MSCs are found to have an efficient immunomodulatory role [100]. Various studies related to COVID-19 and cytokine storm have demonstrated that cytokine levels vary in COVID patients according to the severity of the disease. Patients with less coronavirus load expressed low levels of inflammatory cytokines and enhanced levels of epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VGEF); while patients with a heavy dose of coronavirus expressed a higher level of pro-inflammatory cytokines [145]. MSCs therapy in the case of stem cell therapies is an efficient therapy to treat various diseases, and COVID-19 is one of them. MSCs express various surface markers such as CD-73, CD-90, and CD-105, having the ability to differentiate into MSCs progeny, which are minimal criteria for defining multipotent mesenchymal stromal cells [109]. MSCs have many cell surface markers such as CD146 and CD200, which are unique and non-differentiating in nature. They also possess some matrix and MSC markers such as CD29, CD44, CD71, CD73, and CD105. These markers give MSCs immunotolerant and immunomodulant properties in damaged tissues along with regenerating and rejuvenating properties by exerting their effects on immune cells including T and B lymphocytes, dendritic cells, and macrophages [146,147,148]. SARS-inflammatory Cov-2 response can be used as a primary approach for eliminating the virus. SARS CoV-2 entry results in the release of pro-inflammatory molecules such as interleukin (IL), tumor necrotic factors alpha (TNF-α), and multiple interferons (IF). These can restore and control the immune system, which is helpful for cell therapy [149]. Different investigations have revealed that impairment of mesenchymal stem cells (MSCs) raises the entry of viruses and their pathogenicity [150]. In addition, MSCs mechanism modulates the immune system; these cells have the right to regulate the growth and function of immune cells by reducing the production of TNF-α; MCP1; and anti-inflammatory cytokines such as IL-10 and 12, which result in reduced differentiation and block dendritic cells by generating inflammation and activation of different immune cells [151,152]. As shown in Figure 2, a Mesenchymal stem cell (MSCs) injection in a patient suffering from COVID-19 reduces the secretion of interleukins and inflammatory factors, which prevent further SARS-CoV-2 infection and can be used as a viable alternative treatment option [153].
MSCs have a high proliferation rate and the least social and ethical issues. Due to their ability to self-renew and to differentiate into multiple cell types, stem cells are attractive as an option in cell therapy in the clinic. These cells can be easily obtained from various sources such as fatty tissues, umbilical cord, fetal liver, and bone marrow [101]. Although, stem cell therapies have made some progress, they still have remained relatively slow due to ethical and legal restrictions [154]. MSCs might activate the immune system to prevent the exaggerated release of cytokines, chemokines, and reactive immune cells, resulting in endogenous repair. In a study, researchers performed 10x RNA sequencing to understand the mechanism of MSCs action on COVID-19. In MSCs, ISGs (interferon-stimulated genes) played a significant role in their resistance to viral infections compared to their differentiated descendants [155]. ISGs prevent viral infection by expressing themselves. MSCs can inhibit the action of excessively active immune cells by releasing various cytokine and anti-inflammatory factors including TGF-β and prostaglandin E2 (PGE2) [156]. Moreover, MSCs can enhance the production of lymphocytes and regulatory dendritic cells to increase their antiviral characters that can ultimately lead to a decrease in pro-inflammatory cytokines such as IL-6, IL-8, and TNF-α. These cytokines are the main markers of inflammation and reactive oxygen species to decrease the oxidative stress and inflammation [157]. MSCs can also protect the alveolar epithelial cells by reducing inflammation and normalize the lung functions by modulating pulmonary microenvironment and inhibiting pulmonary fibrosis [158]. MSCs can stimulate alveolar stem cells to repair and regenerate healthy lung parenchyma cells [159]. In addition, many secreted factors having pharmacological effects from MSCs can be used to treat COVID-19. Genetic modification of MSCs to make them able to secrete bioactive molecules is another approach that can be used to treat COVID-19 [160]. Moreover, MSCs can inhibit the abnormally activated T-cells and macrophages, and apart from this, they also can turn them into regulator T-cells and anti-inflammatory macrophages. MSCs prevent pro-inflammatory cytokines from secreting as well, thereby reducing cytokine storms [161]. Apart from the immune system modulation, MSCs hinder the differentiation of monocytes into dendritic cells (DC), resulting in the downregulation of inflammatory cytokines and upregulation of regulatory cytokines. Leng and colleagues recently published an investigation of MSCs in COVID-19 patients from China. Specifically, seven out of ten patients were given intravenous infusions of clinical-grade allogeneic MSC, while the other three patients received saline as a placebo. Two of three patients developed ARDS in the placebo-treated group or expired after 14 days, but rest seven MSC-treated patients recovered. On comparing the MSC-treated group with the placebo group, there was a noticeable reduction in systemic inflammation with a 10-fold decrease in CRP levels, a lower TNF-α level, and increased IL-10 levels [17]. Furthermore, a decrease in serum levels of pro-inflammatory cytokine TNF-α and an increase in anti-inflammatory cytokine IL-10 in patients with COVID-19 following MSC transplantation suggests efficient regulation of cytokine storms [162].

6. Challenges in Stem Cell Therapy

The main challenge in stem cell therapy is the isolation and culture of MSCs. The donor’s age is an essential factor for transplantation because it becomes difficult to obtain an efficient number of MSCs from an aged donor. Apart from age, genetic traits and the donor’s medical history are also essential to consider. Moreover, if a donor obtains MSCs with any form of disease such as diabetes, a loss of function of these cells can be seen [163,164,165,166]. Although MSCs are the safest population of stem cells having negligible risk of endogenous teratogenic potential, some of the MSCs can lead to adverse effects after their in-vivo transplantation [167]. Moreover, MSCs’ immunomodulatory properties are generally not recommended for use in infectious diseases, especially in bacterial infections, which require a robust immune response to eliminate. It was surprising to find out that preclinical evidence indicated that MSCs could enhance antibacterial processes and decrease overactive immune responses, resulting in lethal acute respiratory distress syndrome (ARDS) [168].

7. Conclusions

COVID-19 is a globally emerging public threat, and treatment of the severely infected patient is an international issue of consideration. The prevention and treatment of COVID-19 are ongoing through many therapies, but a complete cure is yet to come. MSCs emerged as an attractive and readily available source that can be further processed to overcome COVID-19 and cytokine storm. However, there are some barriers such as donor heterogeneity, lack of in vitro expansion, and absence of standard procedures to manipulate cells, limiting the potential use of MSCs as therapy against COVID-19 and cytokine storm. Apart from some limitations, MSCs have plasticity and a huge immunomodulatory effect resulting in anti-cytokine storm therapy. If it becomes possible to standardize the therapeutic procedures and sources of MSCs, it will be possible to deal with the COVID-19 and cytokine storm with the help of stem cell therapy.

Author Contributions

T.K.U., R.T. and A.B.S. developed the concept. R.T. and T.K.U. wrote the initial draft of the manuscript; R.T., T.K.U., A.B.S., B.K., M.S. and M.N.P. collected the data; R.T., P.P., H.G. and T.K.U. prepared the figures. R.T., T.K.U., M.S., A.B.S. and H.G. performed the literature review and improved the manuscript. A.B.S., M.S., F.K., P.P., T.K.U., B.K. and M.N.P. significantly reviewed and critically revised the manuscript; A.B.S., M.S., F.K., P.P. and T.K.U. approved the final version of the manuscript. All authors have read and agreed to the published version of the manuscript.


This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2020R1I1A2066868), the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1A5A2019413).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.


The authors are very grateful to Geetika Madan Patel, Centre of Research for Development (CR4D), Parul University, Vadodara, Gujarat, India, for providing the facility. Tarun also acknowledges the Director (R&D) and the team of CR4D, Parul University for continuous support and motivation. Bonglee Kim acknowledges the funding support of Department of Pathology, College of Korean Medicine Kyung Hee University Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, South Korea.

Conflicts of Interest

The authors declare no potential conflict of interest, financial or otherwise.


ARDSAcute respiratory distress syndrome
MSCsMesenchymal stem cells
IL Interleukin
CRPsC-reactive proteins
ESCsEmbryonic stem cells
VEGFVascular endothelial growth factor
FGFFibroblast growth factor
TNFsTumor Necrosis Factors
HGFHepatocyte growth factor
HSCsHematopoietic Stem Cells
ESCsEpithelial Stem Cells
NSCsNeural Stem Cells
NKANumb-associated kinases
ACE-2Angiotensin-converting enzyme-2
ASCsAdult Stem Cells
GSCFGranulocyte Colony-Stimulating Factor
iPSCsInduced Pluripotent Stem Cells
MIP1AMacrophage Inflammatory Protein 1 α


  1. World Health Organization (WHO). Novel Coronavirus (2019-nCoV) Situation Report 22. 2020. Available online:$=$fb6d49b1_2 (accessed on 1 April 2020).
  2. Goel, H.; Goyal, K.; Baranwal, P.; Dixit, A.; Upadhyay, T.K.; Upadhye, V.J. The diagnostics technologies and control of COVID-19. Lett. Appl. NanoBioSci. 2021, 11, 3120–3133. [Google Scholar] [CrossRef]
  3. Chen, N.; Zhou, M.; Dong, X.; Qu, J.; Gong, F.; Han, Y.; Qiu, Y.; Wang, J.; Liu, Y.; Wei, Y.; et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020, 395, 507–513. [Google Scholar] [CrossRef]
  4. Goyal, K.; Goel, H.; Baranwal, P.; Tewary, A.; Dixit, A.; Pandey, A.K.; Benjamin, M.; Tanwar, P.; Dey, A.; Khan, F.; et al. Immunological mechanisms of vaccine-induced protection against SARS-CoV-2 in humans. Immuno 2021, 1, 442–456. [Google Scholar] [CrossRef]
  5. Zhang, J.; Xie, B.; Hashimoto, K. Current status of potential therapeutic candidates for the COVID-19 crisis. Brain Behav. Immun. 2020, 87, 59–73. [Google Scholar] [CrossRef] [PubMed]
  6. Li, J.; Yang, H.; Ann Peer, W.; Richter, G.; Blakeslee, J.; Bandyopadhyay, A.; Titapiwantakun, B.; Undurraga, S.; Khodakovskaya, M.; Richards, E.L.; et al. Arabidopsis H+-PPase AVP1 regulates auxin-mediated organ development. Science 2005, 310, 121–125. [Google Scholar] [CrossRef] [PubMed]
  7. Europe PMC. Available online: (accessed on 22 April 2021).
  8. Volz, E.; Mishra, S.; Chand, M.; Barrett, J.C.; Johnson, R.; Geidelberg, L.; Hinsley, W.R.; Laydon, D.J.; Dabrera, G.; O’Toole, Á.; et al. Transmission of SARS-CoV-2 lineage B. 1.1. 7 in England: Insights from linking epidemiological and genetic data. medRxiv 2021, 593. [Google Scholar] [CrossRef]
  9. Tegally, H.; Wilkinson, E.; Giovanetti, M.; Iranzadeh, A.; Fonseca, V.; Giandhari, J.; Doolabh, D.; Pillay, S.; San, E.J.; Msomi, N.; et al. Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. medRxiv 2020. [Google Scholar] [CrossRef]
  10. Wibmer, C.K.; Ayres, F.; Hermanus, T.; Madzivhandila, M.; Kgagudi, P.; Oosthuysen, B.; Lambson, B.E.; De Oliveira, T.; Vermeulen, M.; Van der Berg, K.; et al. SARS-CoV-2 501Y. V2 escapes neutralization by South African COVID-19 donor plasma. Nat. Med. 2021, 27, 622–625. [Google Scholar] [CrossRef] [PubMed]
  11. Zhang, W.; Davis, B.D.; Chen, S.S.; Martinez, J.M.S.; Plummer, J.T.; Vail, E. Emergence of a novel SARS-CoV-2 strain in Southern California, USA. medRxiv 2021. [Google Scholar] [CrossRef]
  12. Yang, X.; Yu, Y.; Xu, J.; Shu, H.; Liu, H.; Wu, Y.; Zhang, L.; Yu, Z.; Fang, M.; Yu, T.; et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir. Med. 2020, 8, 475–481. [Google Scholar] [CrossRef] [PubMed][Green Version]
  13. Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497–506. [Google Scholar] [CrossRef] [PubMed]
  14. Reghunathan, R.; Jayapal, M.; Hsu, L.Y.; Chng, H.H.; Tai, D.; Leung, B.P.; Melendez, A.J. Expression profile of immune response genes in patients with severe acute respiratory syndrome. BMC Immunol. 2005, 6, 1–11. [Google Scholar] [CrossRef]
  15. Ding, Y.; He, L.I.; Zhang, Q.; Huang, Z.; Che, X.; Hou, J.; Wang, H.; Shen, H.; Qiu, L.; Li, Z.; et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: Implications for pathogenesis and virus transmission pathways. J. Pathol. J. Pathol. Soc. Great Br. Irel. 2004, 203, 622–630. [Google Scholar] [CrossRef]
  16. Soy, M.; Keser, G.; Atagündüz, P.; Tabak, F.; Atagündüz, I.; Kayhan, S. Cytokine storm in COVID-19: Pathogenesis and overview of anti-inflammatory agents used in treatment. Clin. Rheumatol. 2020, 39, 2085–2094. [Google Scholar] [CrossRef]
  17. Leng, Z.; Zhu, R.; Hou, W.; Feng, Y.; Yang, Y.; Han, Q.; Shan, G.; Meng, F.; Du, D.; Wang, S.; et al. Transplantation of ACE2-mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis. 2020, 11, 216. [Google Scholar] [CrossRef] [PubMed]
  18. Lu, R.; Zhao, X.; Li, J.; Niu, P.; Yang, B.; Wu, H.; Wang, W.; Song, H.; Huang, B.; Zhu, N.; et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020, 395, 565–574. [Google Scholar] [CrossRef]
  19. Zhou, P.; Yang, X.L.; Wang, X.G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.R.; Zhu, Y.; Li, B.; Huang, C.L.; et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020, 579, 270–273. [Google Scholar] [CrossRef]
  20. Prockop, D.J.; Oh, J.Y. Mesenchymal stem/stromal cells (MSCs): Role as guardians of inflammation. Mol. Ther. 2012, 20, 14–20. [Google Scholar] [CrossRef]
  21. Lanzoni, G.; Linetsky, E.; Correa, D.; Messinger Cayetano, S.; Alvarez, R.A.; Kouroupis, D.; Alvarez Gil, A.; Poggioli, R.; Ruiz, P.; Marttos, A.C.; et al. Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial. Stem Cells Transl. Med. 2021, 10, 660–673. [Google Scholar] [CrossRef]
  22. Yilmaz, R.; Adas, G.; Cukurova, Z.; Yasar, K.K.; Isiksacan, N.; Oztel, O.N.; Karaoz, E. Mesenchymal stem cells treatment in COVID-19 patient with multi-organ involvement. Bratisl. Lek. Listy 2020, 121, 847–852. [Google Scholar] [CrossRef]
  23. Charo, I.F.; Ransohoff, R.M. The Many Roles of Chemokines and Chemokine Receptors in Inflammation. N. Engl. J. Med. 2006, 354, 610–621. [Google Scholar] [CrossRef] [PubMed]
  24. Dinarello, C.A. Immunological and Inflammatory Functions of the Interleukin-1 Family. Annu. Rev. Immunol. 2009, 27, 519–550. [Google Scholar] [CrossRef] [PubMed]
  25. Behrens, E.M.; Canna, S.W.; Slade, K.; Rao, S.; Kreiger, P.A.; Paessler, M.; Kambayashi, T.; Koretzky, G.A. Repeated TLR9 stimulation results in macrophage activation syndrome–like disease in mice. J. Clin. Investig. 2011, 121, 2264–2277. [Google Scholar] [CrossRef] [PubMed]
  26. Metcalfe, S.M. Mesenchymal stem cells and management of COVID-19 pneumonia. Drug Discov. Today 2020, 5, 100019. [Google Scholar] [CrossRef]
  27. Kato, T. Granulocyte colony-stimulating factor. In Handbook of Hormones; Academic Press: Cambridge, MA, USA, 2021; pp. 467–470. [Google Scholar] [CrossRef]
  28. Xie, M.; Zhang, S.; Dong, F.; Zhang, Q.; Wang, J.; Wang, C.; Zhu, C.; Zhang, S.; Luo, B.; Wu, P.; et al. Granulocyte colony-stimulating factor directly acts on mouse lymphoid-biased but not myeloid-biased hematopoietic stem cells. Haematologica 2021, 106, 1647–1658. [Google Scholar] [CrossRef] [PubMed]
  29. Modi, J.; Menzie-Suderam, J.; Xu, H.; Trujillo, P.; Medley, K.; Marshall, M.L.; Tao, R.; Prentice, H.; Wu, J.Y. Mode of action of granulocyte-colony stimulating factor (G-CSF) as a novel therapy for stroke in a mouse model. J. Biomed. Sci. 2020, 27, 1–19. [Google Scholar] [CrossRef]
  30. Taub, D.D.; Lloyd, A.R.; Conlon, K.; Wang, J.M.; Ortaldo, J.R.; Harada, A.; Matsushima, K.; Kelvin, D.J.; Oppenheim, J.J. Recombinant human interferon-inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cells. J. Exp. Med. 1993, 177, 1809–1814. [Google Scholar] [CrossRef]
  31. Taub, D.D.; Longo, D.L.; Murphy, W.J. Human interferon-inducible protein-10 induces mononuclear cell infiltration in mice and promotes the migration of human T lymphocytes into the peripheral tissues of human peripheral blood lymphocytes-SCID mice. Blood 1996, 87, 1423–1431. [Google Scholar] [CrossRef]
  32. Lacotte, S.; Brun, S.; Muller, S.; Dumortier, H. CXCR3, inflammation, and autoimmune diseases. Ann. N. Y. Acad. Sci. 2009, 1173, 310–317. [Google Scholar] [CrossRef]
  33. Cushing, S.D.; Berliner, J.A.; Valente, A.J.; Territo, M.C.; Navab, M.; Parhami, F.; Gerrity, R.; Schwartz, C.J.; Fogelman, A.M. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc. Natl. Acad. Sci. USA 1990, 87, 5134–5138. [Google Scholar] [CrossRef]
  34. Widera, D.; Holtkamp, W.; Entschladen, F.; Niggemann, B.; Zänker, K.; Kaltschmidt, B.; Kaltschmidt, C. MCP-1 induces migration of adult neural stem cells. Eur. J. Cell Biol. 2004, 83, 381–387. [Google Scholar] [CrossRef] [PubMed]
  35. Singh, S.; Anshita, D.; Ravichandiran, V. MCP-1: Function, regulation, and involvement in disease. Int. Immunopharmacol. 2021, 101, 107598. [Google Scholar] [CrossRef] [PubMed]
  36. Menten, P.; Wuyts, A.; Van Damme, J. Macrophage inflammatory protein-1. Cytokine Growth Factor Rev. 2002, 13, 455–481. [Google Scholar] [CrossRef]
  37. Bhavsar, I.; Miller, C.S.; Al-Sabbagh, M. Macrophage inflammatory protein-1 alpha (MIP-1 alpha)/CCL3: As a biomarker. Gen. Methods Biomark. Res. Appl. 2015, 223–249. [Google Scholar] [CrossRef]
  38. Arenas-Ramirez, N.; Woytschak, J.; Boyman, O. Interleukin-2: Biology, design and application. Trends Immunol. 2015, 36, 763–777. [Google Scholar] [CrossRef]
  39. Liao, W.; Lin, J.X.; Leonard, W.J. IL-2 family cytokines: New insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Curr. Opin. Immunol. 2011, 23, 598–604. [Google Scholar] [CrossRef]
  40. Spolski, R.; Li, P.; Leonard, W.J. Biology and regulation of IL-2: From molecular mechanisms to human therapy. Nat. Rev. Immunol. 2018, 18, 648–659. [Google Scholar] [CrossRef]
  41. Srirangan, S.; Choy, E.H. The role of interleukin 6 in the pathophysiology of rheumatoid arthritis. Ther. Adv. Musculoskelet. Dis. 2010, 2, 247–256. [Google Scholar] [CrossRef]
  42. Dienz, O.; Rincon, M. The effects of IL-6 on CD4 T cell responses. Clin. Immunol. 2009, 130, 27–33. [Google Scholar] [CrossRef][Green Version]
  43. Green, A.M.; DiFazio, R.; Flynn, J.L. IFN-γ from CD4 T cells is essential for host survival and enhances CD8 T cell function during Mycobacterium tuberculosis infection. J. Immunol. 2013, 190, 270–277. [Google Scholar] [CrossRef]
  44. Zamisch, M.; Moore-Scott, B.; Su, D.M.; Lucas, P.J.; Manley, N.; Richie, E.R. Ontogeny and regulation of IL-7-expressing thymic epithelial cells. J. Immunol. 2005, 174, 60–67. [Google Scholar] [CrossRef] [PubMed]
  45. Offner, F.; Plum, J. The role of interleukin-7 in early T-cell development. Leuk. Lymphoma 1998, 30, 87–99. [Google Scholar] [CrossRef] [PubMed]
  46. Idriss, H.T.; Naismith, J.H. TNF-α and the TNF receptor superfamily: Structure-function relationship (s). Microsc. Res. Tech. 2000, 50, 184–195. [Google Scholar] [CrossRef]
  47. Kale, V.P.; Gilhooley, P.J.; Phadtare, S.; Nabavizadeh, A.; Pandey, M.K. Role of gambogic acid in chemosensitization of cancer. In Role of Nutraceuticals in Cancer Chemosensitization; Academic Press: Cambridge, MA, USA, 2018; pp. 151–167. [Google Scholar] [CrossRef]
  48. Mehta, A.K.; Gracias, D.T.; Croft, M. TNF activity and T cells. Cytokine 2018, 101, 14–18. [Google Scholar] [CrossRef]
  49. Remick, D.G. Interleukin-8. Crit. Care Med. 2005, 33, S466–S467. [Google Scholar] [CrossRef]
  50. Hedges, J.C.; Singer, C.A.; Gerthoffer, W.T. Mitogen-activated protein kinases regulate cytokine gene expression in human airway myocytes. Am. J. Respir. 2000, 23, 86–94. [Google Scholar] [CrossRef] [PubMed]
  51. Jiang, W.G.; Sanders, A.J.; Ruge, F.; Harding, K.G. Influence of interleukin-8 (IL-8) and IL-8 receptors on the migration of human keratinocytes, the role of PLC-γ and potential clinical implications. Exp. Ther. Med. 2012, 3, 231–236. [Google Scholar] [CrossRef] [PubMed]
  52. Loick, H.M.; Theissen, J.L. Die Eicosanoide als Mediatoren beim Ards. AINS-Anästhesiol. Intensivmed. Notf. Schmerzther. 1994, 29, 3–9. [Google Scholar] [CrossRef] [PubMed]
  53. Berger, A. What are leukotrienes and how do they work in asthma? BMJ 1999, 319, 90. [Google Scholar] [CrossRef] [PubMed]
  54. Cuzzo, B.; Lappin, S.L. Physiology, Leukotrienes; StatPearls Publishing: Tampa, FL, USA, 2021. [Google Scholar]
  55. Jo-Watanabe, A.; Okuno, T.; Yokomizo, T. The role of leukotrienes as potential therapeutic targets in allergic disorders. Int. J. Mol. Sci. 2019, 20, 3580. [Google Scholar] [CrossRef]
  56. Tang, Y.; Liu, J.; Zhang, D.; Xu, Z.; Ji, J.; Wen, C. Cytokine storm in COVID-19: The current evidence and treatment strategies. Front. Immunol. 2020, 11, 1708. [Google Scholar] [CrossRef] [PubMed]
  57. Ren, K.; Torres, R. Role of interleukin-1β during pain and inflammation. Brain Res. Rev. 2009, 60, 57–64. [Google Scholar] [CrossRef] [PubMed]
  58. Anforth, H.R.; Bluthe, R.M.; Bristow, A.; Hopkins, S.; Lenczowski, M.J.; Luheshi, G.; Lundkvist, J.; Michaud, B.; Mistry, Y.; Van Dam, A.M.; et al. Biological activity and brain actions of recombinant rat interleukin-1alpha and interleukin-1beta. Eur. Cytokine Netw. 1998, 9, 279–288. [Google Scholar] [PubMed]
  59. Heufler, C.; Koch, F.; Stanzl, U.; Topar, G.; Wysocka, M.; Trinchieri, G.; Enk, A.; Steinman, R.M.; Romani, N.; Schuler, G. Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-γ production by T helper 1 cells. Eur. J. Immunol. 1996, 26, 659–668. [Google Scholar] [CrossRef] [PubMed]
  60. Truyen, E.; Coteur, L.; Dilissen, E.; Overbergh, L.; Dupont, L.J.; Ceuppens, J.L.; Bullens, D.M. Evaluation of airway inflammation by quantitative Th1/Th2 cytokine mRNA measurement in sputum of asthma patients. Thorax 2006, 61, 202–208. [Google Scholar] [CrossRef] [PubMed]
  61. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 2003, 3, 133–146. [Google Scholar] [CrossRef]
  62. Drake, L.Y.; Kita, H. IL-33: Biological properties, functions, and roles in airway disease. Immunol. Rev. 2017, 278, 173–184. [Google Scholar] [CrossRef] [PubMed]
  63. Halim, T.Y.; Krauß, R.H.; Sun, A.C.; Takei, F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 2012, 36, 451–463. [Google Scholar] [CrossRef][Green Version]
  64. Lefrançais, E.; Duval, A.; Mirey, E.; Roga, S.; Espinosa, E.; Cayrol, C.; Girard, J.P. Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells. Proc. Natl. Acad. Sci. USA 2014, 111, 15502–15507. [Google Scholar] [CrossRef] [PubMed]
  65. O’Shea, J.J.; Gadina, M.; Siegel, R.M. Cytokines and cytokine receptors. In Clinical immunology; Elsevier: Amsterdam, The Netherlands, 2019; pp. 127–155.e1. [Google Scholar] [CrossRef]
  66. Branton, M.H.; Kopp, J.B. TGF-β and fibrosis. Microbes Infect. 1999, 1, 1349–1365. [Google Scholar] [CrossRef]
  67. Hassan, S.; Shah, H.; Shawana, S. Dysregulated epidermal growth factor and tumor growth factor-beta receptor signaling through GFAP-ACTA2 protein interaction in liver fibrosis. Pak. J. Med. Sci. 2020, 36, 782. [Google Scholar] [CrossRef] [PubMed]
  68. Chevigné, A.; Janji, B.; Meyrath, M.; Reynders, N.; D’uonnolo, G.; Uchański, T.; Xiao, M.; Berchem, G.; Ollert, M.; Kwon, Y.J.; et al. CXCL10 is an agonist of the CC family chemokine scavenger receptor ACKR2/D6. Cancers 2021, 13, 1054. [Google Scholar] [CrossRef]
  69. Tannenbaum, C.S.; Tubbs, R.; Armstrong, D.; Finke, J.H.; Bukowski, R.M.; Hamilton, T.A. The CXC chemokines IP-10 and Mig are necessary for IL-12-mediated regression of the mouse RENCA tumor. J. Immunol. 1998, 161, 927–932. [Google Scholar] [PubMed]
  70. Booth, V.; Keizer, D.W.; Kamphuis, M.B.; Clark-Lewis, I.; Sykes, B.D. The CXCR3 binding chemokine IP-10/CXCL10: Structure and receptor interactions. Biochemistry 2002, 41, 10418–10425. [Google Scholar] [CrossRef] [PubMed]
  71. Tau, G.; Rothman, P. Biologic functions of the IFN-γ receptors. Allergy 1999, 54, 1233. [Google Scholar] [CrossRef] [PubMed]
  72. Dafny, N.; Lincoln, J. The role of interferons on the central nervous system in health and disease. In Reference Module in Biomedical Sciences; Elsevier: Amsterdam, The Netherlands, 2016. [Google Scholar] [CrossRef]
  73. Baron, S.; Tyring, S.K.; Fleischmann, W.R.; Coppenhaver, D.H.; Niesel, D.W.; Klimpel, G.R.; Stanton, G.J.; Hughes, T.K. The interferons: Mechanisms of action and clinical applications. JAMA 1991, 266, 1375–1383. [Google Scholar] [CrossRef] [PubMed]
  74. Dinarello, C.A.; Novick, D.; Kim, S.; Kaplanski, G. Interleukin-18 and IL-18 binding protein. Front. Immunol. 2013, 4, 289. [Google Scholar] [CrossRef]
  75. O’Shea, J.J.; Gadina, M.; Richard; Siegel, M.; Farber, J. 13–Cytokines. In Rheumatology, 6th ed.; Hochberg, M.C., Silman, A.J., Smolen, J.S., Weinblatt, M.E., Weisman, M.H., Eds.; Mosby: Maryland Heights, MO, USA, 2015; pp. 99–112. [Google Scholar] [CrossRef]
  76. Cron, R.Q.; Behrens, E.M. Cytokine Storm Syndrome; Springer Nature: Cham, Switzerland, 2019. [Google Scholar]
  77. Tisoncik, J.R.; Korth, M.J.; Simmons, C.P.; Farrar, J.; Martin, T.R.; Katze, M.G. Into the eye of the cytokine storm. Microbiol. Mol. Biol. Rev. 2012, 76, 16–32. [Google Scholar] [CrossRef] [PubMed]
  78. Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.H.; Nitsche, A.; et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020, 181, 271–280. [Google Scholar] [CrossRef] [PubMed]
  79. Hussman, J.P. Cellular and molecular pathways of COVID-19 and potential points of therapeutic intervention. Front. Pharmacol. 2020, 11, 1169. [Google Scholar] [CrossRef] [PubMed]
  80. Fajgenbaum, D.C.; June, C.H. Cytokine storm. N. Engl. J. Med. 2020, 383, 2255–2273. [Google Scholar] [CrossRef] [PubMed]
  81. Lee, D.W.; Santomasso, B.D.; Locke, F.L.; Ghobadi, A.; Turtle, C.J.; Brudno, J.N.; Maus, M.V.; Park, J.H.; Mead, E.; Pavletic, S.; et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Trans. 2019, 25, 625–638. [Google Scholar] [CrossRef]
  82. Lee, D.W.; Gardner, R.; Porter, D.L.; Louis, C.U.; Ahmed, N.; Jensen, M.; Grupp, S.A.; Mackall, C.L. Current concepts in the diagnosis and management of cytokine release syndrome. Blood Am. J. Hematol. 2014, 124, 188–195. [Google Scholar] [CrossRef] [PubMed]
  83. Zeng, F.; Huang, Y.; Guo, Y.; Yin, M.; Chen, X.; Xiao, L.; Deng, G. Association of inflammatory markers with the severity of COVID-19: A meta-analysis. Int. J. Infect. Dis. 2020, 96, 467–474. [Google Scholar] [CrossRef]
  84. Potempa, L.A.; Rajab, I.M.; Hart, P.C.; Bordon, J.; Fernandez-Botran, R. Insights into the use of C-reactive protein as a diagnostic index of disease severity in COVID-19 infections. Am. J. Trop. Med. Hyg. 2020, 103, 561. [Google Scholar] [CrossRef] [PubMed]
  85. McElvaney, O.J.; McEvoy, N.L.; McElvaney, O.F.; Carroll, T.P.; Murphy, M.P.; Dunlea, D.M.; Ní Choileáin, O.; Clarke, J.; O’Connor, E.; Hogan, G.; et al. Characterization of the inflammatory response to severe COVID-19 illness. Am. J. Respir. Crit. Care Med. 2020, 202, 812–821. [Google Scholar] [CrossRef] [PubMed]
  86. Del Valle, D.M.; Kim-Schulze, S.; Huang, H.H.; Beckmann, N.D.; Nirenberg, S.; Wang, B.; Lavin, Y.; Swartz, T.H.; Madduri, D.; Stock, A.; et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat. Med. 2020, 26, 1636–1643. [Google Scholar] [CrossRef]
  87. Mitra, P.; Misra, S.; Sharma, P. COVID-19 pandemic in India: What lies ahead? J. Clin. Biochem. 2020, 35, 257–259. [Google Scholar] [CrossRef]
  88. Li, X.; Geng, M.; Peng, Y.; Meng, L.; Lu, S. Molecular immune pathogenesis and diagnosis of COVID-19. J. Pharm. Anal. 2020, 10, 102–108. [Google Scholar] [CrossRef] [PubMed]
  89. Shimizu, M. Clinical features of cytokine storm syndrome. In Cytokine Storm Syndrome; Cron, R., Behrens, E., Eds.; Springer: Cham, Switzerland, 2019; pp. 31–42. [Google Scholar] [CrossRef]
  90. Shimabukuro-Vornhagen, A.; Gödel, P.; Subklewe, M.; Stemmler, H.J.; Schlößer, H.A.; Schlaak, M.; Kochanek, M.; Böll, B.; von Bergwelt-Baildon, M.S. Cytokine release syndrome. J. Immunother. Cancer 2018, 6, 1–14. [Google Scholar] [CrossRef]
  91. Tanaka, T.; Narazaki, M.; Kishimoto, T. Immunotherapeutic implications of IL-6 blockade for cytokine storm. Immunotherapy 2016, 8, 959–970. [Google Scholar] [CrossRef] [PubMed]
  92. Hunter, C.A.; Jones, S.A. IL-6 as a keystone cytokine in health and disease. Nat. Immunol. 2015, 16, 448–457. [Google Scholar] [CrossRef]
  93. Sinha, P.; Matthay, M.A.; Calfee, C.S. Is a “cytokine storm” relevant to COVID-19? JAMA Intern. Med. 2020, 180, 1152–1154. [Google Scholar] [CrossRef]
  94. Jensen, S.; Thomsen, A.R. Sensing of RNA viruses: A review of innate immune receptors involved in recognizing RNA virus invasion. J. Virol. 2012, 86, 2900–2910. [Google Scholar] [CrossRef] [PubMed][Green Version]
  95. Park, A.; Iwasaki, A. Type I and type III interferons—Induction, signaling, evasion, and application to combat COVID-19. Cell Host Microbe 2020, 27, 870–878. [Google Scholar] [CrossRef] [PubMed]
  96. Isakson, M.; De Blacam, C.; Whelan, D.; McArdle, A.; Clover, A.J. Mesenchymal stem cells and cutaneous wound healing: Current evidence and future potential. Stem Cells Int. 2015, 2015, 831095. [Google Scholar] [CrossRef] [PubMed]
  97. Cao, Y.; Gang, X.; Sun, C.; Wang, G. Mesenchymal stem cells improve healing of diabetic foot ulcer. J. Diabetes Res. 2017, 2017, 9328347. [Google Scholar] [CrossRef] [PubMed]
  98. Mizukami, H.; Yagihashi, S. Exploring a new therapy for diabetic polyneuropathy–the application of stem cell transplantation. Front. Endocrinol. 2014, 5, 45. [Google Scholar] [CrossRef]
  99. Sasaki, M.; Abe, R.; Fujita, Y.; Ando, S.; Inokuma, D.; Shimizu, H. Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J. Immunol. 2008, 180, 2581–2587. [Google Scholar] [CrossRef] [PubMed]
  100. Golchin, A.; Seyedjafari, E.; Ardeshirylajimi, A. Mesenchymal stem cell therapy for COVID-19: Present or future. Stem Cell Rev. Rep. 2020, 16, 427–433. [Google Scholar] [CrossRef]
  101. Golchin, A.; Farahany, T.Z. Biological products: Cellular therapy and FDA approved products. Stem Cell Rev. Rep. 2019, 15, 166–175. [Google Scholar] [CrossRef] [PubMed]
  102. Chang, Y.; Li, H.; Guo, Z. Mesenchymal stem cell-like properties in fibroblasts. Cell. Physiol. Biochem. 2014, 34, 703–714. [Google Scholar] [CrossRef] [PubMed]
  103. Ankrum, J.A.; Ong, J.F.; Karp, J.M. Mesenchymal stem cells: Immune evasive, not immune privileged. Nat. Biotechnol. 2014, 32, 252–260. [Google Scholar] [CrossRef] [PubMed]
  104. Katsha, A.M.; Ohkouchi, S.; Xin, H.; Kanehira, M.; Sun, R.; Nukiwa, T.; Saijo, Y. Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model. Mol. Ther. 2011, 19, 196–203. [Google Scholar] [CrossRef] [PubMed]
  105. Caplan, A.I. Mesenchymal stem cells. J. Orthop. Surg. Res. 1991, 9, 641–650. [Google Scholar] [CrossRef] [PubMed]
  106. Caplan, A.I.; Correa, D. The MSC: An injury drugstore. Cell Stem Cell 2011, 9, 11–15. [Google Scholar] [CrossRef] [PubMed]
  107. Djouad, F.; Bouffi, C.; Ghannam, S.; Noël, D.; Jorgensen, C. Mesenchymal stem cells: Innovative therapeutic tools for rheumatic diseases. Nat. Rev. Rheumatol. 2009, 5, 392–399. [Google Scholar] [CrossRef] [PubMed]
  108. Nakagami, H.; Morishita, R.; Maeda, K.; Kikuchi, Y.; Ogihara, T.; Kaneda, Y. Adipose tissue-derived stromal cells as a novel option for regenerative cell therapy. J. Atheroscler. Thromb. 2006, 13, 77–81. [Google Scholar] [CrossRef]
  109. Dominici, M.L.B.K.; Le Blanc, K.; Mueller, I.; Slaper-Cortenbach, I.; Marini, F.C.; Krause, D.S.; Deans, R.J.; Keating, A.; Prockop, D.J.; Horwitz, E.M. Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy 2006, 8, 315–317. [Google Scholar] [CrossRef] [PubMed]
  110. Kamihata, H.; Matsubara, H.; Nishiue, T.; Fujiyama, S.; Tsutsumi, Y.; Ozono, R.; Masaki, H.; Mori, Y.; Iba, O.; Tateishi, E.; et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 2001, 104, 1046–1052. [Google Scholar] [CrossRef] [PubMed]
  111. Squillaro, T.; Peluso, G.; Galderisi, U. Clinical trials with mesenchymal stem cells: An update. Cell Transplant. 2016, 25, 829–848. [Google Scholar] [CrossRef]
  112. Crivelli, B.; Chlapanidas, T.; Perteghella, S.; Lucarelli, E.; Pascucci, L.; Brini, A.T.; Ferrero, I.; Marazzi, M.; Pessina, A.; Torre, M.L.; et al. Mesenchymal stem/stromal cell extracellular vesicles: From active principle to next generation drug delivery system. J. Control. Release 2017, 262, 104–117. [Google Scholar] [CrossRef]
  113. Park, W.S.; Ahn, S.Y.; Sung, S.I.; Ahn, J.Y.; Chang, Y.S. Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders. Pediatr. Res. 2018, 83, 214–222. [Google Scholar] [CrossRef] [PubMed]
  114. Lalu, M.M.; McIntyre, L.; Pugliese, C.; Stewart, D.J. Safety of cell therapy with mesenchymal stromal cells (MSCs): A systematic review. D49 Clin. Trials Crit. Care 2010, A6043. [Google Scholar]
  115. Marks, P.W.; Witten, C.M.; Califf, R.M. Clarifying stem-cell therapy’s benefits and risks. N. Engl. J. Med. 2017, 376, 1007–1009. [Google Scholar] [CrossRef] [PubMed][Green Version]
  116. Cyranoski, D. Korean deaths spark inquiry: Cases highlight the challenge of policing multinational trade in stem-cell treatments. Nature 2010, 468, 485–486. [Google Scholar] [CrossRef]
  117. Jung, J.W.; Kwon, M.; Choi, J.C.; Shin, J.W.; Park, I.W.; Choi, B.W.; Kim, J.Y. Familial occurrence of pulmonary embolism after intravenous, adipose tissue-derived stem cell therapy. Yonsei Med. J. 2013, 54, 1293–1296. [Google Scholar] [CrossRef]
  118. Wu, Z.; Zhang, S.; Zhou, L.; Cai, J.; Tan, J.; Gao, X.; Zeng, Z.; Li, D. Thromboembolism induced by umbilical cord mesenchymal stem cell infusion: A report of two cases and literature review. Transplant. Proc. 2017, 49, 1656–1658. [Google Scholar] [CrossRef] [PubMed]
  119. George, M.J.; Prabhakara, K.; Toledano-Furman, N.E.; Wang, Y.W.; Gill, B.S.; Wade, C.E.; Olson, S.D.; Cox Jr, C.S. Clinical cellular therapeutics accelerate clot formation. Stem Cells Transl. Med. 2018, 7, 731–739. [Google Scholar] [CrossRef]
  120. Park, J.S.; Suryaprakash, S.; Lao, Y.H.; Leong, K.W. Engineering mesenchymal stem cells for regenerative medicine and drug delivery. Methods 2015, 84, 3–16. [Google Scholar] [CrossRef]
  121. Glennie, S.; Soeiro, I.; Dyson, P.J.; Lam, E.W.F.; Dazzi, F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005, 105, 2821–2827. [Google Scholar] [CrossRef] [PubMed]
  122. Golchin, A.; Farahany, T.Z.; Khojasteh, A.; Soleimanifar, F.; Ardeshirylajimi, A. The clinical trials of mesenchymal stem cell therapy in skin diseases: An update and concise review. Curr. Stem Cell Res. Ther. 2019, 14, 22–33. [Google Scholar] [CrossRef]
  123. Ogawa, M.; LaRue, A.C.; Mehrotra, M. Hematopoietic stem cells are pluripotent and not just “hematopoietic”. Blood Cells Mol. Dis. 2013, 51, 3–8. [Google Scholar] [CrossRef] [PubMed]
  124. Moore, M.A. Hematopoietic stem cells. In Principles of Tissue Engineering; Academic Press: Cambridge, MA, USA, 2014; pp. 989–1040. [Google Scholar] [CrossRef]
  125. Delaney, C.; Gutman, J.A.; Appelbaum, F.R. Cord blood transplantation for haematological malignancies: Conditioning regimens, double cord transplant and infectious complications. Br. J. Haematol. 2009, 147, 207–216. [Google Scholar] [CrossRef] [PubMed]
  126. Munoz, J.; Shah, N.; Rezvani, K.; Hosing, C.; Bollard, C.M.; Oran, B.; Olson, A.; Popat, U.; Molldrem, J.; McNiece, I.K.; et al. Concise review: Umbilical cord blood transplantation: Past, present, and future. Stem Cells Transl. Med. 2014, 3, 1435–1443. [Google Scholar] [CrossRef] [PubMed]
  127. Wang, Z.; Ema, H. Mechanisms of self-renewal in hematopoietic stem cells. Int. J. Hematol. 2016, 103, 498–509. [Google Scholar] [CrossRef]
  128. Blanpain, C.; Horsley, V.; Fuchs, E. Epithelial stem cells: Turning over new leaves. Cell 2007, 128, 445–458. [Google Scholar] [CrossRef]
  129. Das, D.; Fletcher, R.B.; Ngai, J. Cellular mechanisms of epithelial stem cell self-renewal and differentiation during homeostasis and repair. WIREs Dev. Biol. 2020, 9, e361. [Google Scholar] [CrossRef]
  130. Beattie, R.; Hippenmeyer, S. Mechanisms of radial glia progenitor cell lineage progression. FEBS Lett. 2017, 591, 3993–4008. [Google Scholar] [CrossRef] [PubMed]
  131. Arvidsson, A.; Collin, T.; Kirik, D.; Kokaia, Z.; Lindvall, O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat. Med. 2002, 8, 963–970. [Google Scholar] [CrossRef]
  132. Ilic, D.; Ogilvie, C. Concise review: Human embryonic stem cells—what have we done? What are we doing? Where are we going? Stem Cells 2017, 35, 17–25. [Google Scholar] [CrossRef] [PubMed]
  133. Amit, M.; Itskovitz-Eldor, J. Embryonic stem cells: Isolation, characterization and culture. In Engineering of Stem Cells; Springer: Berlin/Heidelberg, Germany, 2009; pp. 173–184. [Google Scholar] [CrossRef]
  134. Tseng, A.M.; Mahnke, A.H.; Salem, N.A.; Miranda, R.C. Noncoding RNA regulatory networks, epigenetics, and programming stem cell renewal and differentiation: Implications for stem cell therapy. In Epigenetics in Human Disease; Academic Press: Cambridge, MA, USA, 2018; pp. 903–933. [Google Scholar] [CrossRef]
  135. Prochazkova, M.; Chavez, M.G.; Prochazka, J.; Felfy, H.; Mushegyan, V.; Klein, O.D. Embryonic versus adult stem cells. In Stem Cell Biology and Tissue Engineering in Dental Sciences; Academic Press: Cambridge, MA, USA, 2015; pp. 249–262. [Google Scholar] [CrossRef]
  136. Kmiecik, G.; Niklińska, W.; Kuć, P.; Pancewicz-Wojtkiewicz, J.; Fil, D.; Karwowska, A.; Karczewski, J.; Mackiewicz, Z. Fetal membranes as a source of stem cells. Adv. Med. Sci. 2013, 58, 185–195. [Google Scholar] [CrossRef] [PubMed]
  137. Rippon, H.J.; Bishop, A.E. Embryonic stem cells. Cell Prolif. 2004, 37, 23–34. [Google Scholar] [CrossRef] [PubMed]
  138. Gnecchi, M.; Zhang, Z.; Ni, A.; Dzau, V.J. Paracrine mechanisms in adult stem cell signaling and therapy. Circ. Res. 2008, 103, 1204–1219. [Google Scholar] [CrossRef] [PubMed]
  139. Hirschi, K.K.; Li, S.; Roy, K. Induced pluripotent stem cells for regenerative medicine. Annu. Rev. Biomed. Eng. 2014, 16, 277. [Google Scholar] [CrossRef] [PubMed]
  140. Hosoya, M.; Czysz, K. Translational prospects and challenges in human induced pluripotent stem cell research in drug discovery. Cells 2016, 5, 46. [Google Scholar] [CrossRef] [PubMed]
  141. Taura, D.; Sone, M.; Homma, K.; Oyamada, N.; Takahashi, K.; Tamura, N.; Yamanaka, S.; Nakao, K. Induction and isolation of vascular cells from human induced pluripotent stem cells—Brief report. Arterioscler. Thromb. Vasc. Biol. 2009, 29, 1100–1103. [Google Scholar] [CrossRef]
  142. Kumar, D.; Talluri, T.R.; Anand, T.; Kues, W.A. Induced pluripotent stem cells: Mechanisms, achievements and perspectives in farm animals. World J. Stem Cells 2015, 7, 315. [Google Scholar] [CrossRef] [PubMed]
  143. Gnecchi, M.; Melo, L.G. Bone marrow-derived mesenchymal stem cells: Isolation, expansion, characterization, viral transduction, and production of conditioned medium. Methods Mol. Biol. 2009, 482, 281–294. [Google Scholar] [CrossRef] [PubMed]
  144. WHO. 2022. Available online: (accessed on 11 April 2022).
  145. Lucas, C.; Wong, P.; Klein, J.; Castro, T.B.; Silva, J.; Sundaram, M.; Ellingson, M.K.; Mao, T.; Oh, J.E.; Israelow, B.; et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature 2020, 584, 463–469. [Google Scholar] [CrossRef] [PubMed]
  146. Maleki, M.; Ghanbarvand, F.; Behvarz, M.R.; Ejtemaei, M.; Ghadirkhomi, E. Comparison of mesenchymal stem cell markers in multiple human adult stem cells. Int. J. Stem Cells 2014, 7, 118–126. [Google Scholar] [CrossRef] [PubMed][Green Version]
  147. Lv, F.J.; Tuan, R.S.; Cheung, K.M.; Leung, V.Y. Concise review: The surface markers and identity of human mesenchymal stem cells. Stem Cells 2014, 32, 1408–1419. [Google Scholar] [CrossRef] [PubMed]
  148. Weiss, A.R.R.; Dahlke, M.H. Immunomodulation by mesenchymal stem cells (MSCs): Mechanisms of action of living, apoptotic, and dead MSCs. Front. Immunol. 2019, 10, 1191. [Google Scholar] [CrossRef] [PubMed]
  149. Zhu, F.; Xia, Z.F. Paracrine activity of stem cells in therapy for acute lung injury and adult respiratory distress syndrome. J. Trauma Acute Care Surg. 2013, 74, 1351–1356. [Google Scholar] [CrossRef] [PubMed]
  150. Ottaviano, G.; Chiesa, R.; Feuchtinger, T.; Vickers, M.A.; Dickinson, A.; Gennery, A.R.; Veys, P.; Todryk, S. Adoptive T cell therapy strategies for viral infections in patients receiving haematopoietic stem cell transplantation. Cells 2019, 8, 47. [Google Scholar] [CrossRef] [PubMed]
  151. Gao, W.X.; Sun, Y.Q.; Shi, J.; Li, C.L.; Fang, S.B.; Wang, D.; Deng, X.Q.; Wen, W.; Fu, Q.L. Effects of mesenchymal stem cells from human induced pluripotent stem cells on differentiation, maturation, and function of dendritic cells. Stem Cell Res. Ther. 2017, 8, 48. [Google Scholar] [CrossRef] [PubMed]
  152. Romano, B.; Elangovan, S.; Erreni, M.; Sala, E.; Petti, L.; Kunderfranco, P.; Massimino, L.; Restelli, S.; Sinha, S.; Lucchetti, D.; et al. TNF-stimulated Gene-6 is a key regulator in switching stemness and biological properties of mesenchymal stem cells. Stem Cells 2019, 37, 973–987. [Google Scholar] [CrossRef] [PubMed]
  153. Kebria, M.M.; Milan, P.B.; Peyravian, N.; Kiani, J.; Khatibi, S.; Mozafari, M. Stem cell therapy for COVID-19 pneumonia. Mol. Biomed. 2022, 3, 1–20. [Google Scholar] [CrossRef] [PubMed]
  154. Cogle, C.R.; Guthrie, S.M.; Sanders, R.C.; Allen, W.L.; Scott, E.W.; Petersen, B.E. An overview of stem cell research and regulatory issues. Mayo Clin. Proc. 2003, 78, 993–1003. [Google Scholar] [CrossRef]
  155. Wu, X.; Thi, V.L.D.; Huang, Y.; Billerbeck, E.; Saha, D.; Hoffmann, H.H.; Wang, Y.; Silva, L.A.V.; Sarbanes, S.; Sun, T.; et al. Intrinsic immunity shapes viral resistance of stem cells. Cell 2018, 172, 423–438. [Google Scholar] [CrossRef] [PubMed]
  156. Van Den Akker, F.; Deddens, J.C.; Doevendans, P.A.; Sluijter, J.P.G. Cardiac stem cell therapy to modulate inflammation upon myocardial infarction. Biochim. Biophys. Acta (BBA)-Gen. Subj. 2013, 1830, 2449–2458. [Google Scholar] [CrossRef]
  157. Liang, B.; Chen, J.; Li, T.; Wu, H.; Yang, W.; Li, Y.; Li, J.; Yu, C.; Nie, F.; Ma, Z.; et al. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells: A case report. Medicine 2020, 99, e21429. [Google Scholar] [CrossRef]
  158. Song, N.; Wakimoto, H.; Rossignoli, F.; Bhere, D.; Ciccocioppo, R.; Chen, K.S.; Khalsa, J.K.; Mastrolia, I.; Samarelli, A.V.; Dominici, M.; et al. Mesenchymal stem cell immunomodulation: In pursuit of controlling COVID-19 related cytokine storm. Stem Cells 2021, 39, 707–722. [Google Scholar] [CrossRef]
  159. Tropea, K.A.; Leder, E.; Aslam, M.; Lau, A.N.; Raiser, D.M.; Lee, J.H.; Balasubramaniam, V.; Fredenburgh, L.E.; Alex Mitsialis, S.; Kourembanas, S.; et al. Bronchioalveolar stem cells increase after mesenchymal stromal cell treatment in a mouse model of bronchopulmonary dysplasia. Am. J. Physiol. -Lung Cell. Mol. 2012, 302, L829–L837. [Google Scholar] [CrossRef] [PubMed]
  160. Bari, E.; Ferrarotti, I.; Saracino, L.; Perteghella, S.; Torre, M.L.; Corsico, A.G. Mesenchymal stromal cell secretome for severe COVID-19 infections: Premises for the therapeutic use. Cells 2020, 9, 924. [Google Scholar] [CrossRef]
  161. Yagi, H.; Soto-Gutierrez, A.; Parekkadan, B.; Kitagawa, Y.; Tompkins, R.G.; Kobayashi, N.; Yarmush, M.L. Mesenchymal stem cells: Mechanisms of immunomodulation and homing. Cell Transplant. 2010, 19, 667–679. [Google Scholar] [CrossRef] [PubMed]
  162. Aggarwal, S.; Pittenger, M.F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005, 105, 1815–1822. [Google Scholar] [CrossRef] [PubMed]
  163. Dufrane, D. Impact of age on human adipose stem cells for bone tissue engineering. Cell Transplant. 2017, 26, 1496–1504. [Google Scholar] [CrossRef]
  164. Liu, M.; Lei, H.; Dong, P.; Fu, X.; Yang, Z.; Yang, Y.; Ma, J.; Liu, X.; Cao, Y.; Xiao, R. Adipose-derived mesenchymal stem cells from the elderly exhibit decreased migration and differentiation abilities with senescent properties. Cell Transplant. 2017, 26, 1505–1519. [Google Scholar] [CrossRef] [PubMed]
  165. Kokai, L.E.; Traktuev, D.O.; Zhang, L.; Merfeld-Clauss, S.; DiBernardo, G.; Lu, H.; Marra, K.G.; Donnenberg, A.; Donnenberg, V.; Meyer, E.M.; et al. Adipose stem cell function maintained with age: An intra-subject study of long-term cryopreserved cells. Aesthetic Surg. J. 2017, 37, 454–463. [Google Scholar] [CrossRef]
  166. Pachón-Peña, G.; Serena, C.; Ejarque, M.; Petriz, J.; Duran, X.; Oliva-Olivera, W.; Simó, R.; Tinahones, F.J.; Fernández-Veledo, S.; Vendrell, J. Obesity determines the immunophenotypic profile and functional characteristics of human mesenchymal stem cells from adipose tissue. Stem Cells Transl. Med. 2016, 5, 464–475. [Google Scholar] [CrossRef] [PubMed]
  167. Price, M.J.; Chou, C.C.; Frantzen, M.; Miyamoto, T.; Kar, S.; Lee, S.; Shah, P.K.; Martin, B.J.; Lill, M.; Forrester, J.S.; et al. Intravenous mesenchymal stem cell therapy early after reperfused acute myocardial infarction improves left ventricular function and alters electrophysiologic properties. Int. J. Cardiol. 2006, 111, 231–239. [Google Scholar] [CrossRef] [PubMed]
  168. Rubenfeld, G.D.; Caldwell, E.; Peabody, E.; Weaver, J.; Martin, D.P.; Neff, M.; Stern, E.J.; Hudson, L.D. Incidence and outcomes of acute lung injury. N. Engl. J. Med. 2005, 353, 1685–1693. [Google Scholar] [CrossRef] [PubMed][Green Version]
Figure 1. Modulation of immune system by different types of stems cells to prevent cytokine storm.
Figure 1. Modulation of immune system by different types of stems cells to prevent cytokine storm.
Cells 11 02686 g001
Figure 2. Effects of mesenchymal stem cells (MSCs) therapy on the patients of COVID-19.
Figure 2. Effects of mesenchymal stem cells (MSCs) therapy on the patients of COVID-19.
Cells 11 02686 g002
Table 1. Cytokines, their secretary cells, and mode of action.
Table 1. Cytokines, their secretary cells, and mode of action.
FamilyCytokine, Pro-Inflammatory FactorSecreted byTypes of Cells on Which It Acts/FunctionMode of Action/MechanismReferences
CytokineGSCF (Granulocyte Colony-Stimulating Factor)Endothelium, macrophagesMouse lymphoid-biasedAnti-apoptotic, angiogenic, neurogenesis and functions.[26,27,28,29]
CytokineIP10Monocytes, T-cells, endothelial cells, and keratinocytesIt recruits immune cells to fight at inflammatory sitesTo stimulate apoptosis, chemotaxis, cell growth, and angiostasis[26,30,31,32]
ChemokinesMCP1 (Monocyte Chemoattractant Protein 1)Microglial cells, mesangial, epithelial, smooth muscle, astrocytic, monocytic, and endothelialAttracts T- lymphocytes, monocytes, and natural killer cellsIt infiltrates, facilitates the migration of inflammatory cells and other cytokines towards the site of Inflammation.[26,33,34,35]
ChemokinesMIP1A (Macrophage Inflammatory Protein 1 α)Monocytes and macrophagesAct upon inflammatory cells and maintain impulsive immune response.Healing wounded cells and halting stem cells.[36,37]
CytokineIL-2CD4+ T cellsAct against microbial infection as a natural impedance. It also promotes T cells differentiation into an effector T cell and then into memory T cell as the incident with antigen.Ameliorate AICD (Activation Induced Cell Death) and increase the killing activity of Tc (Cytotoxic T) cells and NK cells.[38,39,40]
CytokineIL-6Dendritic cell and macrophagesInflamed acute-phase protein synthesis, neutrophile in bone marrow, and help in the growth of B-cells.IFN-γ secretion is affected by IL-6 through CD4 T cells, i.e., curial interferon that uplifts, IL-6 triggers CD4 cells to release IL-4 and directly affects Th2.[41,42,43]
CytokineIL-7Stromal cells in thymus and bone marrowIt affects mature T-cells and immature B-cells and leads to secondary cytokine release.It involves mechanically on TCR-gamma and TCR-gamma delta thymocyte maturation.[44,45]
TNF-α (Tumor
necrosis factor α)
Macrophages/monocytesPerform miscellaneous functions within the cells during acute inflammation, and it activates and proliferates naïve and effector T cells.Diverse signaling pathways lead to necrosis or apoptosis.[46,47,48]
Chemokine (CXC Family)IL-8Mainly by macrophages /monocytes and some other cell types like epithelial cells, endothelial cells, smooth muscle cells, and airwaysIt has a direct effect on immune cells and polymorphonuclear cells.IL-8 is considered a prognostic and therapeutic factor for wound healing.[49,50,51]
inflammatory mediators
Leukotriene (LT)Mast cellsCreate inflammatory cascade, effect on leukocytes, and stenosis of smooth muscles.Their mode of action depends on the effective binding with G-protein-coupled receptors, and every LT receptor has an abnormal expression pattern and function.[52,53,54,55]
CytokineIL-1βDendritic cell, activated macrophagesPro-inflammatory cytokine and held in inflammation, autoimmune conditions, and pain.IL-1β binds to the IL-1 type 1 receptor (IL-1R1), leads to the illustration of inflammation, and has the potency to induce fever when delivered exogenously.[56,57,58]
CytokineIL-12Dendritic cellsIL-12 receptors are present on T cells and NK cells, stimulating TH1 and NK cell growth while inhibiting TH2 cell responses.This molecule produces interferon (IFN-γ), encourages the differentiation of T helper 1 (TH1) cells, and provides a link between innate defenses and adaptive defenses.[59,60,61]
CytokineIL-33Cellular damage area of bronchial epithelial cells, airway, endothelial cells of high endothelial venulesGenerally, mast cells become degranulated when exposed to IL-33, and the effect also occurs in basophils and granulocytes.It enhances Th2 responses.[62,63,64,65]
(TGF-β) familyTGF-βMonocytes/macrophages, lymphocytes and plateletsIn addition to interacting with the surrounding cells, this TGF-β acts on smooth muscle cells, immune cells, and endothelial cells.The condition causes angiogenesis and immunosuppression, which makes cancer more aggressive.[66,67]
CC Family Chemokine Scavenger ReceptorCXCL-10Dendritic cell and macrophagesThis protein controls the differentiation of naive T cells into T helper 1 (Th1) cells and mediates immune cell migration to the foci.This CXCL-10 chemokine binds to the CXCR-3 receptor to produce its effects in the cell.[56,68,69,70]
IFNatural killer (NK) cells, activated T cells, dendritic cells and macrophages.Several cells, including monocytes, macrophages, T-lymphocytes, glia, and neurons, have IFN receptors.When IFN-γ is produced, its effects are antiviral, antimicrobial, antitumor, and immunomodulatory. IFN proteins beta, alpha, and gamma are what produce those effects.[56,71,72,73]
CytokineIL-18Monocyte/macrophageIL-18 activates th1 cells, and CD8+ T and natural killer (NK) cells are enhanced by it.It increases the cytotoxic activity of CD8+ T cells and NK cells by upregulation of FasL.[74,75]
Table 2. Stem cell type, source, and their mechanism of action.
Table 2. Stem cell type, source, and their mechanism of action.
S. No.Stem CellType of CellIsolated from Which PortionMode of ActionReferences
1.Mesenchymal Stem Cell (MSC)Multipotent stem
Fetal liver, bone marrow, umbilical cord, menstrual blood, dental pulp, adipose tissues, etc.They perform an endogenous repair of stem cells and prevent the excessive release of cytokines from the immune system.[122]
2.Hematopoietic Stem Cells (HSCs)HSCs are pluripotent and have ambient self-renewal efficiency.HSCs are predominantly found in the bone marrow region, sternum, femur portion, umbilical cord, and even in a few segments of peripheral blood.Regulated in two forms of mechanism. The first mechanism says they control the G0 phase, and in another mechanism it is fate determination, i.e., either differentiation or self-renew)[123,124,125,126,127]
3.Epithelial Stem Cells (ESCs) ESCs are multipotent stem cells due to self-renewal capability throughout the life and/or unipotent progenitor cells.They were isolated from the different layers of skin, i.e., from ectoderm, mesoderm, and endoderm.In its action, various cellular-signaling mechanisms take parts, such as bone morphogenetic protein, WNT, and Sonic Hedgehog, which play a prominent part. These signaling pathways govern the conserved mechanisms behind the self-renewal capability of adult epithelial structures.[128,129]
4.Neural Stem Cells (NSCs) They are self-renewal and multipotent stem cells,In the adult mammalian brain, the sub-granular
zone and subventricular zone have the reservoir of NSCs.
The formation of new hippocampal NSCs and its cellular mechanism taking part in it, along with a decrease in neurogenic potential is still unclear and therapeutic cargoes exchange in horizontal to host cell through extracellular vesicles is also not fully understood.[130,131]
5.Embryonic Stem Cells (ESCs)The ESCs or human embryonic stem cells
(hESC) possess tremendous pluripotent property and an extraordinary proliferative and growth capacity.
These ESCs are isolated from the mammalian blastocyst.The ESCs mechanism of action depends on transcription factors associated with four genes viz., Sox2, Oct4, Tcf3, and Nanog that maintain pluripotency.[132,133,134]
6.Adult Stem Cells (ASCs)These are multipotent, undifferentiated cells that renew themselves and preclude them into specialized cell types.ASCs can be isolated from blood, bone marrow, skin, adipose tissue, and liver.Due to environmental stimuli, ASCs release biologically active compounds that lead to exerting paracrine action on different neighboring cells and hence leading to repair, tissue protection, regeneration, self-renewal, and proliferation taking place.[135,136,137,138]
7.Induced Pluripotent Stem Cells (iPSCs)These are (iPSCs) genetically engineered from somatic cells and pluripotent.These are isolated from human adult somatic cells.The remarkable feature of iPSCs to differentiate it into required specialized cell types and this property provides a source for innovative cell therapies with unlimited cell sources.[139,140,141,142]
8.Umbilical cord-derived MSCsThey are multipotent stem cells.Isolated from the human embryo.The mechanism of action (MOA) is still unknown[143]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Upadhyay, T.K.; Trivedi, R.; Khan, F.; Pandey, P.; Sharangi, A.B.; Goel, H.; Saeed, M.; Park, M.N.; Kim, B. Potential Therapeutic Role of Mesenchymal-Derived Stem Cells as an Alternative Therapy to Combat COVID-19 through Cytokines Storm. Cells 2022, 11, 2686.

AMA Style

Upadhyay TK, Trivedi R, Khan F, Pandey P, Sharangi AB, Goel H, Saeed M, Park MN, Kim B. Potential Therapeutic Role of Mesenchymal-Derived Stem Cells as an Alternative Therapy to Combat COVID-19 through Cytokines Storm. Cells. 2022; 11(17):2686.

Chicago/Turabian Style

Upadhyay, Tarun Kumar, Rashmi Trivedi, Fahad Khan, Pratibha Pandey, Amit Baran Sharangi, Harsh Goel, Mohd Saeed, Moon Nyeo Park, and Bonglee Kim. 2022. "Potential Therapeutic Role of Mesenchymal-Derived Stem Cells as an Alternative Therapy to Combat COVID-19 through Cytokines Storm" Cells 11, no. 17: 2686.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop