key: cord-0975983-iizd02fh authors: Li, Zhongwen; Niu, Shuaishuai; Guo, Baojie; Gao, Tingting; Wang, Lei; Wang, Yukai; Wang, Liu; Tan, Yuanqing; Wu, Jun; Hao, Jie title: Stem cell therapy for COVID‐19, ARDS and pulmonary fibrosis date: 2020-10-24 journal: Cell Prolif DOI: 10.1111/cpr.12939 sha: 6636b4b29bbecd7447b9f0ad9b783f72b27d6454 doc_id: 975983 cord_uid: iizd02fh Coronavirus disease 2019 (COVID‐19) is an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). COVID‐19 mainly causes damage to the lung, as well as other organs and systems such as the hearts, the immune system and so on. Although the pathogenesis of COVID‐19 has been fully elucidated, there is no specific therapy for the disease at present, and most treatments are limited to supportive care. Stem cell therapy may be a potential treatment for refractory and unmanageable pulmonary illnesses, which has shown some promising results in preclinical studies. In this review, we systematically summarize the pathogenic progression and potential mechanisms underlying stem cell therapy in COVID‐19, and registered COVID‐19 clinical trials. Of all the stem cell therapies touted for COVID‐19 treatment, mesenchymal stem cells (MSCs) or MSC‐like derivatives have been the most promising in preclinical studies and clinical trials so far. MSCs have been suggested to ameliorate the cytokine release syndrome (CRS) and protect alveolar epithelial cells by secreting many kinds of factors, demonstrating safety and possible efficacy in COVID‐19 patients with acute respiratory distress syndrome (ARDS). However, considering the consistency and uniformity of stem cell quality cannot be quantified nor guaranteed at this point, more work remains to be done in the future. In December 2019, an outbreak of unidentifiable pneumonia cases was first officially reported in Wuhan, China. It was subsequently confirmed that the pneumonia is an acute respiratory infectious disease caused by infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel β-coronavirus which had never been reported before. 1, 2 As the global epidemic grew and spread rapidly, the World Health Organization (WHO) officially named the new type of disease as coronavirus disease 2019 . was confirmed to be more contagious than either the severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS), with a confusing manifestation ranging from asymptomatic patients to severely ill patients with acute respiratory distress syndrome (ARDS) and pulmonary fibrosis, amongst several potential health problems, and has had disastrous consequences for public health management. It can encode 29 proteins and has 79% homology to the SARS virus sequence. The spike glycoprotein (S protein) on its surface is an essential structural protein that mediates its invasion into human cells. Through the host cell receptor-angiotensin converting enzyme 2 (ACE2), SARS-CoV-2 adsorbs onto and enters the host, then replicates, assembles, and releases a large number of viral particles. 3 ACE2 is expressed on the surface membrane of alveolar, tracheal and bronchial epithelial cells in the lung, and monocytes and macrophages in the immune system. It can also be expressed in the heart, kidney and intestines. ACE2 lowers blood pressure and regulates the renin-angiotensin system by inactivating angiotensin II (Ang II) produced by ACE, and serves as a crucial regulator of pulmonary oedema. SARS-CoV-2 utilizes a highly glycosylated homotrimeric S protein to enter the host cell, and its affinity for ACE2 is 10-20 times that of SARS virus, thus enhancing its transmissibility. 4 In fact, although the fatality rate of COVID-19 is lower than SARS (9.6%) and MERS (34.4%), its higher infectious rate has led to a much wider outbreak with significantly more complications in epidemic prevention and control, due to a large number of asymptomatic and mild patients ( Figure 1 ). For patients with symptoms, the incubation period (time from exposure to onset of symptoms) has a wide range but averages to ~4-5 days. 5 The most common symptoms include dry cough, fever and shortness of breath. Other common symptoms are myalgia, fatigue, sore throat, nausea, vomiting, diarrhoea, conjunctivitis, anorexia and headache (cdc.gov/coronavirus/2019-ncov/hcp/ clinical-guidance-management-patients.html). For a small number of severely ill patients, the disease begins to worsen about 5-10 days F I G U R E 1 COVID-19 pathogenic progression after the onset of symptoms, and complications such as acute respiratory distress syndrome (ARDS) and other end-organ failures could occur. 6 The mortality rate is significantly higher amongst elderly adults over 65. Adults with underlying cardiovascular disease, respiratory disease, endocrine metabolic disease, diabetes or a weakened immune system are the most vulnerable to serious complications of COVID-19. 7 One of the reasons for aggravated severe illness in COVID-19 patients aggravation is the excessive immune response associated with the cytokine release syndrome (CRS), which in turn leads to lung tissue damage, repair imbalance and respiratory failure. The patient could also eventually die from multiple organ failure. 8 Extremely high concentrations of IL-6, GCSF, CRP and TNF-α have also been recorded in COVID-19 patients. 10 The excessive inflammatory CRS could also promote thrombosis and deaths by thromboembolism in critically ill patients. [11] [12] [13] At present, there is no specific treatment for CRS. In clinical practice, glucocorticoid injections for systemic immune suppression and cytokine inhibitors have been the primary methods. However, the use of glucocorticoids in viral pneumonia carries additional risks of steroid treatment sequelae such as diabetes and osteonecrosis, so there has been controversy in the academic community. ARDS refers to acute progressive hypoxic respiratory failure caused by various pulmonary and extrapulmonary pathogenic factors other than cardiogenic. 14 According to the Berlin definition, patients with less severe hypoxaemia (as defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 300 or less) are considered to have acute lung injury (ALI), and those with more severe hypoxaemia (as defined by a ratio of 200 or less) are considered to have the ARDS. 15, 16 ARDS is a continuous pathological process, and its early stage is ALI. The main manifestations are sudden progressive dyspnoea, varying degrees of cough, less sputum, late cough and bloody sputum. Arterial hypoxaemia is a characteristic feature, which is irresistible to oxygen therapy. If PaCO2 increased, it indicated that the patient is in critical condition. Early chest X-ray is often negative, and then, interstitial pulmonary oedema occurs, manifested as two lungs scattered in different sizes and fuzzy edge of the patchy increased density shadow. Pulmonary interstitial fibrosis may occur in the late stage. Multiple organ failure may occur after the disease develops. 15 Although many patients who develop ARDS survive the acute phase of the disease, and might even be discharged, a large proportion of them die subsequently from progressive pulmonary fibrosis. 17 Dysregulation of matrix metalloproteinases in the inflammatory phase of ARDS could lead to a complex combination of epithelial and endothelial damage, and thus uncontrolled fibrosis. 18 Continuous and aberrant activation of epithelial cells could lead to cellular senescence and overactive secretion of pro-fibrotic growth factors, chemokines, vascular inhibitors and procoagulant mediators. These factors are collectively referred to as senescence-associated secretory phenotype (SASP) factors. 19 SASP factors can lead to abnormal wound healing, which is characterized by a dysregulated crosstalk between epithelial cells and mesenchymal cells, and the consequent accumulation of myofibroblasts. Fibroblasts and myofibroblasts in fibrotic lungs exhibit markers of stress and senescence, including resistance to apoptosis and excessive production of extracellular matrix components. 20 The resultant increase in matrix stiffness could affect the microenvironment and thus the crosstalk between fibroblasts and epithelial cells, resulting in irreversible damage and fibrosis. 21 Studies have found that COVID-19 can cause multiple organ and tissue damage, especially in the respiratory system. 22, 23 The tracheal and bronchial mucosa exhibited hyperaemia and increased secretions. 13 Although the pathological characteristics of lung lesions caused by SARS-CoV-2 are similar to SARS, there were also significant differences. Parenchymal areas contain diffuse alveolar injury and exudative inflammation. 24 The alveolar cavity is often filled with serum, fibrin exudate and extensive transparent hyaline membrane formations, as observed in autopsies. 22, [25] [26] [27] White blood cells that infiltrate the alveoli are mainly monocytes and macrophages. Type II lung alveolar cell proliferation and focal lung cell shedding can be observed. Pulmonary interstitial fibrosis is frequently observed in cases with a long duration of the disease. COVID-19 can also affect multiple organs with varying degrees of acute damage. SARS-CoV-2 was also detected in the lymph nodes, spleen, heart, liver, gallbladder, kidney, stomach, breast, skin and testis, through qRT-PCR-based viral nucleic acid detection, electron microscopy and immunohistochemical staining. 23 A study noted lesions in the lymphoid hematopoietic organs. 28 Lymphocytes in the spleen and lymph nodes, especially CD4 + and CD8 + T cells, were significantly reduced. Lymphocyte degeneration, necrosis and macrophage proliferation were frequently observed. The myocardium also exhibits cellular degeneration, occasional necrosis, interstitial oedema, and mild infiltration of monocytes, lymphocytes and/or neutrophils. Hepatocyte degeneration, spot necrosis, and small, bridging or large necrosis of neutrophil infiltration are found in the liver. In the kidney, hyperaemia, segmental hyperplasia or necrosis, and protein exudation in the glomerulus were observed. Sometimes pancreatic islet cell degeneration and lysis are detected. The oesophagus, stomach and intestinal mucosal epithelium showed varying degrees of degeneration, necrosis and exfoliation. The testes also showed different degrees of reduction and damage of spermatogenic cells. Brain congestion and oedema, some neuronal degeneration, and ischaemic changes were also detected. Stem cells are endowed with the properties of self-renewal and multi-lineage differentiation potential, thus making them an attractive modality for cell therapy in the clinic. However, due to many ethical and legal restrictions, clinical development and progression of stem cell therapies have been relatively slow. 29 Because adult stem cells are exempt from the aforementioned ethical and legal restrictions, while possessing excellent tissue repair capabilities, usage of adult stem cells has been more popular than embryonic or pluripotent stem cells in the clinic. 30 Accumulating studies have shown that stem cell therapy is becoming one of the emerging treatment strategies for several refractory diseases with F I G U R E 2 The potential mechanisms of MSCs therapy for COVID-19. MSCs have great therapeutic potential in immunomodulation and tissue repair through secretion of soluble paracrine protein factors and exosomes. MSCs can regulate the functions of a variety of immune cells, secrete several cytokines, promote tissue repair and regeneration, and may play important therapeutic roles in patients with COVID-19. MSCs: mesenchymal stem cells; HGF, hepatocyte growth factor; VEGF, vascular endothelial growth factor; KGF, keratinocyte growth factor; FGF, fibroblast growth factor; TGF-β, transforming growth factor-β; TNF-α, tumour necrosis factor-α; MSC-exo, exosomes no known treatments, including viral infections. 31 Newly emerging viral pandemic, which could cause multi-organ damage and for which there are no particular therapies, drugs or vaccines available, is especially amenable to stem cell therapy. With the COVID-19 pandemic, stem cell therapies and especially mesenchymal stem cell (MSC)-related therapies have demonstrated their therapeutic potential for newly emerging diseases with no available treatments ( Figure 2 ). MSCs are derived from the mesoderm and ectoderm of early embryonic development. They express specific cell surface markers such as CD73, CD90, CD105, CD29, CD44, CD146 and CD166, while being negative for CD45, CD31 and CD34. [32] [33] [34] MSCs are also known as mesenchymal stromal cells, and these matrix-derived cells are capable of self-renewal and differentiation into chondrocytes, osteoblasts and adipocytes. 35 MSCs were initially found and isolated from the bone marrow (BM), but were subsequently also discovered in various tissues such as the adipose fat pads, dental pulp, umbilical cord and placenta. 36 Currently, MSCs from different tissues are being tested for their therapeutic effects in COVID- 19. 37 MSCs express low levels of human leucocyte antigen (HLA) class I molecules, and do not express HLA class II molecules or costimulatory molecules such as CD40, CD40L, CD80 and CD86. This expression profile allows MSCs to escape the cytotoxic effects of lymphocytic T cells, B cells and NK cells, were thus termed 'immune-privileged' cells. [38] [39] [40] [41] In addition, MSCs possess immunomodulatory and anti-inflammatory effects, and can detect microenvironmental injury signals to direct pro-regenerative signalling processes, 42 Moreover, compared to standard adult MSCs, they show enhanced immunomodulatory and anti-fibrotic functions, and significantly extended lifespans in vitro for consistent quality in production. A recent report showed that intravenously delivered IMRCs could home into the lungs and inhibit both pulmonary inflammation and fibrosis after bleomycin-induced acute lung injury in mouse models in vivo. 46 Moreover, a pilot study for compassionate use of IMRCs showed that they could ameliorate the ARDS in two severely ill COVID-19 patients. IMRCs' hyper-immunomodulatory function, pro-regenerative paracrine signals and functional inhibition of TGF-β1-induced fibrosis were potential mechanisms for amelioration of pulmonary injury. Clinical trials for IMRCs are now in progress as well. MSCs have been widely used in basic research and clinical studies on immune-mediated inflammatory diseases, such as graftversus-host disease (GvHD), Crohn's disease, inflammatory bowel disease, rheumatoid arthritis and ARDS. MSCs' properties in immunomodulatory and anti-inflammatory signalling make them uniquely suited for these complex multifactorial diseases, including COVID-19. 28 As such, several clinical trials have launched for these diseases. 47, 48 MSCs can activate immune regulatory responses through interactions with a wide repertoire of immune cells and participate in both innate immunity and adaptive immunity regulation. 49 Below, we outline some of the host immune cells that MSCs interact with, either by direct contract or indirectly through paracrine secretion of various cytokines ( Figure 1) to modulate the immune cells. 50,51 imbalance. [56] [57] [58] [59] In fact, in severely ill COVID-19 patients, the number of CD4 + and CD8 + T cells in the peripheral blood is often significantly reduced, while the overall immune system is abnormally activated and dysregulated by the cytokine storm during ARDS, suggesting a severe immune imbalance. Therefore, the immunomodulatory effects of MSCs and IMRCs on T cells may have potential therapeutic significance for patients with COVID-19 and ARDS. MSCs can interfere with the antigen presentation functions, differentiation and maturation of dendritic cells (DC), thereby reducing DC activation and inflammatory factor secretion. 60 MSCs regulate the differentiation of CD11c + B220-DC precursors into regulatory DCs via prostaglandin E2 and PI3K signalling. 61 MSCs vigorously promote the proliferation of mature DCs and drive mature DCs to transdifferentiate into a novel regulatory DC population to escape their apoptotic fate. 62 In addition, MSCs can prevent DCs from secreting IFNγ and promoting T-cell expansion in tumours. 63 Since SARS-CoV-2 infection also results in DC reduction, 64 MSCs could rescue DCs for the treatment of COVID-19. Macrophages are the other major antigen-presenting cell type, and they are one of the cell types considered to play an essential role in ARDS. 65 MSCs can regulate macrophage polarization via secretory exosomes to suppress chronic inflammation and promote tissue healing after injury. 66 MSCs also secrete the TSG-6 factor and IL-10 to inhibit NF-κB signalling and other pro-inflammatory pathways, thereby driving the polarization of pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages. 54, 67 Thus, MSCs could regulate macrophage polarization and their related signalling molecules, to modulate ARDS, the anti-viral immunity, and tissue healing in COVID-19 patients. 68 Neutrophils can kill pathogens (bacteria, fungi and viruses) through an oxidative burst of reactive oxygen species (ROS) and phagocytosis, and they are recruited early to sites of infection to perform their defensive functions. 69 Paradoxically, it has been reported that excessive neutrophil recruitment might exacerbate COVID-19 immunopathology. 70 Clinical studies have found that the number of neutrophils in the bronchoalveolar lavage fluid of ARDS patients is positively correlated with the severity of COVID-19 and the cytokine storm. 71 In fact, the neutrophil to lymphocyte ratio (NLR) can be used as an independent risk factor for severe disease in COVID-19 patients. 72 Intravenous injection of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes into severe COVID-19 patients with ARDS can significantly reduce the production of neutrophils by 32%, thereby reducing their NLR levels and improving their clinical oxygenation index. 73 MSCs can also inhibit excessive proliferation of B cells, prevent their differentiation into plasma cells and reduce excessive levels of immunoglobulin secretion by downregulating the expression of Blimp-1. 55 After MSC treatment, overactivated CXCR3 + NK cells also disappear in 3-6 days, showing that MSCs have a potential regulatory effect on NK cells as well. 74 Severely ill COVID-19 patients often present severe pneumonia, respiratory failure, ARDS and pulmonary fibrosis. During this complex inflammatory pathogenic process, 55,56 the integrity of the lung alveolar capillary membrane is gradually destroyed, contributing to the formation of pulmonary oedema, lung tissue degeneration and fibrosis. MSCs can secrete a variety of growth factors and cytokines to improve the microenvironment of the lung tissue and promote endogenous lung repair, with potential benefits for COVID-19 patients (Figure 2 ). For example, MSCs can promote cell proliferation and tissue damage repair by secreting hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF) and fibroblast growth factor (FGF). 75 MSCs secrete HGF through extracellular vesicles, reduce inflammatory damage and increase autophagy, thereby retaining or restoring the alveolar epithelium and the pulmonary vascular endothelial lining. 76, 77 The HGF, KGF and angiopoietin-1 secreted by MSCs also possess pro-angiogenic, anti-inflammatory and pro-proliferation effects. 42 It has been reported that MSCs can reduce apoptosis of the alveolar epithelial cells and endothelial cell by secretion these three growth factors. [77] [78] [79] The VEGF and FGF secreted by MSCs can also promote lung tissue repair. 80, 81 In addition, MSCs can reduce the levels of pro-fibrotic factors to The MSC-like IMRCs could also reverse pulmonary fibrosis by overexpressing the matrix metalloproteinase MMP1 and reducing collagen I levels during fibrogenesis induced by TGF-β1. 84 MSCs can also promote the repair of other damaged tissues in COVID-19 patients. Pathological results show that SARS-CoV-2 virus can also affect the kidneys, causing severe acute tubular necrosis. 85 Studies have shown that MSCs secrete cytokines to activate a variety of repair mechanisms in acute kidney injury, including anti-inflammatory, anti-apoptotic and pro-angiogenic pathways, thereby promoting the repair of kidney injury. 86, 87 MSCs can also treat COVID-19-related intestinal injury through mucosal repair and epithelial regeneration. 88 Follow-up after treatment is strictly required according to the clinical protocol guidelines. Clinical trials for stem cell therapies against COVID-19 were searched by using the terms 'COVID-19' and 'stem cells' in the ClinicalTrials.gov (Table S1 ). All observational studies and 6 withdrawn clinical studies were excluded from the list. Eventually, 88 clinical trials related to stem cells were found to be registered in different countries. In these clinical studies, the therapeutic efficacy (60 trials) and the safety (32 trials) of stem cells and their derivatives for treating COVID-19 were being investigated. In total, 88 trials were found to be registered to investigate the The source of stem cells used in these trials is a major point of variability amongst the searched studies ( Figure 3C Cell dose and proposed regimens also varied greatly amongst studies. While the MSC infusion dosage ranged over an order of magnitude between 0.5 × 10 6 and 10 × 10 6 cells/kg (Table S1) , the most commonly used infusion dosage was 1 × 10 6 cells/kg. In some studies, stem cells are infused regardless of the weight of the patient. In these cases, the proposed infusion dosage ranged from 1.5 × 10 7 to 75 × 10 7 cells per round regardless of the weight of the patient, with 10 × 10 7 cells per round as the most common dose (Table S1 ). The highest dose of 75 × 10 7 MSCs per round was used for the 'extracorporeal stromal cell therapeutics' against COVID-19-related acute kidney injury (NCT04445220). Of note, higher cell doses will likely bring higher treatment risks. Therefore, it is necessary to find a balance between therapeutic efficacy and safety concerns. Intravenous injection of MSCs may produce a first-order lung effect, 92 which leads to significant cell retention in the lungs, thus providing an advantage for lung tissue repair in COVID-19, ARDS and pulmonary fibrosis. Therefore, most of the ongoing clinical trials proposed to perform intravenous cell infusion (65 out of 88; Figure 3F ). Three studies focused on the administration of MSCs-derived exosomes via the inhalation route. Intramuscular injection of MSCs was used in one study (NCT04389450). The 'extracorporeal stromal cell therapeutics' was used in COVID-19 subjects with acute kidney injury in a study (NCT04445220). However, in 18 studies, the route of MSCs administration was not clearly stated. Although a single round of MSC infusion, as proposed in 20 out of 88 trials, has been shown to provide therapeutic benefits, more than one round may be required to induce complete tissue repair or even to maintain therapeutic benefits ( Figure 3G ). In some studies, the mentioned MSC doses would be injected two (14 out of 88), three (17 out of 88), four (7 out of 88) and even five rounds (3 out of 88) with short time intervals of 2 or 3 days ( Figure 3G ; Table S1 ). Recently, some studies have been published to report the safety and efficacy of stem cell therapy for COVID-19 (Table 1 ). In these pub- The first study for stem cell treatment of COVID-19 by Dr Zhao improved. Additionally, the chest CT scans indicated that the patients' bilateral lung exudate lesions were adsorbed after MB-MSC infusion. Despite their safety and efficacy, clinical applications of primary Of knows yet when the current COVID-19 crisis will end, and when the next crisis will come. The authors declare no conflict of interest. YT, JW and JH conceived the project and supervised the manuscript. ZL, SN, B.G and TG contributed equally to this work and wrote the manuscript with help from all the authors. ZL, SN, BG, TG, LW, YW, L.W., YT, JW and JH participated in the experiments and data analysis. The data that support the findings of this study are available in the Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Clinical features of patients infected with 2019 novel coronavirus in Wuhan Cytokine Storm in COVID-19-Immunopathological Mechanisms, Clinical Considerations, and Therapeutic Approaches: The REPROGRAM Consortium Position Paper Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Cytokine release syndrome in severe COVID-19 Incidence of thrombotic complications in critically ill ICU patients with COVID-19 Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis Characteristics of ischaemic stroke associated with COVID-19 Acute respiratory distress syndrome The acute respiratory distress syndrome Report of the American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy Transepithelial Migration of Neutrophils Mechanisms and Implications for Acute Lung Injury The senescence-associated secretory phenotype and its regulation Idiopathic Pulmonary Fibrosis (IPF): an overview Idiopathic pulmonary fibrosis: pathogenesis and management Pathological findings of COVID-19 associated with acute respiratory distress syndrome Autopsy of COVID-19 victims in China SARS-CoV-2, SARS-CoV, and MERS-COV: A comparative overview A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm Clinicopathologic and Immunohistochemical findings from autopsy of patient with COVID-19 Accelerated hyaluronan concentration as the primary driver of morbidity and mortality in high-risk COVID-19 patients: with therapeutic introduction of an oral hyaluronan inhibitor in the prevention of Induced Hyaluronan Storm Syndrome. medRxiv Autopsy of COVID-19 patients in China An overview of stem cell research and regulatory issues Stem cells therapy as a possible therapeutic option in treating COVID-19 patients Stem cell therapy: a potential approach for treatment of influenza virus and coronavirus-induced acute lung injury Human mesenchymal stem cells -current trends and future prospective Are mesenchymal stromal cells immune cells? Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement Stem cells and cell therapies in lung biology and lung diseases Mesenchymal stem cell perspective: cell biology to clinical progress The rationale of using mesenchymal stem cells in patients with COVID-19-related acute respiratory distress syndrome: What to expect Concise review: current status of stem cells and regenerative medicine in lung biology and diseases Immune modulation by mesenchymal stem cells Immune regulation by mesenchymal stem cells: two sides to the coin Mechanisms of T-cell immunosuppression by mesenchymal stromal cells: what do we know so far? Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics The role of stromal stem cells in tissue regeneration and wound repair Multipotent mesenchymal stromal cells and the innate immune system Novel antiviral strategies in the treatment of COVID-19: A Immunity-and-matrix-regulatory cells derived from human embryonic stem cells safely and effectively treat mouse lung injury and fibrosis Mesenchymal stromal cells: clinical challenges and therapeutic opportunities Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases Mesenchymal stem cells in health and disease The exciting prospects of new therapies with mesenchymal stromal cells Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation Mesenchymal stem cell effects on T-cell effector pathways Stem cell therapy offers a possible safe and promising alternative approach for treating vitiligo: A review The immunomodulatory properties of human bone marrow-derived mesenchymal stromal cells are defined according to multiple immunobiological criteria The immunomodulatory function of mesenchymal stem cells: mode of action and pathways Clinical features of patients infected with 2019 novel coronavirus in Wuhan Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study Clinical and immunological features of severe and moderate coronavirus disease 2019 Cross-Talk Between Mesenchymal Stem/Stromal Cells and Dendritic Cells Mesenchymal stem cells alleviate bacteria-induced liver injury in mice by inducing regulatory dendritic cells Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population Tumor-associated mesenchymal stem cells inhibit naive T cell expansion by blocking cysteine export from dendritic cells Acute SARS-CoV-2 infection impairs dendritic cell and T Cell Responses Macrophage activation syndrome and COVID-19 LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b Kynurenic acid, an IDO metabolite, controls TSG-6-mediated immunosuppression of human mesenchymal stem cells Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages COVID-19 Hyperinflammation: What about Neutrophils? mSphere H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice Neutrophil extracellular traps (NETs) are increased in the alveolar spaces of patients with ventilator-associated pneumonia Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19 Transplantation of ACE2(-) mesenchymal stem cells improves the outcome of patients with COVID-19 Pneumonia Exploiting extracellular matrix-stem cell interactions: a review of natural materials for therapeutic muscle regeneration Mesenchymal stem cell microvesicles restore protein permeability across primary cultures of injured human lung microvascular endothelial cells mTOR/STAT-3 pathway mediates mesenchymal stem cell-secreted hepatocyte growth factor protective effects against lipopolysaccharide-induced vascular endothelial barrier dysfunction and apoptosis Mesenchymal stem cells reduce hypoxia-induced apoptosis in alveolar epithelial cells by modulating HIF and ROS hypoxic signaling Coculture with bone marrow-derived mesenchymal stem cells attenuates inflammation and apoptosis in lipopolysaccharide-stimulated alveolar epithelial cells via enhanced secretion of keratinocyte growth factor and angiopoietin-1 modulating the Toll-like receptor-4 signal pathway Vascular endothelial growth factor (VEGF) in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): paradox or paradigm? Evidence for lung repair and regeneration in humans: key stem cells and therapeutic functions of fibroblast growth factors Emerging role of mesenchymal stem cell-derived exosomes in regenerative medicine Experimental treatment of pulmonary interstitial fibrosis with human umbilical cord blood mesenchymal stem cells Immunity-and-matrix-regulatory cells derived from human embryonic stem cells safely and effectively treat mouse lung injury and fibrosis Is the kidney a target of SARS-CoV-2? Stem Cell Therapies in Kidney Diseases: Progress and Challenges Comparison of stem cell therapies for acute kidney injury Mesenchymal stem cells for the treatment of ulcerative colitis: a systematic review and meta-analysis of experimental and clinical studies Ethical development of stem-cellbased interventions Clinical characteristics of hospitalized patients with SARS-CoV-2 infection: A single arm meta-analysis The long-term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding A pneumonia outbreak associated with a new coronavirus of probable bat origin TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection Mesenchymal stem cell therapy in severe COVID-19: A retrospective study of short-term treatment efficacy and side effects Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells: A case report Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: a phase 1 clinical trial Adiposederived mesenchymal stromal cells for the treatment of patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation. A proof of concept study Endometrial regenerative cells: a novel stem cell population Modified protocol for improvement of differentiation potential of menstrual blood-derived stem cells into adipogenic lineage Menstrual blood-derived stem cells: toward therapeutic mechanisms, novel strategies, and future perspectives in the treatment of diseases Human menstrual blood-derived stem cells ameliorate liver fibrosis in mice by targeting hepatic stellate cells via paracrine mediators Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19 Mesenchymal stem cells and management of COVID-19 pneumonia Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model Therapeutic use of mesenchymal stem cell-derived extracellular vesicles in acute lung injury Mesenchymal stem cell microvesicles attenuate acute lung injury in mice partly mediated by Ang-1 mRNA Mesenchymal stem cell-based immunomodulation: properties and clinical application Repair of Acute Respiratory Distress Syndrome by Stromal Cell Administration in COVID-19 (REALIST-COVID-19): A structured summary of a study protocol for a randomised, controlled trial Safety and efficacy assessment of allogeneic human dental pulp stem cells to treat patients with severe COVID-19: structured summary of a study protocol for a randomized controlled trial (Phase I/II)