key: cord-0721279-dz34rzqz
authors: Yen, B. Linju; Yen, Men‐Luh; Wang, Li‐Tzu; Liu, Ko‐Jiunn; Sytwu, Huey‐Kang
title: Current status of mesenchymal stem cell therapy for immune/inflammatory lung disorders: Gleaning insights for possible use in COVID‐19
date: 2020-06-11
journal: Stem Cells Transl Med
DOI: 10.1002/sctm.20-0186
sha: b587e795a806226c75fa4d9c0a577b63c5f49f04
doc_id: 721279
cord_uid: dz34rzqz

The broad immunomodulatory properties of human mesenchymal stem cells (MSCs) has allowed for wide application in regenerative medicine as well as immune/inflammatory diseases, including unmatched allogeneic use. The novel coronavirus disease COVID‐19 has unleashed a pandemic in record time accompanied by an alarming mortality rate mainly due to pulmonary injury and acute respiratory distress syndrome. Since there are no effective preventive or curative therapies currently, MSC therapy (MSCT) has emerged as a possible candidate despite the lack of preclinical data of MSCs for COVID‐19. Interestingly, MSCT preclinical data specifically on immune/inflammatory disorders of the lungs were among the earliest to be reported in 2003, with the first clinical use of MSCT for graft‐vs‐host disease reported in 2004. Since these first reports, preclinical data showing beneficial effects of MSC immunomodulation have accumulated substantially, and as a consequence, over a third of MSCT clinical trials now target immune/inflammatory diseases. There is much preclinical evidence for MSCT in noninfectious—including chronic obstructive pulmonary disease, asthma, and idiopathic pulmonary fibrosis—as well as infectious bacterial immune/inflammatory lung disorders, with data generally demonstrating therapeutic effects; however, for infectious viral pulmonary conditions, the preclinical evidence is more scarce with some inconsistent outcomes. In this article, we review the mechanistic evidence for clinical use of MSCs in pulmonary immune/inflammatory disorders, and survey the ongoing clinical trials—including for COVID‐19—of MSCT for these diseases, with some perspectives and comment on MSCT for COVID‐19.

Human mesenchymal stem/stromal cells (MSCs) are multilineage somatic progenitors with broad immunomodulatory properties. Since initial isolation from the bone marrow (BM), MSCs have been found in numerous adult and fetal-derived organs/tissues such as adipose tissue, dental pulp, umbilical cord, and placenta. 1 In addition to trilineage paraxial mesodermal differentiation capacity toward bone, cartilage, and fat, the immunomodulatory properties of MSCs not only allow for expansion of therapeutic use from regenerative medicine to immuneand inflammation-related diseases, but also for third party allogeneic use. 2 The first published full report on clinical use of MSCs for immune/inflammatory disease was in 2004, in which allogeneic haploidentical bone marrow mesenchymal stem cell (BMMSC) infusions were given for a pediatric patient with acute refractory graft-vs-host-disease (GVHD). 3 Of note, median survival at that institution was a mere 2 months for the other 24 patients with similarly severe GVHD, while this patient remained well 1 year after MSC treatment. Surprisingly, prior to this clinical case report, there were only a handful of studies demonstrating MSC immunomodulation, with only one study showing in vivo data of prolonged skin engraftment. [4] [5] [6] Since then, MSC immunomodulation has shown to be broad-based, best detailed for CD4 lymphocytes but also for dendritic cells and natural killer cells. 7, 8 The immunomodulatory properties are clinically relevant, as evidenced by the increasing proportions of MSC trials focusing on immune/inflammatory diseases which in recent years has accounted for approximately one-third of the trials. 9 One of the earliest reports demonstrating MSC immunomodulation was in reduction of bleomycin-induced pulmonary inflammation in mice. 10 It comes as somewhat of a surprise that clinical use of MSCs for lung diseases has been relatively slow to start, with most trials initiated in 2015. Moreover, it had been known for over a decade that intravenous delivery of MSCs-the most typical method of intervention for any cell therapy-results in the overwhelming majority of cells (80%90%) lodging in the lungs which is further increased with inflammation. 10, 11 Hence, there is discussion that MSC therapy (MSCT) may be particularly useful in immune/inflammatory pulmonary conditions. 12 However, clinical trials for these diseases were still relatively few until this year: as of 17 May 2020, out of 68 MSC trials for lung immune/inflammatory diseases, 31 trials are specifically for COVID-19 as registered on the NIH Clinical Trial Database (https://ClinicalTrials.gov/) ( Figure 1 ). Due to the rapid global spread of COVID-19, the high mortality rate of those with severe disease, and no proven effective therapies as of yet, a desperate search for possible treatments is ongoing. 13 MSCT is clearly one such attempt, with new trials being added almost daily despite the lack of COVID-19-related preclinical data. In this review, we will examine the mechanistic evidence for clinical use of MSCs in pulmonary immune/inflammatory disorders, and survey the ongoing clinical trials-including for COVID-19-of MSCT for these diseases, with some perspectives and comments on MSCT for COVID-19.

The lungs are in direct exposure to the external environment, requiring constant immune surveillance by the native epithelial cells and resident alveolar macrophages for homeostasis and health. 14 Immune dysregulation and inflammation, therefore, are common components in both infectious and many noninfectious pulmonary diseases, such as obstructive diseases including chronic obstructive pulmonary diseases (COPDs), in which injury is mainly mediated by cytotoxic T cells and neutrophils, and asthma, where type 2 helper T (Th2) lymphocytes and eosinophils are more predominant. 15 In restrictive diseases such as idiopathic pulmonary fibrosis (IPF), resident alveolar macrophages appear critical in mediating the fibrosis. 16 17, 22, 23 and keratinocyte growth factor (KGF) 24 to be involved ( Figure 2 , left box). Rodent studies of asthma demonstrate that MSC induction of CD4 regulatory T cells (Tregs), which are immunomodulatory CD4 cells, is critical in decreasing Th2 responses 25, 26 and Th2 cytokines interleukin-4 (IL-4), IL-5, and IL-13 as well as immunoglobulin E levels to ameliorate disease severity 27, 28 ; one recent study implicated MSC transfer of mitochondria in this process. 29 Surprisingly, in these studies on asthma, no specific MSC paracrine factor was identified, but more recent reports implicate that MSC-expressed micro-RNA and exosomes can improve disease outcome. 30, 31 Despite transforming growth factor-β being a prominent paracrine factor of MSCs 7,32 and also known for strongly inducing fibrosis, MSCT appears to be efficacious even for fibrotic pulmonary conditions, as evidenced by the early study of MSC efficacy for bleomycin-induced lung fibrosis, a preclinical disease model of IPF. 10 MSC-secreted IL-1 receptor antagonist (IL-1RA) was subsequently shown by the same group to be the paracrine factor involved. 33 Moreover, MSCs may enhance resident lung bronchioalveolar stem cells to repair and regenerate healthy lung parenchyma. 34 There has also been a growing number of reports using MSCs other than BMMSCs including umbilical cord MSCs (UCMSCs), 35 The immunomodulatory effects of MSCs may lead one reasonably to avoid using these cells in infectious diseases, especially bacterial infectious since a strong effector response is required for clearance of these rapidly growing microorganisms. But surprisingly, the preclinical data have been rather consistent on MSCs actually enhancing antibacterial processes and decreasing overexuberant immune responses leading to pulmonary injury and acute respiratory distress syndrome (ARDS), a complication which is still associated with high morbidity and mortality. 43 In rodent models of lung injury using either and IL-6, reverse pulmonary tissue damage, and improve survival through numerous paracrine factors including TNF-stimulated gene 6 F I G U R E 2 Mechanisms involved in MSC therapy for immune/inflammatory pulmonary disorders. Mechanisms reported in in vivo preclinical studies of MSC therapy for immune/inflammatory lung diseases of non-infectious etiology-including asthma, IPF, and COPDs-and infectious etiology-including bacterial and/or LPS and viral infection and related ARDS. Detailed descriptions can be found in the text. Ang-1, angiopoietin-1; ARDS, acute respiratory distress syndrome; COPD, chronic obstructive lung disease; EGF, epidermal growth factor; EV, extracellular vesicles; HGF, hepatocyte growth factor; IL-1RA, interleukin-1 receptor antagonist; IPF, idiopathic pulmonary fibrosis; KGF, keratinocyte growth factor; LPS, lipopolysaccharide; MΦ, macrophage; miRs, microRNAs; mitoch, mitochondria; MSC, mesenchymal stem cell; OCR, oxygen consumption rate; PMNs, polymorphonuclear leukocytes/neutrophils; Th2, T helper type 2 lymphocytes; TNF-α, tumor necrosis factor-α; Treg, regulatory T lymphocytes; TSF-6, TNF-stimulated gene 6 protein; VEGF, vascular endothelial growth factor; WBCs, white blood cells protein (TSG-6), 44 angiopoietin-1, 45,46 LL-37, 47 lipocalin-2, 48 KGF, 46, 48, 49 and microRNAs ( Figure 2 , middle box). 50 Beneficial effects of MSCT in ex vivo human lung injury/bacterial infection models were seen as well. 51 Similar to a report for asthma, mitochondrial transfer from MSCT-either directly or through exosomesdecreased pulmonary injury and improved macrophage energetics and antibacterial functions. 52, 53 Other studies have also found that MSCs modulate macrophages from an M1 inflammatory phenotype to a more immunomodulatory M2 phenotype, [54] [55] [56] as has been shown in nonpulmonary in vivo models. 57, 58 It is surprising, however, that no in-depth investigation of MSCs with neutrophils, the first-line and critical leukocyte involved in bacterial clearance, was carried out any of these animal studies, since in vitro reports and one in vivo sepsis model have shown that MSCs preserve neutrophil viability and antibacterial functions. [59] [60] [61] But overall, these preclinical studies of bacterial-related lung injury/pneumonia consistently demonstrate that MSCT improves bacterial clearance and pulmonary tissue repair to impact survival.

Overall, reports on MSCT for viral infections are relatively scarce.

using MSCs from many different organisms, finding that MSCs can be infected with resultant cell lysis and death. 62, 63 For in vivo studies, there are currently only six reports which have examined intravenous MSCT for viral pneumonitis/pneumonia, all focusing on influenza. In the first two studies on the subject, the outcome was negative. Both studies evaluated syngeneic murine as well as allogeneic human BMMSC treatment in mice infected with pulmonary mouse-adapted H1N1 and/or swine H1N1, with no improvement in pulmonary inflammation or survival seen. 64, 65 In the four other more recent reports, however, pulmonary inflammation was improved overall, with survival seen to improve in two out of the three studies which evaluated this endpoint; no specific factor was shown to be responsible ( Figure 2, right box) . Interestingly, all three reports which evaluated survival used non-H1N1 subtypes. The only one beneficial report using H1N1 was a porcine study in which in vivo infection with swine H1N1 in 8-week-old pigs improved lung inflammation after intratracheal administration of syngeneic BMMSC extracellular vesicles; survival was not evaluated. 66 A report using H9N2 found syngeneic BMMSC treatment suppressed infection and improved survival in infected mice, 67 whereas another study using H5N1 found that conditioned medium and exosomes from human UCMSCs but not BMMSCs improved lung injury in infected mice partly due to two paracrine factors, angiopoietin-1 and HGF, but survival was only minimally improved. 68 A more elaborate murine study found that human BMMSCs reduce H5N1-induced lung injury and survival but only in aged mice, partially through the paracrine factors of angiopoietin-1 and KGF; the improved response in aged mice (8-12 months old) but not young mice (6-8 weeks old) to MSCT was in part attributed to more severe disease in these aged hosts, which may allow for exogenous MSCT to exert a more obvious benefit. 69 This report also further discussed that the tissue reparative properties of MSCs may only be apparent with the severe damage caused by highly pathogenic influenza subtypes including H5N1, which is not seen with the less pathogenic H1N1 subtype. The collective results of these in vivo studies, while few, would seem to support this viewpoint. Such differences in the infecting viral subtype and host conditions are unfortunately rarely tackled in preclinical studies, but in clinical practice, differences in patient profiles, including age and sex, are known to highly influence disease progression and outcome-as is strikingly evident with COVID-19, with higher positivity rates and worse outcome in men, and significantly higher mortality in the elderly and those with underlying chronic diseases. 70, 71 Preclinical studies clearly should pay attention to such parameters for improved clinical use and outcome. 

To date, 68 clinical studies using MSCs for pulmonary immune/inflammatory disorders have been registered (Figure 1 and Table S1 for detailed information on each trial). The most commonly targeted disease is COVID-19 with 31 trials. MSCT for ARDS other than for COVID-19 and COPD are the next two most commonly targeted diseases, with 10 trials each. There are six trials for IPF, and two trials for asthma; the rest of the nine trials include trials for cystic fibrosis, lung transplantation, pneumoconiosis, radiation-caused injury, and unspecified lung injury.

MSC sources used are broad (Table 1 and Figure 3) , with the two most common types being BMMSCs (22 trials) and UCMSCs (20 trials), then AdMSCs with 12 trials. A few trials use either dental pulp MSCs (two trials), placenta-MSCs (one trial), and olfactory mucosa MSCs (one trial); eight trials did not specify MSC source. As testament to the strong evidence for MSC immunomodulation, the majority of trials use allogeneic MSCs (49 trials, includes two trials using conditioned medium and exosomes), with all UCMSC trials being allogeneic; 10 trials use autologous sources which are either BMMSCs or AdMSCs, and nine trials were unspecified. There are only two trials using MSCderived products such as conditioned medium or exosomes rather than the cells themselves, and these products are derived from allogeneic AdMSCs or UCMSCs. Trials tend to be at early phases, with 30 being phase 1 trials, 17 being combined phase 1/2 trials, 14 trials in phase 2, 2 trials being a combined phase 2/3 trials, and 1 trial in phase 3; 3 trials are unspecified. As expected, the overwhelming majority of trials deliver MSCs intravenously (60 trials) but surprisingly, except for two trials which did not specified delivery method, the remaining six trials deliver MSCs to the lungs more directly, either through intratracheal/endobronchial delivery (three trials), intranasal delivery (one trial using UCMSC-conditioned medium), aerosolized inhalation (one trial using AdMSC-derived exosomes), or bronchial lavage (one trial) ( Figure 4 ). 88 There has also been much discussion on whether the use of fresh vs cryopreserved MSCs would have therapeutic implications. 89 In the six published clinical reports which all used allogeneic sources, two studies used freshly cultured MSCs 84, 85 whereas the other four studies used previously cryopreserved MSCs [81] [82] [83] ; no clear difference in efficacy could be easily discerned. In addition, the delivery method and dose of cells given, and whether multiple doses should be given, as well as cell numbers used are also critical parameters that likely impact efficacy, but all are difficult to test in human studies. Further accumulation of preclinical data investigating these parameters is urgently needed for better tailoring of specific tissuesource MSCs, MSC preparation, as well as dosing regimens in clinical use to improve outcome.

One startling discovery is that the majority of MSC clinical trials for immune/inflammatory lung disorders currently are for COVID-19, a disease that did not exist 6 months ago. 90 As of this writing, there are (Table S2 with brief details for these trials) . Table S152 for trial details). While it is unclear whether the rapid increase in MSCT trials for COVID-19 is a factor in accelerating the registration of these trials, there is strong interest in using MSCT for severe pulmonary inflammation and complications given the continued lack of curative treatments for ARDS from any cause. 94 The preclinical data on MSCT decreasing TNF-α and IL-6 levels, two pro-inflammatory cytokines highly expressed during cytokine storm, 95 

The authors declared no potential conflicts of interest. 

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

B. Linju Yen https://orcid.org/0000-0002-6905-3018

Mesenchymal stem cell perspective: cell biology to clinical progress

The MSC: an injury drugstore

Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells

Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo

Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli

Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex

Mesenchymal stem cells in health and disease

Multipotent mesenchymal stromal cells and the innate immune system

Human mesenchymal stem cells (MSCs) for treatment towards immune-and inflammation-mediated diseases: review of current clinical trials

Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects

In vivo contribution of murine mesenchymal stem cells into multiple cell-types under minimal damage conditions

Mesenchymal stem cells and the lung

Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review

Lung homeostasis: influence of age, microbes, and the immune system

The asthma-COPD overlap syndrome

Idiopathic pulmonary fibrosis

Mesenchymal stem cells protect cigarette smoke-damaged lung and pulmonary function partly via VEGF-VEGF receptors

Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model

TNF-α and IL-1β-activated human mesenchymal stromal cells increase airway epithelial wound healing in vitro via activation of the epidermal growth factor receptor

Autologous transplantation of adipose tissue-derived stromal cells ameliorates pulmonary emphysema

Human mesenchymal stromal cells exert HGF dependent cytoprotective effects in a human relevant preclinical model of

Adipose stem cell treatment in mice attenuates lung and systemic injury induced by cigarette smoking

Mesenchymal stem cell transplantation increases expression of vascular endothelial growth factor in papaininduced emphysematous lungs and inhibits apoptosis of lung cells

Bone marrow cells repair cigarette smoke-induced emphysema in rats

Mesenchymal stem cell transfer suppresses airway remodeling in a toluene diisocyanate-induced murine asthma model

Functional effects of TGF-β1 on mesenchymal stem cell mobilization in cockroach allergen-induced asthma

Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model

Human pluripotent stem cell-derived mesenchymal stem cells prevent allergic airway inflammation in mice

Connexin 43-mediated mitochondrial transfer of iPSC-MSCs alleviates asthma inflammation

MicroRNAs involved in asthma after mesenchymal stem cells treatment

Mesenchymal stem cell exosomes promote immunosuppression of regulatory T cells in asthma

Immunomodulatory properties of human adult and fetal multipotent mesenchymal stem cells

Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury

Bronchioalveolar stem cells increase after mesenchymal stromal cell treatment in a mouse model of bronchopulmonary dysplasia

Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury

Human umbilical cord blood-derived mesenchymal stem cells attenuate hyperoxia-induced lung injury in neonatal rats

Mesenchymal stromal cells prevent bleomycin-induced lung and skin fibrosis in aged mice and restore wound healing

Transplantation of adipose-derived mesenchymal stem cells attenuates pulmonary fibrosis of silicosis via anti-inflammatory and anti-apoptosis effects in rats

Human placental mesenchymal stem cells of fetal origins-alleviated inflammation and fibrosis by attenuating MyD88 signaling in bleomycin-induced pulmonary fibrosis mice

Hepatocyte growth factor is required for mesenchymal stromal cell protection against bleomycininduced pulmonary fibrosis

Oncostatin M-preconditioned mesenchymal stem cells alleviate bleomycin-induced pulmonary fibrosis through paracrine effects of the hepatocyte growth factor

Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through modulation of monocyte phenotypes

Incidence and outcomes of acute lung injury

Human multipotent stromal cells attenuate lipopolysaccharide-induced acute lung injury in mice via secretion of tumor necrosis factor-α-induced protein 6

Allogeneic human mesenchymal stem cells restore epithelial protein permeability in cultured human alveolar type II cells by secretion of angiopoietin-1

Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1

Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37

Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia

Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice

Mesenchymal stem cell-derived extracellular vesicles decrease lung injury in mice

Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung

Mitochondrial transfer via tunneling nanotubes is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS

Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer

Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice

Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action

Anti-inflammatory roles of mesenchymal stromal cells during acute Streptococcus pneumoniae pulmonary infection in mice

Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production

Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatorylike profile

Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche

Toll-like receptor-3-activated human mesenchymal stromal cells significantly prolong the survival and function of neutrophils

Mesenchymal stromal cells improve survival during sepsis in the absence of heme oxygenase-1: the importance of neutrophils

Influenza virus infects bone marrow mesenchymal stromal cells in vitro: implications for bone marrow transplantation

Tropism of avian influenza A (H5N1) virus to mesenchymal stem cells and CD34+ hematopoietic stem cells

Mesenchymal stromal (stem) cell therapy fails to improve outcomes in experimental severe influenza

Influenza causes prolonged disruption of the alveolar-capillary barrier in mice unresponsive to mesenchymal stem cell therapy

Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model

Mesenchymal stromal cell treatment prevents H9N2 avian influenza virus-induced acute lung injury in mice

Therapeutic implications of human umbilical cord mesenchymal stromal cells in attenuating influenza A (H5N1) virus-associated acute lung injury

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region

Clinical characteristics of coronavirus disease 2019 in China

Lymph node -an organ for T-cell activation and pathogen defense

Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells

Mesenchymal stem cells differentially modulate effector CD8+ T cell subsets and exacerbate experimental autoimmune encephalomyelitis

Mesenchymal stem cells control alloreactive CD8(+) CD28(−) T cells

Differentiation of mesenchymal stem cells from human induced pluripotent stem cells results in downregulation of c-Myc and DNA replication pathways with immunomodulation toward CD4 and CD8 cells

Human mesenchymal stem cells shift CD8+ T cells towards a suppressive phenotype by inducing tolerogenic monocytes

Mesenchymal stromal cells inhibit proliferation of virus-specific CD8(+) T cells

Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses

Mesenchymal stromal cell therapy is associated with increased adenovirus-associated but not cytomegalovirus-associated mortality in children with severe acute graft-versus-host disease

A placebo-controlled, randomized trial of mesenchymal stem cells in COPD

Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study

Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial

A phase 1b study of placentaderived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis

Allogeneic human mesenchymal stem cells in patients with idiopathic pulmonary fibrosis via intravenous delivery (AETHER): a phase I safety clinical trial

In vivo effects of mesenchymal stromal cells in two patients with severe acute respiratory distress syndrome

Clinical study of mesenchymal stem cell treating acute respiratory distress syndrome induced by epidemic influenza A (H7N9) infection, a hint for COVID-19 treatment. Engineering

Efficacy of mesenchymal stromal cell therapy for acute lung injury in preclinical animal models: a systematic review

Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties?

A novel coronavirus from patients with pneumonia in China

Another decade, another coronavirus

Spread of SARS-CoV-2 in the Icelandic population

Transplantation of ACE2(−) mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia

COVID-19: a new virus, but a familiar receptor and cytokine release syndrome

Into the eye of the cytokine storm

ISCT Releases Statement on Unproven Stem Cell Treatments for COVID-19

ISSCR Statement Regarding the Marketing of Unproven Stem Cell Treatments for COVID-19

Current status of mesenchymal stem cell therapy for immune/inflammatory lung disorders: Gleaning insights for possible use in COVID-19