Current status and prospects of basic research and clinical application of mesenchymal stem cells in acute respiratory distress syndrome

Tian-Yu Liang, Li-Hai Lu, Si-Yu Tang, Zi-Hao Zheng, Kai Shi, Jing-Quan Liu

Tian-Yu Liang, Jing-Quan Liu, Emergency and Critical Care Center, Intensive Care Unit,Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou 310014, Zhejiang Province, China

Li-Hai Lu, Zi-Hao Zheng, Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China

Si-Yu Tang, The Second School of Clinical Medicine, Zhejiang Chinese Medical University,Hangzhou 310053, Zhejiang Province, China

Kai Shi, Department of Respiratory Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China

Abstract Acute respiratory distress syndrome (ARDS) is a common and clinically devastating disease that causes respiratory failure. Morbidity and mortality of patients in intensive care units are stubbornly high, and various complications severely affect the quality of life of survivors. The pathophysiology of ARDS includes increased alveolar-capillary membrane permeability, an influx of protein-rich pulmonary edema fluid, and surfactant dysfunction leading to severe hypoxemia. At present, the main treatment for ARDS is mechanical treatment combined with diuretics to reduce pulmonary edema, which primarily improves symptoms, but the prognosis of patients with ARDS is still very poor. Mesenchymal stem cells (MSCs) are stromal cells that possess the capacity to self-renew and also exhibit multilineage differentiation. MSCs can be isolated from a variety of tissues, such as the umbilical cord, endometrial polyps, menstrual blood, bone marrow, and adipose tissues. Studies have confirmed the critical healing and immunomodulatory properties of MSCs in the treatment of a variety of diseases.Recently, the potential of stem cells in treating ARDS has been explored via basic research and clinical trials. The efficacy of MSCs has been shown in a variety of in vivo models of ARDS, reducing bacterial pneumonia and ischemia-reperfusion injury while promoting the repair of ventilator-induced lung injury. This article reviews the current basic research findings and clinical applications of MSCs in the treatment of ARDS in order to emphasize the clinical prospects of MSCs.

Key Words: Acute respiratory distress syndrome; Mesenchymal stem cells; Pulmonary edema; Inflammatory response; Tissue repair; Pulmonary fibrosis

INTRODUCTION

Acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a clinicopathological condition characterized by increased lung fluid, decreased lung compliance, and severe hypoxemia[1,2]. ARDS was defined in 1994 by the American-European Consensus Conference[3]. After several decades of research and discussions,the current internationally recognized definition of ARDS is the Berlin definition which proposes three categories of ARDS based on the severity of hypoxemia: Mild [200 mmHg ＜ arterial oxygen pressure(PaO2)/fraction of inspired oxygen (FiO2) ＜ 300 mmHg], moderate (100 mmHg ＜ PaO2/FiO2＜ 200 mmHg), and severe (PaO2/FiO2＜ 100 mmHg), along with explicit criteria related to the timing of the syndrome’s onset, the origin of edema, and chest radiograph findings[4-6]. The pathogenesis of ARDS is characterized by an unregulated inflammatory cascade with increased pulmonary endothelial and epithelial permeability[7]. Endogenous chemicals and microbial products linked to cell injury are hypothesized to attach to receptors on epithelial cells and alveolar macrophages, triggering an immunological response. The unrestricted synthesis of reactive oxygen species, leukocyte proteases, chemokines,and inflammatory substances that results to gradual lung damage. The immune-mediated reaction is known as a "cytokine storm"[8,9]. The pathophysiological changes that occur during the development of ARDS are shown in Figure 1. Currently, the clinical treatment of ARDS is rather limited and is mainly based on organ function support, such as lung protective ventilation, liver and kidney function protection, gastrointestinal function protection, venous thrombosis prevention, and nutritional support[10]. Despite the profound understanding of the molecular mechanism of ARDS, improvement of pulmonary ventilation strategies, and strengthening of supportive care for critically ill patients, the prognosis of patients with ARDS is still unsatisfactory. Currently, the global mortality rate of ARDS exceeds 40%, whilst 6%-10% of patients with respiratory failure may develop ARDS in the emergency room[11]. The long-term sequelae of ARDS include long-term cognitive impairment, psychological disease, neuromuscular weakness, pulmonary dysfunction, and decline in quality of life because of long-term medical expenses[12]. Therefore, new and safer therapies are urgently needed for ARDS treatment.

Figure 1 Following acute lung injury, pulmonary vascular macrophages produce chemokines to increase vascular permeability, resulting in neutrophil aggregation.

Mesenchymal stem cells

Mesenchymal stem cells (MSCs) were first described by Friedensteinet al[13], as an adherent, fibroblastlike cell population in the bone marrow (BM) that could regenerate rudiments of bonein vivo[13,14].After decades of research, it has been found that MSCs are present in a variety of tissues and organs and can also differentiate into a variety of cells to play related roles (Figure 2)[15,16]. However, the understanding of MSCs is still inadequate. MSCs were officially defined by the International Society of Cell Therapy in 2006 as follows: (1) MSCs must display plastic-adherent capacities; (2) A simultaneous expression of stromal markers, an absence of hematopoietic or endothelial markers and human leukocyte antigen-DR surface molecules; and (3) Anin vitrodifferentiation potential for osteoblasts,adipocytes, and chondroblasts[17,18]. The method of obtaining and culturing MSCs is simpler than other stem cells, and MSCs have broad application prospects in a variety of inflammatory-related diseases because of their unique immunomodulatory properties[19].

Figure 2 Mesenchymal stem cells can be derived from a variety of cell types and can differentiate into different types of cells to play specific roles.

MSCs are considered a new approach for the treatment of ADRS[20]. The mechanism of MSCs in the treatment of ARDS is multifaceted, and the immunomodulatory effect of MSCs is a crucial aspect of it(Figure 3). At present, the collective view of the immune regulation ability of MSCs is based on the secretion of cytokines, such as tumor growth factor (TGF)-B and tumor necrosis factor-stimulated gene-6[21]. By releasing a variety of cytokines and extracellular vesicles (EVs), MSCs play anti-inflammatory and anti-cell death roles and promote the generation of microcirculation, thereby promoting the clearance of bacteria and alveolar fluid, alleviating organ damage, thus alleviating ARDS-related symptoms[22-24].

Figure 3 The main mechanism of mesenchymal stem cell therapy for acute respiratory distress syndrome.

CURRENT BASIC RESEARCH FOR THE USE OF MSCS IN ARDS TREATMENT

Immunoregulation ability of MSCs in ARDS

The hallmark of ARDS is a series of inflammatory responses. Uncontrollable inflammatory responses are known to cause catastrophic damage to various organs[25]. MSCs are pluripotent stem cells with immune properties that can secrete a variety of cytokines, such as anti-inflammatory factors, antiapoptotic factors, and antimicrobial peptides[26-28]. MSCs regulate immune activityviathree different mechanisms: (1) Direct contact with tissue cells; (2) Production of a series of cytokines to regulate cell activities; and (3) Exerting immune effects by regulating the activity of T cells[29-31]. Currently, the MSC treatment of ARDS is mediated by controlling inflammatory responses. Therefore, the related mechanisms have become a hot research topic, and new research findings are constantly emerging,which introduce new views.

MSCs regulate the immune activity of the dendritic cells:Conventional dendritic cells (cDCs) are unique antigen-presenting cells that bridge antigen immunity and innate immunity and can be activated by MSCs as regulatory DCs[32,33]. An existing study has shown that after lung injury induced by lipopolysaccharide, a large number of DCs accumulate in the lungs, which in turn aggravates lung inflammation and lung injury[34]. The underlying mechanism may involve the polarization of the Thelper cell (Th) 1 response and regulating neutrophil infiltration[35,36]. The aggregation of cDCs can lead to the activation of the Th1 pathway and aggravate the inflammatory response. At the same time,cDCs can also recruit neutrophils, prolong the life of neutrophils, upregulate innate immunity, and further intensify the inflammatory response[37,38]. MSCs also abolish the capacity of mDCs to migrate to chemokine (C-C motif) ligand 19, for DCs to display major histocompatibility complex class II peptide complexes recognized by specific antibodies, and for ovalbumin-pulsed DCs to support antigen-specific CD4+ T-cell proliferation[39].

Additionally, many studies have shown that MSC-EVs play key roles in the pathogenesis and progression of acute lung injury (ALI)/ARDS[40]. One of the underlying mechanisms may involve the potential impairment of antigen uptake, which may halt DC maturation[41]. MSC-EVs from the human BM may regulate the levels of maturation and activation markers (CD83, CD38, and CD80) and inflammatory cytokines [interleukin (IL)-6, IL-12p70, and TGF-B]in vitro viaregulating theCCR7gene by carrying miR-21-5p[42]. Additionally, the emerging role of MSC-EVs in facilitating pulmonary epithelium repair, rescuing mitochondrial dysfunction, and restoring pulmonary vascular leakage has been shown[43,44]. Therefore, regulating the maturation of DC cells in the early stage of lung injury can effectively alleviate secondary lung injury[45] (Table 1).

Table 1 Recent studies on the mechanism of mesenchymal stem cell action in acute respiratory distress syndrome

MSCs induce the activation of macrophages:Alveolar macrophages are guardians of the alveoli and airways, and interstitial macrophages are guardians of blood vessels and the lung interstitium[46]. After lung injury, tissue monocyte-derived macrophages accumulate and have increased viability in the lungs, and persist at the lesion for a long time after lung injury[47]. Macrophages respond in a variety of ways, including modulation of function (activation), the release of inflammatory chemical mediators that control immune cell recruitment, and the modulation of epithelial responses[48]. Macrophages can be divided into two phenotypes based on their functions, the M1 type in resting states and the M2 type in the activated state[49]. M1-type macrophages can secrete a variety of cytokines and participate in many processes including pro-inflammatory, pro-apoptosis, free radical formation, and matrix degradation pathways, while M2-type macrophages play a role in anti-inflammatory and anti-cell deathprocesses during the inflammatory response, and promote angiogenesis and tissue repair[50-52]. The transformation of the M1/M2 phenotype helps subside the inflammatory response and alleviate tissue damage. In ARDS, this balance can effectively remove harmful substances and pro-inflammatory factors from the body and promote lung tissue repair. Conversely, the destruction of this balance aggravates the pathological development of ARDS. Studies have shown that MSCs can control the pathological development of ARDS by regulating the polarization of macrophages and effectively promoting the repair process in ARDS[53]. Basic studies have shown that MSC treatment reduces the expression of CD86 on macrophages in the ALI models, indicating that MSCs can inhibit the transformation of macrophages to the M1 phenotype[54]. Several mechanisms of MSCs have been described, such as: (1)MSCS can promote the phenotypic transformation of macrophages through paracrine secretion of soluble cytokines[55]; (2) MSCS promotes macrophage polarization through exosomes[51]; (3) Metabolic Reprogramming[56]; (4) MSCS regulate mitochondrial transfer[57]; and (5) Apoptotic and efferocytosis effects[58]. The involved signaling pathways are as follows: (1) The nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway[59]; (2) The Notch signaling pathway; (3) The Janus kinase-signal transducer and activator of transcription signaling pathway[60]; and (4) The nuclear factor-kappa B signaling pathway[61].

MSCs regulate the T-cell balance:Imbalances between regulatory T cells (Tregs) and IL-17-producing Th17 are a sign of the development of inflammatory response in ARDS[62,63]. The main function of Th17 cells is to promote inflammation, release inflammatory factors, and play an important role in autoimmune diseases. Fortunately, they are precisely regulated by regulatory cells[64]. However, Treg cells can release anti-inflammatory factors (IL-4 and IL-10), control the inflammatory reaction process,and induce tissue damage repair[65,66]. Previous studies have shown that Tregs transferred into ALI animals can reduce the level of alveolar pro-inflammatory cytokines and inhibit neutrophil apoptosis and fibroblast recruitment[67,68]. A recent study also showed that a proportion of Th17 cells and Tregs＞ 0.79 was an independent predictor of 28-d mortality in patients with ARDS[62]. Therefore,maintaining the balance of Tregs and Th17 cells is crucial for patients with ARDS.

Existing studies indicated that,in vitro, MSCs repress the Th17 molecular program through the programmed cell death protein 1 pathway, prevent the differentiation of naive CD4+ T cells into Th17 cells, inhibit the production of inflammatory cytokines by Th17 cells, and induce Treg phenotype[69-71]. A study has shown that TGF-B1, as the main paracrine cytokine of MSCs, can significantly regulate the transformation of T cells into Tregs, disturb the Th17/Treg balance, and significantly contribute to the control of inflammatory response in ARDS[72]. It is also reported that MSCs can prevent the initial differentiation of CD4+ T cells into Th17 cells, inhibit the generation of inflammation, and induce the generation of Tregsin vitro[73]. Several experiments have proved that controlling the level of Th17/Treg is the key to MSC-mediated control of the inflammatory response in ARDS. Therefore, it is extremely critical to find a method to regulate this balance, which may be the basis for a revolutionary breakthrough in the treatment of ARDS.

MSCs promote tissue repair

Lung epithelial cell and endothelial cell damage and the exudation of highly concentrated protein fluid are the basic pathological changes in ARDS. Therefore, the treatment of ARDS requires a combination of a lung-protective ventilation strategy and fluid manipulation[74]. The immediate effect of these strategies is that MSCs can directly participate in the reconstruction of lung injury by migrating to the site of lung injury, but this aspect has less impact on ARDS injury repair[75]. Evidence shows that MSCs can be directly transformed into type II alveolar epithelial cells to support the role of injured cells[74].Meanwhile, cell-to-cell contact also provides a prerequisite for the control of inflammatory responses[76]. The formation and tissue damage of pulmonary edema is also related to the dysfunction of the pulmonary vascular system. The increased permeability of pulmonary capillaries leads to a series of serious consequences, such as the exudation of a variety of cells and cytokines and the formation of intravascular microthrombosis. Studies have shown that MSCs can also enhance the barrier system of the pulmonary vascular system, which is beneficial for promoting the repair of lung tissue[77].Hepatocyte growth factor, angiopoietin-1, and keratinocyte growth factor secreted by MSCs can improve vascular endothelial barrier function[78-82]. Genetic engineeringin situhas shown that MSCs could promote the potential of pulmonary angiogenesis[83]. Therefore, various results have shown that MSCs could inhibit pulmonary edema and also provide the basis for the regeneration of lung tissue.

Alleviation of pulmonary fibrosis

The cellular basis of the lung is composed of alveoli, various types of parenchymal cells, and BMderived cells[84]. The interaction between various cells is crucial for maintaining the basic functions of the lungs[85]. Although lung protective ventilation strategies have been applied in clinical practice,ARDS survivors still have related health problems, and some patients develop fibroproliferative responses characterized by fibroblast accumulation and deposition of collagen and other extracellular matrix components in the lungs[86]. After ALI, vascular permeability increases, plasma exudates, and protein fluid aggregates, leading to pulmonary edema. Inflammatory factors from the coagulation/anticoagulation system and inflammatory system enter the lungs and damage the alveolar-capillary membrane barrier[87]. In the early inflammatory phase of ARDS, various immune cells continuously release a variety of harmful substances, including reactive oxygen species and nitrogen, as well as proteolytic enzymes such as elastase and matrix metalloproteinases, leading to lung endothelial and epithelial cell damage[86,88]. Persistent damage and failure to quickly repair this damage are the main factors that induce a pathological fibroproliferative response[89]. Late in the inflammatory response,massive and persistent accumulation of macrophages, fibroblasts, fibroblasts, and myofibroblasts in the alveolar space results in excessive deposition of fibronectin, collagen types I and III, and other components of the extracellular matrix[90,91]. The pro-fibrotic/anti-fibrotic balance is disrupted, and the fibrogenic effect increases dramatically, leading to irreversible pulmonary fibrosis. MSCs have shown gratifying advantages in anti-fibrotic effects. In preclinical models of lung fibrosis produced by bleomycin, silica, paraquat, and radiation, MSCs obviously show the ability to prolong life time[92-95].However, MSC control of pulmonary fibrosis is also a double-edged sword. Studies have shown that MSCS can differentiate into ATII cellsin vitro, inhibit the production of degradation enzymes, and thereby inhibit the secretion of pro-fibrotic factors by various immune cells[96]. There is also evidence that abnormally activated Wnt/B-catenin and TGF-B signaling pathways can induce the differentiation of pulmonary intrinsic MSCs into myofibroblasts and promote the development of pulmonary fibrosis[97].

CLINICAL EXPERIENCE USING MSCS FOR ARDS

To date, experience with the application of MSCs in patients is limited. The data of the available clinical evidence is summarized in Table 2. Wilson and his colleagues reported the results of the phase I stem cell research for ARDS treatment (START) in 2015[98]. Patients with moderate to severe ARDS received a single intravenous dose of low [1 × 106MSCs/kg predicted body weight (PBW)], medium (5 × 106MSCs/kg PBW), or high (1 × 107MSCs/kg PBW) (n= 3/dose). All patients tolerated MSC infusion without prespecified infusion-related adverse events. High-dose MSCs improved daily SOFA scores compared with low-dose MSCs. Based on these promising results, the knowledge of the safety of administering MSCs to critically ill patients with ARDS is improving. A phase 2a clinical trial to evaluate the safety of BM-MSCs administered to patients with moderate to severe ARDS has also been conducted[99]. The primary outcome was safety, and secondary outcomes included respiratory,systemic, and serum biomarker endpoints. The study included 60 patients with ARDS, and intravenous Adipose-MSCs, 1 × 106/kg predicted body weight,vsthe placebo was administered; however, there wasno difference in the outcome in patients treated with Adipose-MSCsvsthe placebo. In another phase I study, nine consecutive patients were enrolled, between December 2017 and August 2019, the first three patients got low-dose human umbilical cord-derived MSCs, the following three patients received an intermediate dosage, and the last three patients received a high dose[100]. The results of the first phase of clinical trials demonstrated that a single dose of human umbilical cord-derived MSCs was safe and showed good results in all nine patients with ARDS. Swedish researchers tested the systemic administration of allogeneic BM-derived MSCs (2 × 106cells/kg) in two patients with severe refractory ARDS,both of whom recovered from multiple organ failure and showed reduced markers of systemic and pulmonary inflammation[101]. In summary, clinical studies report that MSC administration is safe for patients with ARDS, with few adverse reactions. However, due to the relatively small number of patients in these studies, further research is needed to test the curative effect.

Table 2 Clinical study characteristics

MSCS FOR CORONAVIRUS DISEASE 2019-INDUCED ARDS

Coronavirus disease 2019 (COVID-19) is an infectious disease responsible for the COVID-19 pandemic,caused by a novel coronavirus called severe acute respiratory syndrome-coronavirus 2[102,103].COVID-19 has various respiratory and non-respiratory clinical manifestations, including mild or severe influenza-like syndrome, pneumonia, or respiratory failure, which may eventually lead to sepsis with multiple organ failure. The most common reason for being admitted to intensive care units is a respiratory failure caused by ARDS[104,105]. In a case series, Hashemianet al[106] found that multiple infusions of high-dose allogeneic prenatal MSCs are safe and can relieve the respiratory distress of severe patients with COVID-19 and inhibit the inflammatory response[106]. 24 participants were randomly assigned to either the umbilical cord-derived mesenchymal stem cell (UC-MSC) therapy or the control group in a double-blind, phase ½a randomized controlled trial. The UC-MSC treatment group got two intravenous infusions of 100 ± 20 × 106UC-MSCs, while the control group received two infusions of vehicle solution[107]. The primary endpoint was safety (adverse events) after 6 h; cardiac arrest or death within 24 h post-infusion) and secondary endpoints included patient survival at 31 d after the first infusion and time to recovery. Serious adverse events related to UC-MSC infusion were not observed. Thus, UC-MSC is safe to inject into patients with COVID-19-induced ARDS. In subjects who received UC-MSC treatment, inflammatory cytokines decreased significantly on the sixth day. In a recent clinical research, 40 COVID-19 patients who were critically unwell got either saline or intravenous UC-MSCs[108]. The findings revealed that the survival rate of patients in the UC-MSCs group was 2.5 times greater than that of the control group. Among patients with complications, the UCMSCs group had a fourfold greater survival rate than the control group. A multicenter, double-blind,randomized, placebo-controlled trial (STROMA-CoV-2) in France, with 45 enrolled patients, has also been conducted[109]. Patients were randomly assigned to receive three intravenous infusions of 1 × 106UC-MSCs/kg or placebo (0.9% NaCl) over 5 d after recruitment. PaO2/FiO2changes between D0 and D7 did not differ significantly between the UC-MSCs and placebo groups. Six (28.6%) of the 21 UC-MSCs patients and six (25%) of the 24 (25%) placebo patients had serious adverse events not related to UCMSCs treatment. A phase I/II clinical study was also done in patients with severe COVID-19 to assess the safety and effectiveness of three intravenous infusions of BM-derived MSCs at 3-d intervals[110].Eight intensive care unit patients requiring supplemental oxygen were treated with BM-MSCs. Survival was significantly higher in the MSC group at 28 and 60 d, but there was no significant difference in the number of invasive ventilation-free days, high flow nasal oxygenation-free days, oxygen support-free days, or intensive care unit-free days. MSC infusion was well tolerated, and no adverse effects associated with MSC infusion were reported. Furthermore, a single-center, open-label, phase 1 clinical trial enrolled 20 confirmed COVID-19 patients with mild-to-moderate degree ARDS, who were divided into two groups: The control and the intervention group (UC-MSCs)[111]. The patients received three intravenous infusions of UC-MSCs (1 × 106cells/kg BW per injection) every other day. There were no adverse effects to cell infusion throughout the clinical study, oxygenation was greatly enhanced, antiinflammatory factor levels were significantly increased, and pro-inflammatory factor levels were dramatically lowered. This intervention may reduce cytokine storms and restore respiratory function.

To summarize, MSCs from different tissues, such as BM, adipose, UC, and placental tissues, have entered the clinical trial stage. Some studies have used MSCs to treat COVID-19-induced ARDS.

PROSPECT

With the progress of scientific research, our understanding of the physiological and pathological processes of ARDS has gradually deepened, and the relevant treatment methods are also improving year by year. However, the final prognosis of patients has not improved much; therefore, it is particularly important to find a method to treat ARDS. MSCs have a variety of characteristics that are striking.At present, as a potential therapeutic method, MSCs have gradually entered the international arena of research and have been unanimously recognized by scientists worldwide. Their application has achieved some effect in improving the survival rate of patients with ARDS. However, because of various reasons, only a few clinical trials are conducted. Although the achievements of basic research are emerging endlessly, there is a theoretical basis for MSC use to enter clinical treatment, and the side effects of MSCs are not clear. Moreover, their clinical application involves ethical issues. As a cell therapy, its safety needs a lot of control experiments to be proven. This has hindered the successful application of MSCs. Fortunately, the basic experimental research on their mechanism of action is becoming more and more in-depth, and the application value of MSC therapy is also much clearer.Their successful application for the treatment of ARDS is expected to improve the quality of life of patients.

CONCLUSION

Due to the impasse that has been reached in the treatment of ARDS, MSC therapy has gained increasing attention. MSCs are known for their anti-inflammatory, differentiation, paracrine, and microvesicle transport abilities, which could perfectly target the pathological mechanisms of ARDS, providing a theoretical basis for treatment and precision treatment. Despite the current evaluation of MSC treatment of ARDS, further research is needed to observe the specific response to MSC treatment in the long term.

ACKNOWLEDGEMENTS

We thank the authors of the primary studies for their timely and helpful responses to our information requests.

FOOTNOTES

Author contributions:All the authors had full access to all the data of the article, who were responsible for data integrity and accuracy; Liu JQ and Liang TY drafted the manuscript; Tang SY, Zheng ZH and Shi K designed the tables and figures; Lu LH worked on supervision; All authors approved the final version of the manuscript.

Supported byThe Youth Fund project of the Natural Science Foundation of Zhejiang Province, No. LQ20H15010; and Zhejiang Traditional Chinese Medicine Science and Technology Planning Project, No. 2023ZL575.

Conflict-of-interest statement:All the authors report no relevant conflicts of interest for this article.

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Country/Territory of origin:China

ORCID number:Tian-Yu Liang 0000-0001-6772-9187; Kai Shi 0000-0002-2600-2966; Jing-Quan Liu 0000-0002-4956-7118.

S-Editor:Fan JR

L-Editor:A

P-Editor:Fan JR