Research Status of the Safety and Efficacy of Mesenchymal Stem Cells in the Treatment of COVID-19-Related Pneumonia: A Systematic Review and Meta-Analysis

Abstract

Mesenchymal stem cell (MSC) therapy is considered one of the most promising treatments in the context of the coronavirus disease 2019 (COVID-19) pandemic. However, the safety and effectiveness of MSCs in the treatment of COVID-19-associated pneumonia patients need to be systematically reviewed and analyzed. Two independent researchers searched for relevant studies published between October 2019 and April 2021 in the PubMed, Embase, Cochrane Library, WAN FANG, and CNKI databases. All relevant randomized controlled trials, clinically controlled studies, retrospective studies, case reports, letters (with valid data), and case series were included in this meta-analysis. A fixed-effects model and 95% confidence interval (CI) were used to analyze the results. A total of 22 studies involving 371 patients were included in the present study. Allogeneic MSCs from umbilical cord, adipose tissue, menstrual blood, placental tissue, Wharton's jelly, or unreported sources were administered in 247 participants. Combined results revealed that MSC therapy significantly reduced the incidence of adverse events [AEs; odds ratio (OR) = 0.43, 95% CI = 0.22–0.84, P = 0.01] and mortality (OR = 0.17, 95% CI = 0.06–0.49, P < 0.01), and the difference compared with control group was statistically significant. No serious MSC treatment-related AEs were reported. Lung function, radiographic outcomes, and inflammation- and immunity-related biomarker levels all showed improving trends. Therefore, MSC therapy is an effective and safe method for the treatment of COVID-19-associated pneumonia and shows advantages in reducing AEs and mortality. However, a standard and effective MSC treatment program must be developed.

Introduction

Coronavirus disease 2019 (COVID-19), an infectious disease caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been sweeping the globe. According to data reported by the World Health Organization, as of June 13, 2021, 175,333,154 confirmed cases of COVID-19 have been documented in countries, areas, or territories worldwide, resulting in 3,793,230 deaths, and 2,655,782 new cases and 72,528 new deaths were reported in the past week [1]. COVID-19 has been associated with an intensive care unit (ICU) admission rate of 5% among proven cases of infection [2] and a high mortality rate for critically ill patients [3]. These unsetting numbers have prompted an urgent need for treatments that can resolve serious cases and prevent fatal consequences [4].

Based on preclinical and clinical studies, mesenchymal stem cells (MSCs) can regulate inflammation and remodeling processes and correct alveolar-capillary dysfunction; thus, MSCs are considered as a potential treatment for COVID-19 [5,6]. MSCs are multipotent cells and can be obtained from a variety of tissues, preferably bone marrow, adipose tissue, placental tissue, umbilical cord, and dental pulp [7 –12].

Notably, a controlled study by Leng et al. [13] showed that seven patients in the MSC treatment group were cured or the symptoms were significantly improved after 14 days of angiotensin-converting enzyme 2 (ACE2)-negative MSC injection, and inflammation and immune function levels were also ameliorated without observed adverse effects. The outcomes of three patients in the control group included one death, one case of acute respiratory distress syndrome (ARDS), and one remained in a severely condition. Therefore, the authors believed that intravenous transplantation of MSCs was safe and effective for the treatment of patients with COVID-19 pneumonia, especially critically severe patients. Fortunately, the application of MSCs in the treatment of COVID-19 has been well studied not only in terms of symptomatic efficacy but also in inflammation, immunity, and molecular mechanisms [14,15].

Therefore, this article conducted a systematic review and meta-analysis of the currently available literature on MSC treatment of COVID-19 since COVID-19 was first reported in 2019 to analyze its safety and efficacy and investigate the potential value of MSC therapy in patients with COVID-19.

Methods

Literature search

The systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [16]. The literature was searched with no language restrictions by two independent researchers. Since COVID-19 was first reported in Wuhan, China, and subsequently confirmed [17,18], we searched for articles published between October 2019 and April 2021 in PubMed, Embase, Cochrane Library, WAN FANG, and CNKI databases. The terms used for the search were as follows: “novel coronavirus” OR “2019 coronavirus disease” OR “novel coronavirus disease 2019” OR “2019-nCoV” OR “COVID-19” OR “SARS CoV-2” OR “severe acute respiratory syndrome-coronavirus-2” and “stem cell.” Articles from the same authors or institutions were examined, and duplicate data sets were excluded. The number of articles included and excluded was shown in a flow chart (Fig. 1).

FIG. 1.

Flow chart. MSC, mesenchymal stem cell.

Eligibility criteria

We included randomized controlled trials (RCTs), clinically controlled trials (CCTs), retrospective studies, case reports, letters (with valid data), and case series evaluating the safety and/or efficacy of MSCs administered to adult patients diagnosed with COVID-19 pneumonia from any cause. Culture-expanded or minimally manipulated MSCs were included. Studies were excluded if they did not report original data (eg, reviews, editorials, letters, commentaries, opinions, guidelines, or errata).

Data extraction

The extracted data were as follows. Data in articles were extracted independently by two reviewers and verified by the third reviewer if a disagreement arose.

General data

General data are shown in Tables 1 –3 (author name, publication year, country, study design, number of cases, age, gender, and follow-up data are shown in Table 1; baseline disease severity, comorbidities, general conditions, and imaging outcomes are shown in Table 2; MSC sources, the gender and number of donors, surface markers, MSC dose per time, frequency, cell viability, and transplantation routes are shown in Table 3). Following established clinical guidelines for the diagnosis and treatment of COVID-19, disease severity was classified as mild, common, severe, or critical [19,20].

Table 1.

Study and Patient characteristics

Authors (year), country	Study design	Total, n, MSC; Ctrl	Mean age, years, MSC; Ctrl	Gender, n (male/female), MSC; Ctrl	Follow-up, days
Leng et al. (2020) [13], China	Phase 1, CCT	10 (7; 3)	57.0; 65.0	4/3; 0/3	14
Meng et al. (2020) [22], China	Phase 1, CCT	18 (9; 9)	45.1; 49.6	7/2; 4/5	28
Shu et al. (2020) [23], China	RCT	41 (12; 29)	61.0; 57.9	8/4; 16/13	28
Xu et al. (2021) [24], China	Phase 1, CCT	44 (26; 18)	58.3; 61.1	17/9; 13/5	30
Shi et al. (2021) [25], China	Phase 2, RCT	100 (65; 35)	60.7; 59.9	37/28; 19/16	28
Lanzoni et al. (2021) [26], United States	Phase 1/2a, RCT	24 (12; 12)	58.6; 58.8	5/7; 8/4	31
Häberle et al. (2021) [32], Germany	CCT	23 (5; 18)	59; 39	3/2; 13/5	NR
Sánchez-Guijo et al. (2020) [33], Spain	Case series	13	60.3	1/12	28
Guo et al. (2020) [34], China	Research letter	31	70 (median)	25/6	NR
Feng et al. (2020) [35], China	Case series	16	61.8	12/4	28
Chen et al. (2020) [36], China	Retrospective study, letter	25	70 (median)	20/5	NR
Hashemian et al. (2021) [10], Iran	Case series	11	53.8	8/3	60
Iglesias et al. (2021) [27], Mexico	Case series	5	52.6	4/1	21
Yilmaz et al. (2020) [37], Turkey	Case report	1	51	1/0	14
Zengin et al. (2020) [38], Turkey	Case report	1	72	1/0	60
Tang et al. (2020) [28], China	Case report	2	Case 1: 37 Case 2: 71	1/1	14
Zhang et al. (2020) [12], China	Case report	1	54	1/0	7
Peng et al. (2020) [29], China	Case report	1	66	0/1	11
Soler et al. (2020) [39], Spain	Letter	1	NR	NR	7
Zhu et al. (2020) [30], China	Case report	1	48	1/0	14
Liang et al. (2020) [31], China	Case report	1	65	0/1	18
Tao et al. (2020) [40], China	Case report	1	72	1/0	41

CCT, clinically controlled trial; Ctrl, control group; MSC, mesenchymal stem cell; RCT, randomized controlled trial; NR, not reported.

Table 2.

Baseline General, Imaging Outcomes, and Disease Severity

Authors	Baseline general, n	Imaging outcomes	Comorbidities, n, MSC; Ctrl	Disease severity, n, MSC; Ctrl
Leng et al. [13]	MSC; Ctrl: Fever: 7; 2, cough, weak, poor appetite: 7; 3, shortness of breath: 7; 3, SaO₂: 92%; 92%	NR	HT: 1; NR	Severe: 4; 0, critical: 3; 3
Meng et al. [22]	NR	NR	HT: 1; 1, DM: 1; 0, FLD: 1; 0, asthma: 0; 1	Moderate:5; 5, severe: 4; 4
Shu et al. [23]	MSC; Ctrl: Fever: 10; 26, cough: 8; 19, respiratory rate >24/min: 11; 20	MSC; Ctrl (chest CT): Number of lobes involved: 4 (4, 5); 4 (3.5, 5), GGO: 12 (100%); 29 (100%), linear opacities: 10 (83.33%); 26 (89.66%), consolidation: 11 (91.67%); 25 (86.21%), interlobular septal thickening: 10 (83.33%); 25 (86.21%), crazy-paving pattern: 7 (58.33%); 15 (51.72%), subpleural curvilinear line: 6 (50.00%); 10 (34.48%), bronchial wall thickening: 8 (66.67%); 19 (65.52%), lymph node enlargement: 5 (41.67%); 15 (51.72%), pleural effusion: 2 (16.67%); 3 (10.34%)	HT: 3; 6, DM: 3; 5	Severe: 12; 29
Xu et al. [24]	MSC; Ctrl: Fever: 13; 8, cough: 16; 10, expiratory dyspnea: 8; 8, sore throat: 2; 2, chest tightness: 6; 9	NR	NR	Severe: 16; 10, critical: 10; 8
Shi et al. [25]	NR	MSC; Ctrl (chest CT): Lesion proportion (%): total lesion volume (in cm³)/whole lung volume (in cm³): 26.31 (11.62–38.42); 27.98 (11.57–44.14), solid component lesion proportion (%): Solid component lesion volume (in cm³)/whole lung volume (in cm³): 2.59 (0.69–5.20); 2.52 (0.77–4.91)	HT: 17; 10, DM: 12; 5, CB: 2; 3, COPD: 2; 0	Severe: 65; 35
Lanzoni et al. [26]	MSC; Ctrl: PaO₂/FiO₂ ratio (mmHg): 126.75; 117.75	NR	HT: 7; 9, DM: 5; 6, obesity: 11; 5, cancer: 0; 1, HD: 1; 3	ARDS severity: Mild-to-moderate: 3; 3, moderate-to-severe: 9; 9
Häberle et al. [32]	All patients have severe dyspnea. MSC; Ctrl: ECMO: 4/5; 9/18, Temperature, °C: 37 (IQR 36.6–38.2); 39 (IQR 38–39.4), PaO₂/FiO₂ ratio (mmHg): 68 (IQR 58–84); 87 (IQR 68–92)	MSC; Ctrl: Murray lung injury score: 2.8 (IQR 2.0–3.6); 3.5 (IQR 3.3–4)	HT: 1; 13, HD: 0; 5, CAF: 0; 2, COPD: 0; 1, asthma: 0; 1, DM: 0; 2, smoker: 0; 3	Severe: 5; 18
Sánchez-Guijo et al. [33]	NR	NR	HT: 7, DM: 1, COPD: 2, hypothyroidism: 1, HBV: 1, smoker: 5	Critical: 13
Guo et al. [34]	MSC: Fever: 24 (77.4%), cough: 25 (80.6%), dyspnea: 17 (54.8%), chest congestion: 14 (45.2%), fatigue: 12 (38.7%), PaO₂/FiO₂ (mmHg): 242 (200–294)	MSC (chest CT): Bilateral pneumonia: 31 (100%), multiple mottling/GGO: 26 (83.9%)	HT: 13, COPD: 6, CAD: 5, DM: 5	Severe/critical: 23/8
Feng et al. [35]	MSC: The oxygenation index in severe patients (n = 8) and critically severe patients (n = 7) was 285.50 (197.50–469.00) mmHg and 177.14 (92.50–316.00) mmHg, respectively, with the mean oxygenation index in total 258.80 (92.50–469.00) mmHg	NR	HT: 8, DM: 6, CKD: 3, HBV:1, BA: 1, AD: 1, anemia: 1	Severe/critical: 9/7
Chen et al. [36]	NR	NR	NR	Severe: 25
Hashemian et al. [10]	MSC: Fever: 10 (91%), cough: 10 (91%), dyspnea: 10 (91%), respiratory rate (>30): 11 (100%). PaO₂/FiO₂ radio (IQR) 79.39% (35%)	MSC (chest CT): Lung involvement, which included variable degrees of mixed GGO, crazy paving pattern, or consolidations with peripheral subpleural dominancy, in addition to vascular dilation, traction bronchiectasis, and pleural effusion in some cases	HT: 3, DM: 4, CMP: 1, CLL: 1	Critical: 11
Iglesias et al. [27]	MSC: All patients showed varying degrees of fever, cough, dyspnea, shortness of breath, rapid heartbeat, and PaO₂/FiO₂ decreased to an average of about 73 mmHg	MSC: Chest CT of five patients all showed severe pneumonia	DM: 2, HT: 1, PAD: 1, morbid obesity: 3, hypothyroidism: 1, dyslipidemia: 1, pulmonary fibrosis: 1	Critical: 5
Yilmaz et al. [37]	MSC: Cough, myalgia, high fever (39.5°C), and diarrhea. The patient developed severe bilateral pneumonia, ARDS, and multiple organ failure	MSC (chest CT): The upper and lower lobes of both lungs were commonly held. The lesions seen in both lungs had GGO, and areas of consolidation were compatible with COVID-19 infection	No	Critical
Zengin et al. [38]	MSC: Fever, tonsillitis, aphthous stomatitis, shortness of breath	MSC (chest X-ray): Atelectatic areas in the middle and lower parts of the lungs, in addition to the earlier image of GGO and patchy infiltration	HT, DM and hyperlipidemia	Critical
Tang et al. [28]	MSC: Case 1: Fever. SaO₂: 92%; PaO₂: 66 mmHg, FiO₂: 100% Case 2: Dyspnea, cough, and shortness of breath. SaO₂: 98%, PaO₂: 99 mmHg, and FiO₂: 80%	MSC: Case 1: The chest X-ray indicated large, patchy, and high-density lesions in the bilateral lungs, and the costal diaphragm angle was not clear Case 2: The chest X-ray indicated patchy and high-density shadows in the lower lung fields and the left middle lung	Case 1: HT Case 2: NR	NR
Zhang et al. [12]	MSC: High fever, weakness, shortness of breath, and low oxygen saturation	MSC: CT clearly showed evidence of pneumonia and GGO in bilateral lungs	DM	Critical
Peng et al. [29]	MSC: On the fourth day after convalescent plasma treatment (treatment before MSC injection), the absorption of pulmonary exudative lesions was not obvious, the symptoms of dyspnea have not been significantly improved, and high-flow nasal cannula oxygen therapy were still required	MSC: Comparison of the two chest CT scans before MSC treatment, the pulmonary exudative lesions have no significant improvement	NR	Severe
Zhu et al. [30]	MSC: Fever, cough, sputum, dyspnea, poor appetite, poor mental state, and fatigue. SaO₂: 75%–80%	MSC: CT images showed GGO in both lungs	NR	Critical
Soler et al. [39]	MSC: General malaise, fever and weakness, cough attack, and anorexia, dyspnea. SaO₂: 92%	MSC: CT showed a new ground-glass peripheral bronchopulmonary image at the bottom of the left upper lobe, and the persistent presence of thickened surrounding tissues of the right lung parenchyma and blood vessels	No	NR
Liang et al. [31]	MSC: Severe pneumonia (mixed type), ARDS, multiorgan injury (liver, respiratory system, and blood), moderate anemia, electrolyte disturbance, immunosuppression, acute gastrointestinal bleeding, and other symptoms	MSC: X-ray examination showed GGO in right lung	DM, HT	Critical
Tao et al. [40]	MSC: Fever, chest tightness, asthma. PaO₂ 48.0 mmHg, PaCO₂ 51.0 mmHg, PaO₂/FiO₂ 69 mmHg	MSC: Chest CT showed pneumonia-like properties and enlarged lesions with patchy consolidation on both sides of lung	DM, HT	Critical

AD, Alzheimer's disease; ARDS, acute respiratory distress syndrome; BA, bronchial asthma; CAD, coronary artery disease; CAF, chronic atrial fibrillation; CB, chronic bronchitis; CKD, chronic kidney failure; CLL, chronic lymphocytic leukemia; CMP, cardiomyopathy; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; CT, computed tomography; DM, diabetes mellitus; ECMO, extracorporeal membrane oxygenation; FLD, fatty liver disease; GGO, ground-glass opacity; HBV, hepatitis B virus; HD, heart disease; HT, hypertension; IQR, interquartile range; PaCO₂, arterial blood partial pressure of CO₂; PAD, peripheral artery disease; PaO₂/FiO₂, arterial blood partial pressure of oxygen/fraction of inspiration O₂; SaO₂, oxygen saturation.

Table 3.

Characteristics of Mesenchymal Stem Cells and Intervention Methods

Authors	MSC source	Donor, n (gender)	Surface marker	MSC dose, per time	Viability, %	Frequency, n (%)	Transplantation route
Leng et al. [13]	NR	NR	Negative: CD19, CD34, CD14, CD45, HLA-DR Positive CD73, CD105, CD90	1 × 10⁶ cells/kg	NR	Once 7 (100)	IV
Meng et al. [22]	UC	NR	Negative: CD19, CD34, CD11b, CD45, HLA-DR Positive: CD73, CD105, CD90	3 × 10⁷ cells	NR	Three times 9 (100)	IV
Shu et al. [23]	UC	NR	Negative: CD34, CD45, CD14, CD11b, CD79α, CD19, HLA-DR Positive: CD73, CD105, CD90	2 × 10⁶ cells/kg	NR	Once 12 (100)	IV
Xu et al. [24]	MB	3 (female)	Negative: CD117, CD34, CD45, HLA-DR Positive: CD29, CD73, CD105, CD90	3 × 10⁷ cells	>90	Three times 26 (100)	IV
Shi et al. [25]	UC	NR	Negative: CD19, CD34, CD11b, CD45, HLA-DR Positive: CD73, CD105, CD90	4 × 10⁷ cells	88.4	Three times 65 (100)	IV
Lanzoni et al. [26]	UC	NR	CD90/CD105 > 95% CD34/CD45 < 5%	98.7 × 10⁶ cells	>80	Twice 12 (100)	IV
Häberle et al. [32]	NR	8 (NR)	NR	1 × 10⁶ cells/kg	>90	Twice 3 (60) Three times 2 (40)	IV
Sánchez-Guijo et al. [33]	AT	NR	NR	1 × 10⁶ cells/kg	NR	Once 2 (15.4) Twice 10 (76.9) Three times 1 (7.7)	IV
Guo et al. [34]	UC	NR	NR	1 × 10⁶ cells/kg	NR	Once 11 (35.5) Twice 9 (29.0) Three times 11 (35.5)	IV
Feng et al. [35]	UC	NR	NR	1 × 10⁸ cells	NR	Three times 15 (93.8) Four times 1 (6.2)	IV
Chen et al. [36]	NR	NR	NR	1 × 10⁶ cells/kg	NR	Once 7 (28.0) Twice 7 (28.0) Three times 11 (44.0)	IV
Hashemian et al. [10]	UC or PL	NR	Negative: CD31, CD45, CD34, CD11b, HLD-R Positive: CD29, CD105, CD90, CD73	200 × 10⁶ cells	92.7 (88.7–94.2)	Twice 1 (9.1) Three times 10 (90.9)	IV
Iglesias et al. [27]	UC	NR	Negative: CD45, CD34, HLA-DR Positive: CD44, CD105, CD90, CD73	1 × 10⁶ cells/kg	99.95	Once 5 (100)	IV
Yilmaz et al. [37]	WJ	NR	NR	NR	NR	Four times 1 (100)	The first three times: IV The fourth time: IV+intrathecal
Zengin et al. [38]	UC	NR	NR	1 × 10⁶ cells/kg	NR	Twice 1 (100)	Intratracheal+IV
Tang et al. [28]	MB	1 (female)	Negative: CD34, CD45, CD133, HLA-DR Positive: CD29, CD73, CD90, CD105, CD9, CD44, HLA-ABC	1 × 10⁶ cells/kg	90–95	Three times 2 (100)	IV
Zhang et al. [12]	WJ	NR	Negative: CD45, CD34 Positive: CD73, CD105, CD90	1 × 10⁶ cells/kg	>90	Once 1 (100)	IV
Peng et al. [29]	UC	NR	NR	1 × 10⁶ cells/kg	95.78	Three times 1 (100)	IV
Soler et al. [39]	NR	NR	NR	1 × 10⁶ cells/kg	NR	Once 1 (100)	IV
Zhu et al. [30]	UC	NR	NR	1 × 10⁶ cells/kg	NR	Once 1 (100)	IV
Liang et al. [31]	UC	NR	Negative: CD19, CD34, CD11b, CD45, HLA-DR Positive: CD73, CD105, CD90, CD44	5 × 10⁷ cells	>90	Three times 1 (100)	IV
Tao et al. [40]	WJ	NR	NR	1.5 × 10⁶ cells/kg	NR	Five times 1 (100)	IV

AT, adipose tissue; IV, intravenous; MB, menstrual blood; PL, placenta; UC, umbilical cord; WJ, Wharton's jelly.

Outcomes

The primary outcome was safety based on the number of patients with adverse events (AEs), frequency of AEs, serious AEs (SAEs), and MSC treatment-related AEs. Clinical outcomes included general clinical symptoms (fever, cough, dyspnea, respiratory rate, etc.), blood oxygen indexes [arterial partial pressure of oxygen (PaO₂), the fraction of inspired O₂ (FiO₂), PaO₂/FiO₂, arterial or peripheral oxygen saturation (SaO₂ or SpO₂, respectively), etc.], six- or seven-category scale scores, the time from intervention to recovery, and mortality. Radiographic outcomes included findings on lung computed tomography (CT) scans or chest X-ray imaging.

Laboratory outcomes included the time until nucleic acid became negative, immune cell levels [dendritic cells (DCs), lymphocytes (LYMs), natural killer cells (NK cells), T cells, B cells, neutrophils (NEs), and white blood cells (WBCs)], and inflammatory cytokines [alanine aminotransferase (ALT), ammonia, aspartate transaminase (AST), bilirubin, blood creatinine, B-type natriuretic peptide, blood urea nitrogen], creatine kinase (CK), CK-MB, C-reactive protein (CRP), cardiac troponin T, D-dimer, ferritin, fibrinogen, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ (INF-γ or IFN-γ), IFN-g, interleukin (IL)-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-18, IL-22, interferon-inducible protein-10 (IP-10), lactate, lactate dehydrogenase (LDH), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), myoglobin, procalcitonin, platelet-derived growth factor-BB (PDGF-BB), regulated upon activation normal T cell expressed and secreted factor (RANTES), tumor necrosis factor-α (TNF-α), TNF-β, triglyceride, and vascular endothelial growth factor.

Quality assessment

The methodological quality of each study included in the present meta-analysis was evaluated by the National Heart, Lung, and Blood Institute (NHLBI) quality assessment tools (Supplementary Table S1) [21]. All studies were classified as either good, fair, or poor.

Statistical analysis

Data are presented as n (%) for categorical variables and as the mean ± standard deviation for continuous variables. Mortality and the number of patients with AEs were the only two outcomes considered appropriate for a meta-analysis. The Review Manager v.5.3 software was used to merge in each study, and overall estimates of effects were shown in the form of forest plot. We used I ² indicator to evaluate heterogeneity between studies. Sensitivity analysis was performed by eliminating one included study at a time, and subgroup analysis was performed to examine the source of the heterogeneity when heterogeneity existed (I ² > 50%). A random-effects model was used if heterogeneity still existed. Otherwise, a fixed-effects model was used (I ² < 50%). The final selected model was used to summarize the odds ratios (ORs) of the included studies. We were unable to evaluate publication bias due to the small number of available studies.

Results

The literature search identified 1,582 unique citations. Abstract and full-text screening identified 22 studies with 371 patients to be included for the data extraction. All included studies were assessed as good [10,12,22 –31] or fair [13,32 –40] according to the NHLBI quality assessment tool (Supplementary Table S2).

Study characteristics

The 22 selected studies [10,12,13,22 –40] included 4 CCTs, 3 RCTs, 4 case series, 3 letters, and 8 case reports, 7 of which were comparative studies with control groups. All 22 studies reported mortality and laboratory outcomes (n = 371); 17 studies reported AEs and SAEs (n = 273); and 20 studies reported general clinical symptoms and imaging outcomes after MSC treatment (n = 324). A total of 247 patients received MSC therapy, while 124 patients participated as controls (Table 1).

Patient characteristics

The 22 studies were from 7 countries and regions, including China (n = 14) [12,13,22 –25,28 –31,34 –36,40], the United States (n = 1) [26], Germany (n = 1) [32], Spain (n = 2) [33,39], Iran (n = 1) [10], Mexico (n = 1) [27], and Turkey (n = 2) [37,38]. Eleven studies reported on baseline oxygenation indicators [10,13,26 –28,30,32,34,35,39,40]. General symptoms such as fever, cough, and dyspnea were reported in 16 studies [10,12,13,23,24,27 –32,34,37 –40], and lung imaging evaluation showed COVID-19-related pneumonia in 15 studies [10,12,23,25,27 –32,34,37 –40]. Disease severity was critical (n = 63), severe (n = 260), and moderate (n = 10) in 19 studies [10,12,13,22 –25,27,29 –38,40] and the patients in one study were divided into mild-to-moderate (n = 6) and moderate-to-severe (n = 18) groups according to the severity of ARDS [26].

The average ages of study participants were 45.1 to 61.0 years for the MSC group and 39.0 to 65.0 years for the control group in the comparative studies [13,22 –26,32]. In the comparative studies, disease severity in the MSC group was critical (n = 13), severe (n = 115), and moderate (n = 8), whereas that in the control group was critical (n = 11), severe (n = 105), and moderate (n = 8) [13,22 –26,32]. The most common comorbidities, including hypertension (n = 105), diabetes mellitus (n = 61), obesity (n = 19), chronic obstructive pulmonary disease (n = 11), and heart disease (n = 9), were reported in 18 studies [10,12,13,22,23,25 –28,30 –35,37,38,40]. Differences in the follow-up time after MSC treatment were also identified in these studies, with follow-up times ranging from 1 week to 2 months, which was mainly due to the times when patients recovered and were discharged from the hospital or when patients died (Tables 1 and 2).

Intervention method

Culture-expanded allogeneic MSCs were used in all 22 included studies. Allogeneic umbilical cord-derived MSCs were used in 12 studies [22,23,25,26,27,29 –31,34,35,38,39], Wharton's jelly-derived MSCs in 3 studies [12,37,40], menstrual blood-derived MSCs were used in 2 studies [24,28], and adipose tissue- or placenta-derived MSCs were separately used in 1 study [10,33]. Four studies did not report the tissue origin of the MSCs [13,32,36,39] (Table 3). Characterization was reported in most studies, with significant differences in details. Characterization of MSCs was reported in 11 studies, including most of the following markers: positivity for CD9, CD29, CD44, CD73, CD90, CD105, and HLA-ABC, and negativity for CD11b, CD14, CD19, CD31, CD34, CD45, CD79α, CD133, and HLA-DR [10,12,13,22 –28,31]. Viability was reported to be >80% [10,12,24 –29,31,32].

MSCs were mainly injected intravenously (n = 245), and two other patients were injected intratracheally and intravenously [37,38]. MSC infusion frequencies ranged from a single infusion to five infusions (n = 47, 43, 154, 2, 1). MSC dosing ranged from 1 to 2 million cells per kilogram of body weight, or a uniform dose of 30 to 200 million cells was administered. Only one study did not report the dose [37].

Safety

Adverse events

We extracted data from 16 studies on the number of AEs and the number of patients with AEs to describe the occurrence of AEs (Table 4) [10,12,13,22,24 –26,27,29 –31,33,36 –39]. In the MSC group, 48.33% (87/180) of patients have appeared AEs, and the total number of AEs was 167. Additionally, according to research by Feng et al., hypoalbuminemia, insomnia, gastrointestinal diseases, and paroxysmal arrhythmia occurred in the surviving patients [35].

Table 4.

Adverse Events and Mortality

Authors	Number of patients with AEs, n (%), MSC; Ctrl	Number of AEs, n, MSC; Ctrl	Number of SAEs, n, MSC; Ctrl	Number of AEs treatment-related, n, MSC; Ctrl	Mortality, n (%), MSC; Ctrl
Leng et al. [13]	0; 2 (33.3)	0; 2	0; 2	No; NR	0; 1 (33.3)
Meng et al. [22]	4 (44.44); 9 (100)	5; 9	0	3; NR	0; 0
Shu et al. [23]	NR	NR	0; 3	NR	0; 3 (10.3)
Xu et al. [24]	20 (76.92); 18 (100)	56; 59	10; 15	NR	2 (7.7); 6 (33.3)
Shi et al. [25]	37 (56.92); 21 (60.00)	37; 21	1; 0	NR	0; 0
Lanzoni et al. [26]	8 (66.7); 11 (91.7)	35; 53	4; 19	Possible 1; 1	2 (16.7); 7 (58.3)
Häberle et al. [32]	NR	NR	1; 10	NR	1 (20); 10 (55.6)
Sánchez-Guijo et al. [33]	2 (15.38); —	2; —	2; —	0; —	2 (15.4); —
Guo et al. [34]	NR; —	NR; —	4; —	0; —	4 (12.9); —
Feng et al. [35]	Hypoalbuminemia, insomnia, gastrointestinal diseases, and paroxysmal arrhythmia have occurred in the surviving patients	NR; —	2; —	0; —	2 (12.5); —
Chen et al. [36]	3; —	3; —	NR; —	3; —	0; —
Hashemian et al. [10]	7; —	7; —	5; —	2; —	5 (45.5); —
Iglesias et al. [27]	5; —	17; —	2; —	6; —	2 (40); —
Yilmaz et al. [37]	1; —	1; —	1; —	0; —	0; —
Zengin et al. [38]	0; —	0; —	0; —	0; —	0; —
Tang et al. [28]	NR; —	NR; —	NR; —	NR; —	0; —
Zhang et al. [12]	0; —	0; —	0; —	0; —	0; —
Peng et al. [29]	0; —	0; —	0; —	0; —	0; —
Soler et al. [39]	0; —	0; —	0; —	0; —	0; —
Zhu et al. [30]	0; —	0; —	0; —	0; —	0; —
Liang et al. [31]	0; —	0; —	0; —	0; —	0; —
Tao et al. [40]	NR; —	NR; —	NR; —	0; —	1; —

AEs, adverse events; SAEs, serious adverse events.

Notably, 15 treatment-related AEs were reported in 5 studies. Meng et al. reported that two patients receiving MSCs developed transient facial flushing and fever immediately upon infusion, which resolved spontaneously within 4 h; another moderately ill patient developed transient fever within 2 h that resolved within 24 h [22]. Chen et al. reported that three patients experienced treatment-related AEs, specifically liver dysfunction, heart failure, and allergic rash [36]. Hashemian et al. reported that two patients developed shivering during the initial MSC infusion, which was relieved by supportive treatment in <1 h [10]. Iglesias et al. reported that one patient had muscle contractions in the extremities; another patient had muscle contractions in the extremities and chest, PO₂ decreased to 78%, arterial hypertension, and compromised respiratory effort; and the third patient developed hypotension [27]. In the study of Lanzoni et al., a treatment-related AE was reported without specific description [26].

AE incidence rates between MSC group and control group were compared in five studies (n = 196) [13,22,24 –26]. The overall AE incidence rates were 58.0% (69/119) for MSC-treated patients and 77.9% (60 of 77) for controls, and the difference was statistically significant [OR = 0.43, 95% confidence interval (CI) = 0.22–0.84, P = 0.01] (Fig. 2).

FIG. 2.

Pooled estimate for the number of adverse events. Ctrl, control.

Serious AEs

In our data extraction process, the number of deaths was included in the number of SAEs if the study did not describe SAEs in detail and only reported mortality. The results showed that 32 SAEs occurred in 219 MSC-treated patients in 19 studies (Table 4) [10,12,13,22 –27,29 –35,37 –39]. No MSC treatment-related SAEs were reported.

The 10 SAEs reported in Xu et al.'s study included severe liver dysfunction (n = 1), expiratory dyspnea (n = 1), respiratory failure (n = 1), ARDS (n = 1), shock (n = 3), multifunctional organ failure (n = 2), and gastrointestinal bleeding (n = 1) [24]. Shi et al. reported one case of pneumothorax in the MSC group, and the patient recovered naturally after conservative treatment [25]. Lanzoni et al. reported four SAEs without detailed descriptions [26]. Häberle et al. reported a case of death due to multiple organ failure [32]. Sánchez-Guijo et al. reported that two patients died: one patient died from massive gastrointestinal bleeding, and the other patient died of secondary fungal pneumonia caused by Saccharomyces spp. [33]. Guo et al. reported four patients died without detailed descriptions [34]. Two SAEs occurred during the trial reported by Feng et al. [35]. The two patients suffered from bacterial pneumonia and septic shock and died of multiple organ failure or circulation and respiratory failure, respectively. Hashemian et al. reported the deaths of four patients due to multiple organ failure, and one patient died due to cardiac arrest [10]. Iglesias et al. reported that a patient developed left lower extremity arterial thrombosis, hemodynamic deterioration, D-dimer concentration of 7,268 ng/mL, and death; Enterobacter cloacae were cultured in aspirated samples from the patient's trachea. Another patient developed hemodynamic alterations, epistaxis, and hematuria, and died 13 days after MSC infusion [27]. In the case report of Yilmaz et al., a patient was diagnosed with upper gastrointestinal bleeding, but the patient's vital signs were stable after effective treatment [37]. Among the 7 controlled studies, 136 patients in the MSC group had 16 SAEs, while 124 patients in the control group had 49 SAEs [13,22 –26,32].

Efficacy

Mortality

Mortality was reported in all included studies (Table 4), and the overall mortality rate was 12.94% (48/371). The mortality rate among MSC-treated patients was 8.50% (21/247). Comparisons between the MSC group and the control group were made in seven studies (n = 260), and there was a trend toward a decreased mortality rate noted in the MSC group in all seven studies [13,22 –26,32]. The overall mortality rates were 3.68% (5/137) for MSC-treated patients and 21.77% (27/124) for controls. There was a favorable trend observed, and the difference was statistically significant (OR = 0.17, 95% CI = 0.06–0.49, P < 0.01). However, the certainty of the evidence for the impact on mortality was limited due to differences in the baseline conditions of the included patients and the imprecision and methodological limitations of the included trials (Fig. 3 and Tables 1 and 2).

FIG. 3.

Pooled estimate for mortality. (A) Forest plots of mortality. (B) Funnel plot of mortality.

Changes in general clinical symptoms and lung function

The results showed that the average time from the first injection to recovery or discharge from the hospital ranged from ∼2 to 24 days for MSC-treated patients (Table 5) [10,12,13,22 –24,26,27,29 –31,33,39,40]. In several controlled studies, Shu et al., Xu et al., and Lanzoni et al. reported that the average time required to improve (or recover) in the MSC group was shorter than that in the control group, and the difference was statistically significant [23,24,26]. However, Meng et al. reported that the time from admission to discharge was similar between the two groups [22]; and Xu et al. reported no significant difference in either the length of hospital stay or the number of days in the ICU between the two groups [24].

Table 5.

Clinical Symptoms and Imaging Outcomes

Authors	The time from intervention to recovery	General clinical symptoms	Imaging outcomes
Leng et al. [13]	NR	MSC: Day 4, the respiratory rate was decreased to the normal range, fever and shortness of breath disappeared, and SaO₂ rose from 89% to 98% Ctrl: NR	MSC: Day 9, the GGO and pneumonia infiltration were largely reduced Ctrl: NR
Meng et al. [22]	The interval between admission and discharge: MSC vs. Ctrl: 20.00 (17.50–24.50) days vs. 23.00 (20.00–27.00) days	MSC: In most severe patients, the PaO₂/FiO₂ ratio improved	MSC: CT scans indicated that patients showed absorption of pulmonary pathological changes. The severe patient 9 showed that the lung lesions were well controlled within 6 days, and completely faded away within 2 weeks Ctrl: The lung lesions of the severe patient 7 still existed at discharge
Shu et al. [23]	The time to clinical improvement in the MSC group was shorter than that in the Ctrl group: 9.0 (6.0–13.0) days vs. 14.0 (9.5–21.0) days, P < 0.01	The oxygenation index of MSC group recovered to the normal range faster than Ctrl group MSC vs. Ctrl Clinical improvement, n (%): Day 3: 2 (16.67) vs. 1 (3.45). Day 7: 7 (58.33) vs. 5 (17.24), P < 0.05. Day 14: 11 (91.67) vs. 15 (51.72), P < 0.05. Day 28: 12 (100) vs. 25 (86.21), hospital stay: median (IQR): 20.00 (16.00–24.00) days; 24.00 (20.00–26.50) days Seven-category scale (scale 1–7): Day 7: 0/1/7/3/1/0/0 vs. 0/0/3/19/5/2/0. Day 14: 0/5/6/1/0/0/0 vs. 0/5/17/1/2/1/3	Two weeks: Chest CT indicated that CT scores, the number of lobes involved, GGO, and consolidation, which reflected reduced lung inflammation in the MSC group, were significantly better than those in the Ctrl group MSC vs. Ctrl CT score: 8.50 (7.25–9.00) vs. 10.00 (8.50–12.50); P < 0.05, number of lobes involved: 2 (2, 2) vs. 3 (2, 3); P < 0.01, GGO: 4 (33.33%) vs. 19 (70.37%); P < 0.05, consolidation: 4 (33.33%) vs. 20 (74.07%); P < 0.05
Xu et al. [24]	The average time to improvement: MSC vs. Ctrl: (3.00 ± 3.05) days vs. (8.80 ± 10.77) days, P < 0.05 There was no significant difference in either the length of hospital stay or in the number of days in the ICU between the two groups	MSC: There were no significant differences in FiO₂ and SaO₂ before and after MSC infusion, but SpO₂ (from 94.72% ± 3.4% to 96.04% ± 5.93%) and PaO₂ (from 78.89 ± 25.86 mmHg to 95.62 ± 39.49 mmHg) were significantly improved	One month: The relative improvement rate was higher for the MSC group than it was for the Ctrl group. MSC vs. Ctrl: 85.0% (17/20) vs. 50% (6/12)
Häberle et al. [32]	NR	At discharge, the MSC-treated patients showed a significantly lower Murray score of 0.3 + 0.1 than the Ctrl patients, who presented an average score of 1.3 + 1.1	NR
Lanzoni et al. [26]	Time to recovery was significantly shorter in the MSC group than in the Ctrl group (P < 0.05). The hazard ratio for recovery comparing the Ctrl group with the MSC group was 0.29 (95% CI: 0.09 to 0.95)	NR	NR
Shi et al. [25]	NR	MSC: Day 1, the cough showed a significant improvement compared with the Ctrl group, but no difference was found at other time points. Days 1, 3, and 5, the expiratory dyspnea showed a significant improvement compared with the Ctrl group, but no difference was found at days 7, 14, and 30 MSC vs. Ctrl Six-category scale (scale 1–6): Day 10, 11/8/44/2/0/0; 6/6/23/0/0/0, 6-MWT: Day 28, median (IQR): 420.00 (392.00–465.00) months vs. 403.00 (352.00–447.00) months, mMRC dyspnea score (grade 0–4): 29/24/5/3/0 vs. 13/16/4/1/1, SaO₂: 97.10% vs. 96.97%	MSC vs. Ctrl Day 28: The change of total lesion proportion of the whole lung volume (median, 95% CI, %): −19.4 (−53.40 to −2.62) vs. −7.30 (−46.59 to 19.12), the change of solid component lesions (median, 95% CI, %): −57.70 (−74.95 to −36.56) vs. −44.45 (−62.24 to −8.82); P < 0.05, The change of GGO (%): −14.95 (−51.55 to 7.29) vs. −3.94 (−43.99 to 32.55)
Sánchez-Guijo et al. [33]	MSC: After a median follow-up of 16 days (IQR 9 days) after the first dose of MSCs, 9 (70%) patients had improved clinically and 7 (53%) were extubated with a median time from the first MSC dose to extubation of 7 days (IQR 14 days)	NR	MSC: Radiological improvement in sequential X-rays was confirmed in 4 patients
Guo et al. [34]	NR	MSC: PaO₂/FiO₂: Increased from 242 (200–294) mmHg to 332 (288–364) mmHg, P < 0.01	NR
Feng et al. [35]	NR	MSC: The oxygenation index increased into 329.00 (197.70–604.00) mmHg and 316.84 (93.30–531.00) mmHg in severe patients (n = 9) and critically severe patients (n = 6) with the oxygenation index in total 325.70 (93.30–604.00) mmHg on day 7. The oxygenation index was 356.95 (107.50–452.40) mmHg and 453.79 (306.00–552.30) mmHg in severe patients (n = 4) and critically severe patients (n = 4) with the oxygenation index in total 394.79 (107.50–552.30) mmHg on day 14	MSC: The radiological presentations (GGO) all showed improvement compared with baseline
Chen et al. [36]	NR	MSC: All cases gained clinical improvement	MSC: After MSC therapy, 16 cases (64%) gained CT scan improvement
Hashemian et al. [10]	MSC: Five patients significantly improved and were discharged from the ICU, 2 to 7 days after the infusions	MSC: The results of the survivors showed that the median time to relief after the first infusion was 2.5 days for fever, 3 days for respiratory rate (≤24/min), and 2 days for cough (mild or absent). Most patients described significant relief of their dyspnea and there was a decrease in respiratory rate within 48–96 h after the first cell infusion. The saturation of pulse oxygen significantly improved in survivors (9.2 [3.7–14.6] %) compared with nonsurvivors (6.6 [5.01–11.0] %)	MSC: The lung CT was available after therapy in three survived cases. The lung CT scans of two patients showed significant resolution of opacities and the subpleural bands after completion of MSC therapy
Iglesias et al. [27]	MSC: Patient 1: Discharged from the ICU on day 10 and discharged from the hospital 2 weeks later. Patient 2: Discharged from the ICU on day 12 and discharged from the hospital 4 days later. Patient 3: Discharged from the hospital on day 21. Patients 4 and 5 died	MSC: The PaO₂/FiO₂ value improved immediately after injection of MSCs, and gradually increased in the next 7 days	MSC: Chest CT showed that the proportion of damaged lung parenchyma in the three surviving patients was significantly reduced following MSC treatment, while that in the two patients who died did not decrease but increased
Yilmaz et al. [37]	NR	MSC: After the first two times of MSC injection, the patient was awakened and extubated. The patient's vital signs were improved, especially after intrathecal and systemic MSC transplantation. After the patient had been extubated, his neurological symptoms regressed, consciousness restored, and he could speak. After system transplantation of MSCs, the ejection fraction increased from 25% during cardiac arrest to 60%. After four times of MSC transplantation, the patient's heart functions have returned to normal	MSC: After the last time of MSC transplantation, bilateral lung symptoms regressed on control thorax CT
Tang et al. [28]	NR	MSC: Case 1: Day 5: The symptoms of fever and dyspnea improved. SaO₂: 97%, PaO₂: 86 mmHg, FiO₂: 55% Case 2: Day 7: SaO₂: 99%, PaO₂: 169 mmHg, and FiO₂: 30%	MSC: Case 1: The X-ray on day 1 and 5 showed the absorption of the exudate lesions in the bilateral lungs Case 2: The chest X-ray showed the absorption of high-density exudate in the lower lung fields and left middle lung
Zhang et al. [12]	MSC: After 1 week of MSC treatment, the patient felt better and was discharged after another day	MSC: Day 2, fever and shortness of breath disappeared. All the symptoms disappeared, and the SaO₂ rose to 98% at rest after transplantation 2–7 days	MSC: Day 6, chest CT imaging showed that the GGO and pneumonia infiltration had largely reduced
Zengin et al. [38]	NR	MSC: Following MSC transplantation, the need for inotropic agents started to disappear, hypoxemia, acidosis, and electrolyte imbalance started to improve. Day 10, the patient was extubated and continued to be monitored in the ward, initially receiving nasal oxygen, which was later discontinued. Two months, the patient had normal clinical and laboratory signs and no adverse effects due to the procedure were identified	MSC: Day 7, lung chest X-ray showed slight regression in the GGO imaged infiltration in the middle right lung periphery and significant regression in the low-density infiltrations in the lower right lung and lateral left lung
Peng et al. [29]	MSC: Day 11, the patient recovered and discharged	MSC: The symptoms of dyspnea and dry cough improved significantly, and the endurance of daily activities improved. Oxygenation index and PaO₂ gradually increased	MSC: Day 5, the chest CT showed the bilateral infiltration was absorbed obviously
Soler et al. [39]	MSC: Day 6, the patient was discharged from the hospital	MSC: Day 4, the lung function test was completely normal. Day 5, the clinical symptoms related to the coronavirus had disappeared, but the loss of appetite and fatigue were maintained	MSC: Day 5, CT showed significant improvement in the right pneumonia
Zhu et al. [30]	MSC: Day 13, the patient was discharged from the hospital	MSC: Day 2, SpO₂ recovered from 87% to 95%. Day 6, the cough symptoms of the patient were relieved, and there was no sputum when coughing, and the ventilator was removed	MSC: Day 7, CT showed that the GGO and pneumonia infiltration had reduced obviously
Liang et al. [31]	MSC: Day 18, the patient was discharged from the hospital	MSC: Day 8, the patient was transferred out of ICU, and most of the vital signs and clinical laboratory indexes recovered to the normal level	MSC: CT images showed that the pulmonary inflammatory reaction was greatly alleviated
Tao et al. [40]	MSC: Day 11, the patient received lung transplantation. But died 77 days after lung transplantation because of transplant rejection	MSC: Day 2, the consciousness and mental status began to get better. Pulmonary static compliance increased significantly, and PaO₂/FiO₂ mostly maintained above 200 mmHg. ECMO and mechanical ventilation could not be removed due to no significant improvement in lung function	MSC: CT scan revealed more patchy shadows, grid-like changes, and enlarged heart, with shadows of gas and effusion in mediastinum and thoraxes, respectively

Day: Time starts from the first injection of MSC.

6-MWT, the 6-minute walk test; CI, confidence interval; ICU, intensive care unit; SpO₂, peripheral oxygen saturation.

Changes in general clinical symptoms and pulmonary function (including the oxygenation index and chest radiology examinations) after treatment were recorded in 21 studies (Table 5) [10,12,13,22 –25,27 –40]. Different studies used different assessment indicators for lung function, which complicated the extraction of the outcomes. General clinical symptoms and pulmonary function (such as SaO_2, PaO₂/FiO_2, the oxygenation index, and chest CT or X-ray) were found to improve in the early days after MSC treatment in most studies. Some studies reported that the MSC group showed a significant clinical improvement compared with the control group, and the oxygenation index in the MSC group recovered to the normal range faster than that in the control group [23,25,32]. Additionally, some indicators (including CT scores, the number of lobes involved, ground-glass opacity, and consolidation, etc.) reflecting the lung inflammation were significantly better in the MSC group than that in the control group [22 –25].

However, a study reported that cough showed significant improvement in the MSC group compared with the control group at day 1 after MSC treatment, but no difference was found at other time points; the expiratory dyspnea showed significant improvement in the MSC group compared with the control group at days 1, 3, and 5, but no difference was found at days 7, 14, and 30 [25]. Another study reported that pulse oxygen saturation significantly improved in survivors compared with nonsurvivors, even though all patients received MSC treatment [10].

Laboratory outcomes

The laboratory outcomes are shown in Table 6. The negative status of HCoV-19 nucleic acid was evaluated in 11 studies [12,13,22,24,26,28 –31,34,39]. The average time from the first injection to a negative nucleic acid test ranged from ∼4 to 15.8 days for MSC-treated patients. Comparisons between the MSC group and the control group were made in two studies, and no significant difference was found between the two groups [24,26].

Table 6.

Laboratory Outcome

Authors	HCoV-19 nucleic acid detection	Immune cells	Inflammatory cytokines
Leng et al. [13]	MSC: The critically severe patient 1: 13 days after transplantation, nucleic acid turned to be negative. Patients 3, 4, and 5 also turned to be negative for nucleic acid until this report date Ctrl: NR	MSC: Two common type patients (patient 4 and 5): there was nearly no increase of regulatory T cells (CXCR3⁻) or DCs (CXCR3⁻). The severe patients: both the regulatory T cells and DCs increased after the cell therapy. The critically severe patient 1: Day 6, the overactivated T cells and NK cells nearly disappeared and the numbers of the other cell subpopulations were almost restored to the normal levels, especially the regulatory DC (CD14⁺CD11c⁺CD11b^mid) population Ctrl: No significant DCs (CXCR3⁻) enhancement was observed	MSC: The critically severe patient 1: CRP level decreased from 105.5 to 10.1 g/L; AST, CK activity and myoglobin were decreased to normal reference values in 2–4 days after treatment. Compared with Ctrl group, the decrease ratio of TNF-α and the increase ratio of IL-10 before and after MSC treatment of MSC group were significant (P < 0.05). The serum levels of IP-10 and VEGF were both increased, though not significantly
Meng et al. [22]	The anti-SARS-CoV-2 IgM antibody tests were positive for all patients. The median IgG and IgM antibodies titer numerically but not statistically decreased between the two group	NR	The laboratory parameters improved in both groups MSC: Two moderate type patients and two severe type patients with high baseline IL-6 exhibited a decline of IL-6 within 3 days after MSC infusion and remained stable during the following 4 days. No such trend in the patients with lower plasma IL-6 levels, which suggested that the patients with high IL-6 might be more likely to benefit from MSC treatment There was a reduced trend in the levels of inflammatory cytokines (including IFN-γ, TNF-α, MCP-1, IP-10, IL-22, IL-1Ra, IL-18, IL-8, and MIP-1) within 14 days Ctrl: NR
Shu et al. [23]	NR	Compared with the Ctrl group, the time for the LYMs count of the MSC group to return to the normal range was significantly faster	Day 3: Compared with the Ctrl group, CRP and IL-6 levels were significantly decreased from of stem cell infusion in the MSC group
Xu et al. [24]	The nucleic acid turns into negative time: MSC (15.75 ± 13.71) days; Ctrl (18.31 ± 9.86) days	NR	MSC: There were no significant differences in CRP and IL-6 before and after MSC infusion Ctrl: NR
Shi et al. [25]	NR	There was no significant difference in the subsets of peripheral LYM counts (CD4⁺ T cells, CD8⁺ T cells, B cells, NK cells) between the two groups at Days 0, 6, 10, and 14	There was no significant difference in plasma markers (IL-6, IL-8, IFN-γ, IL-1Ra, IL-18, MCP-1, MIP-1α, and IP-10) between the two groups at Days 0, 6, 10, and 14
Häberle et al. [32]	NR	MSC: Compared with the Ctrl group, significant reduction in WBCs and NEs, and significant increase in LYMs were be found	MSC: Compared with the Ctrl group, CRP and IL-6 were not significant difference; but ferritin levels showed a significant increase
Lanzoni et al. [26]	The median viral load at day 0 or 6 did not differ significantly between MSC group and Ctrl group	NR	Day 6, the concentrations of GM-CSF, IFN-g, IL-5, IL-6, IL-7, TNF-α, TNF-β, PDGF-BB. and RANTES in MSC group were significantly lower than those in Ctrl group (P < 0.05). The difference of IL-2 is very close to statistical significance (P = 0.051). In longitudinal analysis, only in MSC group, the inflammatory cytokine concentration showed a statistically significant decrease from day 0 to 6
Sánchez-Guijo et al. [33]	NR	MSC: LYMs subset analysis was available in six improved patients at day 10, and the levels of total LYMs (5/6), B cells (4/6), CD4⁺ cells (5/6), CD8⁺ cells (5/6), and T (6/6) cells were observed an increase	MSC: Day 5, a decrease in inflammatory parameters associated with MSC therapy was observed in the nine improved clinically patients (n): D-dimer: 5/8; Ferritin: 5/8; CRP: 8/9; Fibrinogen: 5/9; LDH: 9/9
Guo et al. [34]	MSC: After the first infusion of MSCs, the SARS-CoV-2 PCR results of 30 patients (96.8%) became negative after a mean time of 10.7 ± 4.2 days	MSC: Comparison before and after MSC treatment: WBCs ( × 10⁹/mL): 6.72 ± 2.62 vs. 6.43 ± 1.72, P = 0.346l; LYMs ( × 10⁹/mL): 1.09 (0.68–1.35) vs. 1.43 (1.02–2.20) P < 0.01	MSC: Comparison before and after MSC treatment: CRP (mg/L): 13.39 (1.30–38.86) vs. 0.50 (0.50–6.40) P < 0.01, PCT (ng/mL): 0.07 (0.05–0.09) vs. 0.04 (0.03–0.06) P < 0.01, IL-6 (pg/mL): 13.78 (5.69–25.26) vs. 4.86 (2.13–8.19) P < 0.001, D-dimer (ng/mL): 495 (320–727) vs. 288 (197–537) P < 0.01
Feng et al. [35]	NR	MSC: The WBC count was similar in each follow-up, whereas the LYMs count showed recovery after MSC transplantation Only got 5 (5/16) patients' results enrolled at day 28: The CD4⁺ T cells, CD8⁺ T cells, and NK cells showed recovery after MSC transplantation	MSC: The cytokines, including IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and CRP, varied in the normal range after MSC transplantation. PCT level was relatively low in the enrolled patients
Chen et al. [36]	NR	NR	MSC: Inflammation indexes, including WBC counts, CRP, PCT, and IL-6 did not change significantly after MSC therapy. However, the serum levels of LAC, cTnT, and CK-MB elevated significantly
Hashemian et al. [10]	NR	NR	MSC: Analysis of biomarkers on day 0 (baseline) and day 5 after the first infusion (24 h after the last infusion) showed a significant reduction in IL-8, TNF-α, and CRP in all six survivors. Serum IL-6 levels decreased in 5 (5/6) patients and INF-γ levels decreased in 4 (4/6) patients. Anti-inflammatory cytokines, including IL-4 and IL-10 levels, increased in 4 (4/6) patients, but the differences were not statistically significant
Iglesias et al. [27]	NR	MSC: Total LYMs were minimally elevated 7 days postinfusion. Only patient 1 had a decrease in total LYMs from 1,570 to 984/mL	MSC: All patients developed increased D-dimer concentrations after the first 24 h postinfusion of between 2,738 and 4,712 ng/mL. After this time, D-dimer concentrations decreased; however, there were value fluctuations due to patients' added complications. CRP concentrations remained normal in patients 1, 2, and 3 during the first 7 days. In the patients who died (patients 4 and 5), CRP concentrations increased during the same period
Yilmaz et al. [37]	NR	MSC: The number of TH-2 cells increased, and the number of TH-1 cells decreased in the immune modulation after MSC transplantation. After the first MSC transplant, the proportions of CD4⁺ T cells and CD8⁺ T cells were 66% and 26.7%, respectively. After the second and third MSC transplantations, the proportion of CD4⁺ T cells was 42.9% and 39.1%, while that of CD8⁺ T cells was 18.7% and 22%, respectively	MSC: After the first MSC transplantation, the values of AST, ALT, LDH, CK, pro-BNP, ferritin, triglyceride, fibrinogen, ammonia, and myoglobin began to decrease. The second time the MSCs had been given, CRP reached normal values
Zengin et al. [38]	NR	NR	MSC: The CRP levels regressed
Tang et al. [28]	MSC: Case 1: The patient's nucleic acid test turned negative Case 2: The patient's nucleic acid test turned negative on day 8	MSC: Case 1: The LYMs increased. Case 2: The LYMs increased.	MSC: Case 1: The inflammation indicators (CRP, IL-6) decreased Case 2: The inflammation indicators (CRP) decreased
Zhang et al. [12]	MSC: Day 6, nucleic acid turned to be negative	MSC: The immunoregulatory function of MSC contributed to the main efficacy outcome. The percentage and counts of CD3⁺ T cells, CD4⁺ T cells, and CD8⁺ T cells were increased	MSC: The CRP levels and inflammatory factors (IL-6 and TNF-α) were all decreased after MSC treatment
Peng et al. [29]	MSC: Day 4, the nucleic acid test was negative	MSC: The absolute NE counts continued to decrease; the absolute LYM counts gradually increased	MSC: IL-6 continued to decrease
Zhu et al. [30]	MSC: Day 13, the nucleic acid was negative	MSC: One week, the absolute number of LYMs of the patient was significantly increased (total LYMs: from 201 to 651/mL; T cells: from 152 to 547/mL; B cells: from 21.8 to 46.8/mL; NK cells from 17.9 to 29.3/mL). Day 13, the number of LYMs and NEs returned to normal	MSC: Time to return to normal range: Day 5: BUN; day 10: AST, ALT; day 13: CRP, PCT
Soler et al. [39]	MSC: Day 4, the nucleic acid was negative	NR	MSC: Day 5, all biochemical indicators were within the normal range
Liang et al. [31]	MSC: Day 8, the nucleic acid was negative	MSC: After the second administration, the WBC counts and NE counts decreased to the normal level, along with the LYM counts increased to the normal level as well. The counts of CD3⁺ T cells, CD4⁺ T cells, and CD8⁺ T cells also remarkably increased to normal levels. The NEs-to-LYMs ratio also decreased gradually	MSC: After the second administration, the concentrations of serum bilirubin, CRP, ALT and AST gradually reduced, along with some other vital signs also improved. The D-dimer levels also decreased gradually
Tao et al. [40]		MSC: The number of LYMs began to increase. However, the number of WBCs and NEs remained high	MSC: Blood creatinine and BUN declined remarkably, suggesting renal function began to improve

Day: Time starts from the first injection of MSC.

ALT, alanine aminotransferase; AST, aspartate transaminase; BNP, B-type natriuretic peptide; BUN, blood urea nitrogen; CK, creatine kinase; CK-MB, creatine kinase-MB; CRP, C-reactive protein; cTnT, cardiac troponin T; DCs, dendritic cells; GM-CSF, granulocyte/macrophage colony-stimulating factor; IFN-g, interferon-g; IL, interleukin; INF-γ or IFN-γ, interferon-γ; IP-10, interferon-inducible protein-10; LAC, lactate; LDH, lactate dehydrogenase; LYMs, lymphocytes; MCP-1, monocyte chemotactic protein-1; MIP-1α, macrophage inflammatory protein-1α; NEs, neutrophils; NK, natural killer; PCR, polymerase chain reaction; PCT, procalcitonin; PDGF-BB, platelet-derived growth factor-BB; RANTES, regulated upon activation normal T cell expressed and secreted factor; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; WBCs, white blood cells.

Immune cells were tested in 15 studies [12,13,23,25,27 –35,37,40]. Increases in DCs, LYMs, NK cells, T cells, and B cells, and the decrease of NEs and WBCs were found in most of the studies. However, Guo et al. reported that there was no significant difference in WBCs before and after MSC treatment [34], and Iglesias et al. reported that only one patient (1/5) had a decrease in total LYMs from 1,570 to 984/mL at 7 days postinfusion [27]. In the controlled studies, significant reductions in WBCs and NEs and a significant increase in LYMs were found in the MSC group compared with the control group [23,32]. However, one study reported no significant difference in subsets of peripheral LYM counts (CD4⁺ T cells, CD8⁺ T cells, B cells, NK cells) between the two groups at days 0, 6, 10, and 14 after the first MSC injection [25].

Inflammatory cytokines were evaluated in all studies. Most studies found that serum cytokines, chemokines, and growth factors improve to varying degrees following MSC therapy. Two controlled studies reported that the concentrations of CRP, GM-CSF, IFN-g, IL-5, IL-6, IL-7, TNF-α, TNF-β, PDGF-BB, and RANTES in the MSC group were significantly lower than those in the control group [23,26]. However, we also noticed no significant difference in plasma markers (IL-6, IL-8, IFN-γ, IL-1Ra, IL-18, MCP-1, MIP-1α, and IP-10) between the two groups reported in the two controlled studies [25,32].

Discussion

Specific vaccines against the SARS-CoV-2 virus have been produced and promoted. In mainland China, people are being vaccinated for free in a planned manner, and nearly 1.1 billion doses of SARS-CoV-2 vaccines have been administered as of June 23, 2021 [41]. However, the shortage of vaccines, vaccine-related AEs, and virus variants have kept some countries and regions in the shadow of the raging COVID-19 epidemic [42 –46]. Therefore, other active treatments are still essential. At present, a considerable number of studies have analyzed the possibility of MSCs for the treatment of COVID-19, and some clinical trial results have confirmed their effectiveness. Therefore, this meta-analysis reviewed published results of MSC treatment of COVID-19 patients with a focus on safety, efficacy, and related pulmonary and immunologic responses. Our analysis of relevant studies found that MSC therapy is safe and shows the potential to mitigate immunity- and inflammation-related damage to the lungs and other organs and decrease the mortality of COVID-19 patients.

Safety

Safety is the primary concern for any new therapies, especially in patients at a high risk of death due to treatment, and was carefully assessed in MSC-treated patients in the reviewed studies. This study analyzed the occurrence of AEs and found that the MSC group had fewer patients with AEs than the control group in five controlled studies [13,22,24 –26], and the difference was statistically significant. Fifteen transient AEs related to MSC treatment were reported [10,22,26,27,36], most of which resolved spontaneously in a short time. Regrettably, 32 SAEs occurred in the 219 MSC-treated patients, but the authors of these studies believed that none of these SAEs was related to MSC therapy [10,12,13,22 –27,29 –35,37 –39]. Additionally, the number of SAEs in the MSC group was also lower than that in the control group in the controlled studies [13,22 –26,32]. The safety observed is consistent with observations in other human clinical trials involving MSC treatment [47,48].

The primary outcome used to analyze the potential efficacy of MSC therapy in this study was the mortality of patients with COVID-19. A systematic review of human ARDS from the Qu et al. believes that cell-based treatment may reduce COVID-19 mortality [49]. The present study found that all seven controlled studies reported that the MSC group had reduced mortality [13,22 –26,32], and the pooled estimates of mortality showed that the mortality rate of the MSC group was significantly lower compared with the control group (3.68% vs. 21.77%). The difference suggests that MSC treatment may be effective in reducing the mortality of these patients.

COVID-19 is characterized by notable hematological manifestations, thrombocytopenia, and coagulation abnormalities on presentation and is associated with poor outcomes during the disease courses [50]. A study reported that despite low-molecular-weight heparin prophylaxis or full anticoagulant therapy, the incidence of deep vein thrombosis, mainly asymptomatic, in hospitalized COVID-19 patients was 14.5% [51]. However, some patients had to discontinue anticoagulation therapy due to bleeding or anemia and eventually died of hemodynamic disorders [27]. Notably, 10 patients were already in very serious condition before receiving MSC treatment and died of multiple organ failure or hemodynamic disorders [10,27,32,35,39]. Although their condition improved within a few days after MSC transplantation, this sympathetic treatment failed to save their lives. Therefore, the authors of the present study considered that although MSC treatment may play a positive role in most COVID-19 patients and help save their lives, there are still individual differences in its efficacy.

Efficacy

The results of three studies showed that the average time of improvement (or recovery) in the MSC group was significantly shorter than that in the control group [23,24,26], while two studies showed that the length of hospital stay was not different between the two groups [22,24]. The authors of the present study believe that the reason for this difference is that the time from symptom onset to COVID-19 diagnosis or hospitalization differed in these studies. Therefore, the difference in the length of hospital stay between these studies is not considered statistically significant because of the small number of included cases and a lack of uniform admission criteria.

Hashemian et al. reported that nonsurvivors' pulse oxygen saturation did not show the same improvement as that of survivors even though all patients received MSC treatment [10]. A case report showed that the patient's consciousness and mental state began to improve after MSC treatment, and the patient's pulmonary compliance increased significantly, but extracorporeal membrane oxygenation and mechanical ventilation could not be discontinued because no significant improvement in lung function and chest CT scans was identified. The treatment results were not satisfactory even after receiving five MSC injections, and the patient was fortunate to receive a lung transplant but regrettably died of transplant rejection [40].

However, general clinical symptoms, pulmonary function, and radiographic imaging were found to be improved in the early days after MSC treatment in most included studies, and the improvement in the MSC group was significantly better than that in the control group. Intravenously infused MSCs have been found to migrate directly to the lung, where they can secrete a variety of factors with important roles in immune regulation, protection of alveolar epithelial cells, resistance to pulmonary fibrosis, and improvement of lung function. MSCs show considerable benefits for the treatment of severe lung diseases in COVID-19 [52,53]. The findings of this study also further support the use of MSCs to treat COVID-19-related pulmonary function decline.

The interaction between viral infection and the immune system determines the occurrence and development of SARS-CoV-2. Previous studies have shown that dysregulation of the immune system, including lymphopenia and cytokine storms, may be key factors related to disease severity in COVID-19 patients [49,54]. Moreover, Chen et al. found that the absolute numbers of T cells, CD4⁺ T cells, and CD8⁺ T cells in almost all patients decreased, and the numbers in severe cases were significantly lower than those in moderate cases. Additionally, severe cases are more prone to the development of dyspnea, lymphopenia, and hypoalbuminemia, with higher levels of ALT, LDH, CRP, ferritin, and D-dimer, than moderate COVID-19 cases [20]. In severe cases, patients with COVID-19 pneumonia may progress to ARDS due to elevated levels of inflammatory cytokines. Therefore, some scholars believe that the best strategy to treat COVID-19 pneumonia probably involves reconciling the strong inflammatory response of the host immune system and regeneration of impaired cells [55].

Previous studies demonstrated that the secretion of multiple functional factors of MSCs, such as cytokines, chemokines, angiogenic factors, growth factors, exosomes, and extracellular vesicles, is the main mechanism of these cells' therapeutic effect. These multiple functional mechanisms render MSCs suitable for the treatment of complex and multifactorial diseases for which no other confirmed drug treatments are available, such as COVID-19-related pneumonia and other inflammatory diseases involving cytokine storms [14,56,57]. The present study found that MSC therapy has a positive impact on the immune and inflammatory processes that lead to organ damage in COVID-19 patients. Most of the included studies showed that the number of immune cells improved and serum inflammatory factors gradually abated with MSC treatment. Additionally, patients' WBC counts returned to the normal range before MSC injection, resulting in no significant difference before and after MSC treatment in Guo's study [34].

Other findings

Hoffmann et al. demonstrated that SARS-CoV-2 uses the SARS-CoV receptor ACE2 to enter cells, and the virus uses host cell transmembrane serine protease II (TMPRSS2) to initiate spike envelope protein [58]. ACE2 and TMPRSS2 exist on the surfaces of various human cells, including alveolar cells and capillary endothelial cells, while studies reported that human MSCs express neither ACE2 nor TMPRSS2, and human MSCs derived from fetal and adult tissues are not allowed to be infected with SARS-CoV-2 [13,59,60]. These research results further allow MSC therapy to gain the attention of more professionals combating COVID-19 pneumonia.

We also found that the three most common comorbidities were hypertension, diabetes mellitus, and obesity, which is consistent with the concerns of many previous authors [61 –64]. Because diabetes mellitus has a chronic course, some elderly hypertension patients require treatment with ACE inhibitors, which may increase ACE2 expression. In addition, pioglitazone and liraglutide, which are used to control blood glucose levels, have been found to upregulate ACE2 expression in experimental models [65 –67]. Previous studies also confirmed that comorbidities such as hypertension, diabetes, and obesity are risk factors for severe symptoms and increased mortality in COVID-19 patients [61 –65,68].

Research significance

This comprehensive systematic review and meta-analysis of published reports on MSC therapy for COVID-19 have yielded several important findings. Primarily, the number of patients with AEs in the MSC group was significantly lower than that in the control group, and the mortality rate was also significantly reduced (3.68% vs. 21.77%). Only 36 SAEs occurred in 219 patients treated with MSCs, none of which was related to MSC transplantation. Additionally, MSC therapy plays an active role in restoring lung function and improving symptoms. Furthermore, MSC therapy is beneficial for managing cytokine storms and correcting immune disorders. This study provides a sympathetic treatment option for doctors and patients in areas still under the shadow of the COVID-19 outbreak and summarizes experiences that may help when addressing new challenges in the future.

Limitations

Although we did our best to include all clinical reports on MSCs for the treatment of COVID-19-related pneumonia in this systematic review, toward the end of the project, targeted studies remain limited, and the included studies did not have a standardized treatment plan and evaluation criteria for MSCs. Therefore, large-scale RCTs are urgently needed. Moreover, selection bias may exist, and the description of the evaluation in published results may be insufficient.

Conclusion

This systematic review and meta-analysis of existing studies demonstrated the safety and effectiveness of MSCs in the treatment of COVID-19-related pneumonia. Adequately powered clinical trials are urgently needed to test the clinical results of MSC therapy in patients with COVID-19 and SARS-CoV-2 infection and to explore a standard MSC therapy program.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by the Jiangsu Provincial Medical Youth Talent [Grant No. QNRC2016342]; Project on Maternal and Child Health Talents of Jiangsu Province [Grant No. F201801]; and Six Talent Peaks Project in Jiangsu Province [Grant No. LGY2019035]. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this article.

Supplementary Material

Supplementary Table S1

Supplementary Table S2

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