Therapeutic potential of mesenchymal stromal cells in COVID-19: a meta-analysis of clinical trials conducted since the pandemic onset

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can induce immune dysregulation and multi-organ injury; mesenchymal stromal cell (MSC) therapy has shown promise in clinical trials for COVID-19 and may have broader applicability to pneumonia induced by respiratory viruses (e.g., the influenza virus). This meta-analysis synthesized the available comparative clinical evidence on the safety and efficacy of MSCs in patients with moderate to critical COVID-19 and examined the reported outcomes relevant to Long-COVID. Methods: We searched the PubMed, Embase, and CNKI databases for original, comparative studies in moderate, severe, or critical COVID-19 published up to September 2, 2024. Twenty-four eligible studies (13 RCTs and 11 non-randomized controlled trials; n=1080) were included in the mortality meta-analysis. Patients were assigned to either the intervention group (MSC therapy plus standard care) or the control group (standard care with or without placebo). The primary efficacy outcome was all-cause mortality, while the primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs). Secondary outcomes included clinical recovery, hospitalization metrics, chest imaging, and inflammatory biomarkers. We performed a pooled meta-analysis on mortality with subgroup analyses (by disease severity, administration route, dosing frequency, and study design), assessment of publication bias (using funnel plots and Egger's test), and evaluation of the quality of evidence via the GRADE approach. AEs/SAEs were analyzed using meta-analysis and descriptive statistics, while other secondary outcomes were summarized descriptively. Results: MSC therapy significantly reduced all-cause mortality (MSC: 26.4% vs control: 31.9%; fixed-effect OR=0.74, 95% CI 0.55–0.99), with low heterogeneity (I2=2.8%, P=0.422[Q-test]) and no publication bias. The quality of evidence was moderate (according to the GRADE assessment). The subgroup analysis revealed a significant survival benefit in severe/critical patients (OR=0.73, 95% CI 0.54–0.98) but not in studies that included moderate cases (OR=0.91, 95% CI 0.23–3.65). No significant heterogeneity was found across study designs, administration routes, or dosing frequencies, which confirmed the robustness of the primary findings while indicating insufficient evidence to determine the optimal regimen. The secondary outcomes suggested improvements in clinical recovery, pulmonary function, and pro-/anti-inflammatory cytokine balance in patients that received MSC therapy. Limited studies with long-term follow-up indicated potential benefits for Long-COVID outcomes (e.g., fatigue, quality of life, residual CT abnormalities, and exercise tolerance). No significant differences were observed in AEs or SAEs post-MSC infusion, which suggested that MSC therapy was well tolerated. Conclusion: This meta-analysis indicated that MSC therapy may reduce mortality in patients with severe or critical COVID-19, demonstrating a favorable safety profile and potential benefits for Long-COVID and other viral pneumonias. Further large-scale, rigorous RCTs and mechanistic studies are warranted to strengthen the evidence base and standardize MSC administration regimens (source, dosing, frequency).

1. Introduction

Coronavirus Disease 2019 (COVID-19) has exerted profound and lasting impacts on global health and economies [1]. By February 2025, the World Health Organization (WHO) reported more than 770 million confirmed cases and 7 million deaths worldwide [2]. Although vaccination campaigns, antiviral drug development, and public health measures have curbed the pandemic, sporadic transmission waves continue to occur in localized regions [3]. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) damages alveolar epithelial cells and systemic target organs [4–6], leading to pulmonary tissue injury, excessive immune activation, cytokine storm syndrome (CSS), and coagulation abnormalities [7, 8]. Severe infections may progress to acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), or even death [9]. Importantly, SARS-CoV-2 infection also leaves a considerable proportion of survivors exhibiting multi-system sequelae [10, 11], with severe cases facing poorer prognosis and higher Long-COVID risk, worsening quality of life and health burdens [12–15]. Meanwhile, ongoing viral mutations contribute to immune escape, increased transmissibility, and breakthrough infections [3, 16–18], posing a continued threat to immunocompromised individuals and those with comorbidities.

The challenges presented by COVID-19 reflect the broader threat of virus-induced pneumonia, including influenza and other respiratory viral infections, which similarly cause acute lung injury, immune dysregulation, and systemic complications [19–21]. Current therapeutic options for severe viral pneumonia remain limited: antivirals, glucocorticoids, plasma exchange, and monoclonal antibodies provide only partial benefit, and optimal regimens for high-risk patients are lacking [22–24]. These limitations underscore the urgent need for novel or adjunctive therapeutic strategies to reduce mortality, improve recovery, and mitigate sequelae.