Comment

Our previous publications about UC-MSCs and their immune modulations include hypothesizing the benefits of UC-MSCs in COVID-19 treatment in 20201 and summarizing clinical trials using UC-MSCs for COVID-19 in 20212. Examining 16 publications covering 395 COVID-19 patients treated with UC-MSCs overall, we found that all publications showed that UC-MSC transplantation is safe, well tolerated, improves COVID-19 symptoms, and significantly decreases mortality2.

The latest publication of Lei Shi (2022) in eBiomedicine (part of The Lancet, https://doi.org/10.1016/j.ebiom.2021.103789) from the previous month about the 1-year follow-up results of a randomized, double-blind, placebo-controlled trial strongly confirmed our observations shared in previous reviews3. In this study, there were 65 COVID-19 patients transplanted with UC-MSCs and 35 COVID-19 patients in the placebo group. The authors focused on the effects of UC-MSC transplantation on lung recovery, which was evaluated based on CT images and the 6-MWD test at 3, 6, 9, and 12 months. Note that at Month 6, 6 patients (6/51 patients) in the UC-MSC transplantation group had normal CT images; in contrast, none of the patients in the placebo group had normal CT images (p = 0.087). At Month 12, the number of patients with normal CT images increased to 10 in the UC-MSC transplantation group, but not in the placebo group (p = 0.013). The CT imaging results were supported by the 6-MWD tests in both groups. Although the 6-MWD scores gradually increased in both groups over time at 3, 6, 9, and 12 months, the patients in the UC-MSC transplantation group increased from 440 m at Month 3 to 478 m at Month 12, compared to 420 m at Month 3 to 441 m at Month 12 for the placebo group3.

These results showed that patients with UC-MSC transplantation displayed good lung function and structure recovery compared to the non-transplantation group. Thus, alongside some previous publications, these observations confirm the roles of UC-MSCs4, 5, 6, 7. However, whether UC-MSCs can help recover or regenerate damaged lungs in COVID-19 patients is not yet well understood.

With their strong modulation potentials, UC-MSCs can suppress cytokine storms in COVID-19 patients. Accordingly, we proposed some hypotheses regarding the effects of UC-MSCs on lung recovery as a result of minimizing damage during the cytokine storm and inhibiting fibrosis.

Cytokine storms and cytokine release syndrome are life-threatening systemic inflammatory syndromes related to elevated levels of circulating cytokines and immune cell hyperactivation, which can be triggered by various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders8. COVID-19 patients can encounter heterogeneous symptoms ranging from mild fatigue to life-threatening pneumonia, cytokine storms, and multi-organ failure9. Cytokine storms in COVID-19 patients are usually characterized by high concentrations of IL-1 beta, IL-6, IP-10, TNF, interferon-gamma, macrophage inflammatory protein (MIP) 1 alpha and 1 beta, and VEGF10. A high concentration of these cytokines has been significantly associated with pneumonia in COVID-19 patients and the severity of lung injury11. UC-MSCs can effectively reduce the level of these cytokines; therefore, they can stop or reduce the effects of cytokine storms in COVID-19 patients12, 13, 14, 15, 16. By this mechanism, lung damage or lung lesions are reduced in the case of UC-MSC transplantation; therefore, lung recovery is expected to be faster and easier in COVID-19 patients transplanted with UC-MSCs. This means that the efficacy of UC-MSC transplantation will be clear if the transplantation is performed before the cytokine storm is done. According to Shcherbak . (2021), the basic risk factors for cytokine storms in COVID-19 patients include male sex, over 40 years of age, a positive test result for SARS-CoV-2 RNA, NEWS score dynamics, serum IL-6 greater than 23 pg/ml, serum CRP 50 mg/L or greater, and absolute lymphocyte count less than 0.72 × 10/L17. Thus, COVID-19 patients with basic risk factors for cytokine storms should be transplanted with UC-MSCs.

UC-MSCs can inhibit lung fibrosis after damage, making them a treatment of interest given that post-COVID-19 lung fibrosis was observed in approximately half of survivors in the study18. In other studies, MSCs showed anti-fibrotic effects on irradiated lungs via endogenous secretion of HGF and PGF219 and robust regulatory T-cell induction in bleomycin-induced pulmonary fibrosis20. In a meta-analysis of preclinical studies, Li . (2021) analyzed 24 articles on the treatment of pulmonary fibrosis in an animal model using MSCs; this analysis showed that MSC therapy improved the survival rate and reduced pulmonary fibrosis scores21. In a recent review, Chen . (2021) summarized 110 publications on the applications of MSCs in pulmonary diseases22, including acute/viral pulmonary disease, community-acquired pneumonia (CAP), chronic obstructive pulmonary disease (COPD), bronchopulmonary dysplasia (BPD), interstitial lung diseases (ILD), chronic pulmonary fibrosis, bronchiolitis obliterans syndrome (BOS), and lung cancer. This review confirmed that MSC transplantation is a promising therapeutic approach for treating lung disease22. Furthermore, in a case report by Silva et al. (2021), UC-MSC transplantation corresponded to immunomodulatory and anti-fibrotic effects in a critically ill patient with COVID-19 presenting with lung fibrosis23.

Based on the current results, UC-MSC transplantation should be considered as an adjuvant treatment in patients at high risk for cytokine storms, which includes those with COVID-19. Indeed, UC-MSC transplantation minimizes the lung damage caused by cytokine storms and inhibits lung fibrosis in post-COVID-19 patients. Although more large studies are required on this topic, the current data about the safety and long-term effects of UC-MSC transplantation for COVID-19 patients are sufficient for this therapy to be considered as an option in such cases.

Abbreviations

6-MWD test: The -min walk test, COVID-19: Coronavirus disease 2019, CT: Computed tomography, UC-MSC: Umbilical cord derived mesenchymal stem cell

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Authors equally contributed to this work, read and approved the final manuscript.

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