**8. Clinical Trials of MSCs Transplantation in Patients with COVID-19 Pneumonia**

MSC products are quickly arising as promising treatment candidates for the COVID-19 pandemic. It is well known that septic shock is associated with a considerable viral load in terms of both mortality and morbidity for survivors of this illness. Preclinical sepsis studies advise that mesenchymal stromal/stem cells (MSCs) may moderate inflammation, improve pathogen clearance and tissue repair and reduce death. Because MSCs have not been assessed in humans with septic shock, a clinical trial that examines safety and tolerability of MSCs is mandatory before proceeding to a randomized controlled trial to study patient outcomes. This has been performed by L.A. McIntyre et al. [79] and their results show that the infusion of freshly cultured allogenic bone-marrow-derived MSCs, up to a dose of 3 million cells/kg, into patients with septic shock seems safe and, consequently, the results of the phase I dose escalation and safety trial provide researchers with the rationale and argument to now conduct larger trials to study the efficacy of MSCs in a clinical trial in patients with septic shock [80]; the clinical trial is registered with the www.clinicaltrials.gov (NCT02421484) reference.

Preclinical and early clinical data suggest that human umbilical cord stromal MCSs, because of their anti-inflammatory and immunomodulatory actions, are able to heal tissues affected and thus improve recovery rates [81]. Additionally, this treatment also seems to be antimicrobial. Two recent studies from China [78,82] have examined whether MSCs could be useful for treating SARS-CoV-2/COVID pneumonia, based on known immune modulatory and reparative abilities of stem cells. Both studies show an outstanding reversal of symptoms, even in severe to critical circumstances. These clinical studies not only recognize a novel therapeutic approach, but also the reality of natural processes able to reduce acute inflammatory pneumonia.

Following the intravenous transplantation of MSCs, a noteworthy population of cells accumulates in the lung, which together with their immunomodulatory effect, could protect alveolar epithelial cells, recover the pulmonary microenvironment, avoid pulmonary fibrosis and cure lung dysfunction. It has been suggested that MSCs have cured or significantly improved the functional outcomes of seven patients without any detected side effects. The pulmonary function and symptoms of these seven patients were significantly improved in two days after MSCs transplantation. Furthermore, the gene expression profile revealed MSCs were ACE2- and TMPRSS2, which showed that the MSCs were free from the SARS-CoV-2 infection. Thus, the intravenous cellular transplantation was safe and efficient for handling in patients with COVID pneumonia, particularly for the patients in a seriously severe condition [78].

Given the uncertainties in this area, Golchin et al. [83] have reviewed published clinical trials and hypotheses to offer useful information to researchers and those involved in stem-cell therapy. In their study, they considered a new approach to enhance patients' immunological responses to COVID-19 pneumonia using MSCs and debating the aspects of this proposed treatment. However, currently, there are no approved MSC-based approaches for the prevention and/or treatment of COVID-19 patients; nevertheless, clinical trials are ongoing.

The immunomodulatory and anti-inflammatory properties of MSCs in the treatment of respiratory diseases have been confirmed by 17 completed clinical studies, and also more than 70 trials have been registered in this regard (https://clinicaltrials.gov).

Many of the critically ill COVID-19 patients are in a hypercoagulable or procoagulant situation and with a high probability for disseminated intravascular coagulation, thromboembolism and thrombotic multiorgan catastrophe, another cause of the high death rate. Therefore, it is mandatory to only use well-characterized and safe MSCs in the most urgent and experimental treatments [84]. Moreover, in order to alleviate patients with SARS-CoV-2 infection, the obvious risk of adverse thrombotic reactions after the transplant of high doses of poorly typified cell product, an obligatory a set of

significant procedures for combining innate immune hemocompatibility examination into the usual patients' characterization and clinical procedures, before applying MSCs cell therapies has been proposed [84].

Of course, cost effectiveness and the speed of medicinal formulation and transport are topics to be considered for MSCs-based therapy for COVID-19, but without a doubt, whatever the cost the life of a human being is priceless. Nevertheless, the clinical use of MSCs therapy to treat COVID-19 seems promising. Therefore, bearing in mind that MSCs therapy could become an important contribution to terminate the high COVID-19 death rates and prevent long-term functional side effects in those who survive disease, it is essential that the funding agencies invest more into the development of MSCs suitable for safe clinical applications [71].

However, it is very important to underline that scientists are tirelessly trying to obtain a vaccine for SARS-CoV-2 infection and COVID-19 pneumonia, as well as therapeutics to treat this disease [83], and that now a vaccine to protect against SARS-CoV-2 infection has been assessed for safety, tolerability and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored vaccine expressing the spike glycoprotein of a grave acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variety [85]. These recently published results show that the vaccine is safe and immunogenic at 28 days postvaccination. Humoral responses against SARS-CoV-2 hit the highest point at day 28 postvaccination in healthy adults, and quick specific T-cell responses were observed from day 14 postvaccination. These findings imply that the Ad5 vectored SARS-CoV-2/COVID vaccine deserves more research [85] and an ongoing phase 2 trial in China (NCT04341389) will offer more data on the safety and immunogenicity of the Ad5 vectored SARS-CoV-2/COVID-19 vaccine. The progress in this field is extremely fast, and an excellent update on the subject can be found in [86].
