COVID-19 causes fever, cough, respiratory tract inflammation, acute respiratory distress syndrome (ARDS), viral sepsis and multisystemic disease [1, 2]. Clinical experience thus far shows that COVID-19 is highly heterogeneous, ranging from being asymptomatic and mild to severe and causing death. Host factors including age, sex, and comorbid conditions are key determinants of disease severity and progression. Aging itself is a prominent risk factor for severe disease and death from COVID-19 . In our study, A total of 210 cases diagnosed with COVID-19 were studied. 57 patients were female, and 153 patients were male with mean ages of 56.84 ± 14.12 and 59.99 ± 11.06, respectively. There was not statistically significant difference between men and women in the terms of age (p = 0.09). While the mean age of intubated patients was 61.22 ± 11.77, the mean age of unintubated patients was 57.36 ± 12.00. There was a statistically significant relation between intubation status in terms of age (OR = 3.868, 95% CI = 0.574–7.152 p = 0.02).
Popkin et al. shown in meta-analysis that individuals with obesity were more at risk for COVID-19 positive, > 46.0% higher (OR = 1.46; 95% CI, 1.30–1.65; p < 0.0001); for hospitalization, 113% higher (OR = 2.13; 95% CI, 1.74–2.60; p < 0.0001); for ICU admission, 74% higher (OR = 1.74; 95% CI, 1.46–2.08); and for mortality, 48% increase in deaths (OR = 1.48; 95% CI, 1.22–1.80; p < 0.001) . In our study, while the mean weight of intubated patients was 90.63 ± 12.86, the mean weigh of unintubated patients was 83.86 ± 11.66. There was a statistically significant relation between intubation status in terms of weigh (OR = 6.768, 95% CI = 3.423–10.112 p < 0.001). In the linear regression model, the dependent variable, intubation condition was significantly associated with weight (p = 0.001). The linear regression analysis confirmed that the high weight was associated with the risk of intubation in COVID-19.
Mesenchymal stem cells are considered to have extensive clinical application possibilities, including ARDS . MSCs have broad bioactivities, including repair, immunomodulation, increased alveolar fluid clearance, and regulation of pulmonary vascular endothelial permeability . MSCs have a wide range of sources, such as the bone marrow, umbilical cord, adipose tissue, amniotic membrane, and several other tissues . MSCs from different sources have significant similarities, such as being adherent and teardrop- or spindle-shaped . MSCs have the upsides of self-renewal, multidirectional differentiation, and immunomodulation towards suppressing proinflammatory factors. In Accord with these findings, it has been shown that stem cells from the placenta and human umbilical cord showed decreased lung tissue damage in mouse bleomycin models . In clinical setting, immunomodulatory properties of MSCs have been shown in numerous pathological conditions, e.g., bronchopulmonary dysplasia, asthma, acute lung injury, chronic obstructive pneumonic illness, idiopathic aspiratory fibrosis [23, 24]. Studies suggest that MSCs from different sources have different levels of immunoregulatory efficiency. Najar and his colleques revealed in their study that Warton Jelly derived MSCs were found to be the most effective in immunomodulation .
Toll-like receptors (TLRs) family has a crucial activity in the innate immune system for the recognition of pathogen-associated molecular patterns (PAMPs), starting primary reaction to pathogens and helping to recognise virus, bacteria, protozoa, and fungi; and are commonly associated with chronic inflammatory and autoimmune diseases . TLRs play an important role in immunomodulation by cell-to-cell contact and MSC-secreted soluble factors [27, 28].
It has been reported that some patients who survived acute phase of ARDS due to COVID-19 die afterwards due to progressive pulmonary fibrosis . Disproportionate activation and proliferation of myofibroblasts results in deposition of the extracellular matrix (ECM) components which deteriorates functions of related tissues and fibrotic states are estimated to contribute to almost 50% of mortalities in the developed world . During inflammatory phase of ARDS, dysregulation and overproduction of matrix metalloproteinases could occur and lead to a complex combination of epithelial and endothelial damage, thus uncontrolled fibrosis .
Overactive secretion of pro-fibrotic growth factors, chemokines and procoagulant mediators are collectively referred as senescence-associated secretory phenotype (SASP) factors. Secretion of these mediators trigger progressive and excessive activation of epithelial cells characterized by dysregulated crosstalk between epithelial cells and mesenchymal cells. Consequent accumulation and activation of myofibroblasts affect the crosstalk between fibroblasts and epithelial cells to exhibit markers of stress and senescence which in turn lead to resistance to apoptosis and excessive production of extracellular matrix components [32, 33].
Inflammation in lung tissue results in alveolar pneumocyte damage and resultant fibroblast activation triggers pulmonary fibrosis through myofibroblast differentiation which might proceed for a long time . Darwish et al. have shown that umbilical cord derived MSCs (UC-MSCs) have the potential to alleviate H5N1 infection induced acute lung injury. Inflammatory cytokine profiles seen in H5N1 infection is similar to COVID-19 such as high levels of IL-6, GCSF, IP10, MCP-1, MIP1 α, and TNF-α [6, 35, 36]. These inflammatory cytokines can activate MSCs to secrete immunosuppressive factors consisting of IDO, TSG6, NO, IL-10, CCL2, galectins, PGE2, and TGF-β and then modulating tissue homeostasis .
In recent studies clinical improvement was observed in severe COVID-19 patients, shortening the ICU stay [13, 14]. In a proof-of-concept study significant benefit of laboratory prognostic markers was evaluated consistent with other study findings in COVID-19 patients who had received MSCs transplantation [15, 38]. In another clinical trial with randomised, double-blind, placebo-controlled of phase 2 were done on 100 severe COVID-19 patients with lung damage. They were randomly assigned to receive either UC-MSCs 4 × 107 cells per infusion to 65 patients or placebo (35 patients) on day 0, 3, and 6. It was shown that UC-MSCs treatment is safe and have promissing reatment potential for COVID-19 patients. Improvement in whole lung lesion volume were reported with a better recovery rate compared to the placebo group .
Important pathological hallmark of COVID-19 in pulmonary vasculature is pulmonary hypertension as a part of systemic endothelial dysfunction [39, 40]. Endothelial dysfunction and damage explain most of the pathological processes triggered and involved in COVID-19 and mesenchymal cells seem to be promising agents to alleviate such widespread cellular damage [41, 42].
Despite ever increasing number of studies, randomized controlled multicenter clinical trials are certainly needed to achieve standardization of MSC therapy protocols for cell-based treatments in COVID-19 [5, 15, 43–45].
This study was investigated the impact of UC-MSCs therapy in 210 patients with COVID-19 (99 patient with critically severe, 111 patients with severe clinical symptoms). Patients were followed after by pulmonary function and clinical symptoms after the injection. Patients were observed for 2–3 weeks after MSCs transplantation. In our study we have revealed a clinical success rate of 61% in UC-MSC transplanted severe/critically severe COVID-19 patients. We have also observed that the response to MSC treatment is more accurate in severe patients during early stages of cytokine storm than the patients who were entubated and had lung incury due to the hyperimmunity tissue destruction. The results showed that significantly higher survival was observed in patients who underwent UC-MSCs before intubation (p < 0.001).
Here we could discuss about the two phases of UC-MSC treatment in COVID-19 disease due to the clinical aspects we have observed in these patients (Fig. 3). In this study, severe patients who were unintubated were in the Phase I, while critical patients who were intubated were in the Phase II. In Phase I, we assume to alleviate the cytokine storm in severe COVID-19 patients with MSC transplantation. The immunmodulatory efficacy of MSCs has been revealed in many studies [7, 12, 46]. In this period of the disease, we could conclude to achieve a beneficial result of the UC-MSC treatment by a proven pathway of immun regulation. We could recommend one iv MSCs dose in the literature as 1–2 x106/kg as effective for phase I COVID-19 patients . Phase II (supportive treatment for organ recovery): Here we could comment on the treatment mechanism of the MSCs as a supportive treatment for original healing of the alveolar epithelial cells in critically severe COVID-19 patients. This may be achieved by anti inflammatory/antifibrosis supportive effect of MSCs which was determined in various studies [5, 6, 35, 36]. Anti inflammatory supportive effect provides to increase oxygenation in destroyed tissue, which gaines time for patient organ recovery. In our study, it was observed that the SaO2 parameter tended to improve after UC-MSC therapy compared to all groups. Especially, in discharged cases SaO2 parameter was statistically significant (p = 0.01).
UC-MSCs supportive treatment as prevention of fibrosis, which is seen in the COVID-19 patients as a disease complication is vital. We have scientific evidence that the accelerated regenerative original tissue healing may be achieved with MSCs treatment, but this may take some time not less than a couple of weeks, which was explored in many studies .