Microencapsulated Wharton Jelly-Derived Adult Mesenchymal Stem Cells As A Potential New Therapeutic Tool For Patients With Covid-19 Disease: An In Vitro Study

Background: The recent newly appeared Coronavirus disease (COVID-19), caused by an enveloped RNA virus named "severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)", is associated with severe respiratory morbidity and mortality. Recent studies have shown that lymphopenia and a cytokine mass release represent important pathogenic features, with clinical evidence of dyspnea and hypoxemia, often leading to acute respiratory distress syndrome (ARDS), in severely ill patients, with a high death toll. Currently, stem cells are actively being investigated for their potential use in many "untreatable" diseases. In this regard and in particular, Mesenchymal Stem Cells (MSC), due to their intrinsic features, including either ability to impact on regulation of the immune system, or association with both anti-viral and anti-inflammatory properties, or potential for differentiation into several cell lineages, have become a promising tool for cell and molecular-based therapies. On this background, we wished to explore whether human umbilical cord-derived mesenchymal stem cells (hUCMS) would represent a potential viable therapeutic approach for the management of critically ill COVID19 patients. Methods: We tested the hUCMS effects on peripheral blood mononuclear cell (PBMCs) retrieved from patients with COVID19 (Ethical Committee CEAS Umbria, Italy CER N degrees 3658/20 7, May, 2020), both as free cell monolayers and after envelopment in sodium alginate microcapsules. Both cell systems, after priming with IFN-gamma, proved able to produce several immunomodulatory molecules such as IDO1 and HLAG5, although only the microencapsulated hUCMS were associated with massive and dose-dependent production of these factors. Results: The microencapsulated hUCMS improved allo-suppression in mixed lymphocytes reactions (MLRs), while also blunting T helper 1 and T helper 17 responses, that are involved with the cytokine storm and greatly contribute to the patient death. Moreover, we observed that both free and microencapsulated hUCMS permitted 5 days survival of in vitro culture maintained PBMCs extracted from very ill patients. Conclusion: We have provided evidence that microencapsulated hUCMS in vitro, seem to represent a powerful tool to impact on several immune pathways, clearly deranged in COVID19 patients. Further study is necessary to begin in vivo assessment of this experimental system, upon determining both, the most appropriate time of the disease onset for intervention, and cell dosage/patient of our experimental product.