Stem cells and COVID-19: are the human amniotic cells a new hope for therapies against the SARS-CoV-2 virus?

Abstract

A new coronavirus respiratory disease (COVID-19) caused by the SARS-CoV-2 virus, surprised the entire world, producing social, economic, and health problems. The COVID-19 triggers a lung infection with a multiple proinflammatory cytokine storm in severe patients. Without effective and safe treatments, COVID-19 has killed thousands of people, becoming a pandemic. Stem cells have been suggested as a therapy for lung-related diseases. In particular, mesenchymal stem cells (MSCs) have been successfully tested in some clinical trials in patients with COVID-19. The encouraging results positioned MSCs as a possible cell therapy for COVID-19. The amniotic membrane from the human placenta at term is a valuable stem cell source, including human amniotic epithelial cells (hAECs) and human mesenchymal stromal cells (hAMSCs). Interestingly, amnion cells have immunoregulatory, regenerative, and anti-inflammatory properties. Moreover, hAECs and hAMSCs have been used both in preclinical studies and in clinical trials against respiratory diseases. They have reduced the inflammatory response and restored the pulmonary tissue architecture in lung injury in vivo models. Here, we review the existing data about the stem cells use for COVID-19 treatment, including the ongoing clinical trials. We also consider the non-cellular therapies that are being applied. Finally, we discuss the human amniotic membrane cells use in patients who suffer from immune/inflammatory lung diseases and hypothesize their possible use as a successful treatment against COVID-19.

Keywords: Amnion; COVID-19; Human amniotic epithelial cells; Human amniotic mesenchymal stromal cells; Mesenchymal stem cells; SARS-CoV-2; Stem cell therapy; Stem cells.

Fig. 1

SARS-CoV-2 structure and cell entry. a The coronavirus (CoVs) structure is complex and includes the three principal structural proteins: the spike glycoprotein (S), the transmembrane glycoprotein (M), and the nucleocapsid protein (N). The glycoprotein S is found in the viral envelope. The envelope (E) protein is a minor transmembrane protein present in the structural region. The CoVs genome is formed by a positive sense single-stranded RNA of 30 kb in size. b As a coronavirus, SARS-CoV-2 uses the S glycoprotein to facilitate entry to the host cell. This virus principally targets the respiratory epithelial cells, that express the angiotensin-converting enzyme 2 receptor (ACE2). The S protein binds to ACE2 allowing the virus access to the host cells cytosol. Proteases like TMPRRS2, cathepsin, or furin, help to viral and cellular membranes fusion through the S protein cleavage. After the viral entry, the replicase gene from the virion genomic RNA is translated. Then, the viral RNA is synthesized and the replicase complexes assembly. In the endoplasmic reticulum occurs the translation of the structural glycoproteins S, M, and E. All the translated proteins interact for CoVs assembling. Once the virions are formed, they are transported to the host cell surface in vesicles and then released by exocytosis. (This figure was created with BioRender.com)

Fig. 2

Perspectives of amniotic membrane stem cell therapy against COVID-19. Stem cells isolated from the amnion of the human placenta at term include hAECs and hAMSCs. HAMSCs and hAECs have immunoregulatory, anti-inflammatory, and regenerative properties. These features position amniotic stem cells as candidate for a successful treatment against COVID-19. The amniotic membrane stem cell therapy could attenuate the cytokine storm that occurs in acute respiratory distress syndrome (ARDS) caused by the SARS-CoV-2 virus. Amnion cells could modulate the proliferation, function, and migration of immune cells such as T and B lymphocytes, NK cells, DC, neutrophils, and macrophages. Thus, hAECs and hAMSCs would stimulate regulatory immune cells decreasing the pulmonary inflammatory microenvironment. Moreover, amniotic membrane cells would reduce proinflammatory cytokines (TNF-α, IFN-γ, IL-6, and MCP-1) and increase the release of soluble anti-inflammatory factors (IL-10, IL-1β, PGE2, MIF, VEGF, and IDO). Additionally, amnion cells could exert an anti-fibrotic effect at the lung injury focus through TGF-β factor inhibition. Altogether, human amniotic membrane stem cell therapy would prevent multiple organ failure progression in patients who suffer from COVID-19 (This figure was created with BioRender.com)