**5. The mesenchymal stem cells or medicinal signalling cells**

Human mesenchymal stromal cells are also recognised as mesenchymal stem cells and medicinal signaling cells (MSCs). The reason of why the MSCs are named as 'mesenchymal' is their residence in the mesodermal niche, and their multipotency. They are also termed as mesenchymal stromal cells, if they fulfill the minimum criteria of adherence, expression of CD105, CD73, and CD90, absence of CD45, CD34, CD14 or CD11b, CD79a or CD19, and HLA-DR cell surface markers as well as gives rise to descendant lineages including myocytes, adipocytes, chondrocytes, and osteocytes [95, 96] as characterized by International Society of Stromal Therapy (ISCT) in 2005 [97].

Since initial isolation from the bone marrow (BM), MSCs have been found in numerous adult and fetal-derived organs/tissues such as adipose tissue, dental pulp, umbilical cord, and placenta [98]. For translational research, MSCs are categorized into different generations according to their preparation strategy as minimally manipulated, culture-expanded, lineage induced, or genetically modified [99].

Another recommendation of naming is "medicinal signaling cells", as inspired by the fact that these cells possess the properties of homing and secrete bioactive factors that possess the immunomodulatory and regenerative potential. These features give these cells the ability to act as drugs in situ and they have shown site-specific therapeutic outcomes. The infused exogenous MSCs were shown to signal resident stem cells of the patient to repair the damage via their bioactive factors instead of undergoing their differentiation [100]. For both research and clinical purposes, large amounts of MSCs can be isolated from the embryo, fetus as well as adult stem cell sources, including bone marrow, umbilical cord blood, adipose tissue, menstrual blood, Wharton's jelly, amniotic fluid and human deciduous teeth [101, 102].

Our age is the time of MSCs, thanks to the self-renewal and differentiation properties, have already demonstrated a promising role in treating numerous life-threatening diseases as part of the modern research and regenerative medicine [103]. Depending on their origin, stem cells can be divided into three categories of embryonic, fetal and adult stem cells [104]. Indeed, fetal and embryonic stem cells have a higher potential than adult stem cells. The adults stem cells are more used in the research and development because they have the availability and less ethical issues. Bone marrow, fat tissue, human dental pulp and umbilical cord blood are amongs the numerous sources of adult stem cells, which are of crucial importance in regenerative medicine. The technology, moreover, allow these stem cells to be isolated and protected in stem cell banks under low temperature for many years without losing their potential. Particularly, the umbilical cord blood and bone marrow are the reservoirs of both hematopoietic stem cells and MSCs. It has been known that the MSCs are the most explored and exploited categories of stem cells in treating various disorders [102].

MSCs have the differentiation capacity toward trilineage paraxial mesodermal derivates such as bone, cartilage, and fat. Besides, immunomodulatory properties of MSCs allow for expansion of therapeutic use of them in regenerative medicine in inflammatory diseases, in addition to the allogeneic allogeneic use [105–108]. Interestingly, the first published evidence in the allogeneic MSCs use in inflammatory disease is a pediatric case with acute refractory graft-vs-host-disease (GVHD) in 2004 in which MSCs derived form bone marrow were given. In this study, the patient transplanted MSCs survived in well condition 1 year after MSC treatment, while other 24 patients having severe GVHD showed the median survival rate as 2 months [109]. After this pioneering evidence, MSC immunomodulation has shown to be broadbased, best detailed for CD4 lymphocytes but also for dendritic cells and natural killer cells [110, 111]. As evident by the increasing MSC trials focusing on immune/inflammatory diseases in recent years which are accounted for almost one-third of the trials, the clinical importance of the immunomodulatory properties is compromised [112–114]. General charateristics of the MSCs is their being fibroblast shaped cells which are plastic adherent; fulfilling the criteria of stem cells and MSC as well as stromal cell types [109, 115]. The immunomodulatory activities are suggested to include:


c.production of IL-10 and decreased production of TNF-α and IL-12 [116, 117].

In addition, MSCs have powerful antifibrotic effects which may alleviate lung fibrosis [118, 119].

Lately, there have been increasing reports revealing that the MSCs induce therapeutic characteristics by releasing bioactive substances known as secretomes in a paracrine path [120]. The soluable proteins such as chemokines, growth factors, cytokines, and extracellular vesicles (EVs) including microvesicles and exosomes present in the MSC-secretomes [121]. MSCs, like all other stem cells, when the culture medium or secretome are injected into the patients, show paracrine signalling to take in these molecules to the cells in vicinity [122]. The exosomes contain bioactive molecules, including microRNAs (miRNA), transfer RNAs (tRNA), long noncoding RNAs (lncRNA), growth factors, proteins, and lipids. Of note, the lipid content of the exosomes is an added value by facilitating the infusion of the exosomes attracted to the plasma membrane of the neighboring cells [123]. Once the molecules content of the secretome is internalized, the neighboring cells modulate various downstream pathways, including immunomodulation, suppression of apoptosis, prevention of fibrosis, and remodelling or repair of the damaged tissues [120, 124].

Several studies with drugs targeting GM-CSF, IL-6, IL-1, IL-2 and TNF-α is already in the pipeline which aims to calm down the inflammatory response in COVID-19 patients. MSCs are well-known for their immuno-modulatory properties including the anti-inflammatory cytokines/chemokines secretion, anti-apoptotic effect and their reparative ability for the damaged epithelial cells. Their inherent nature to migrate towards injured lungs and secretion of paracrine factors which protects and repair alveolar cells; make MSCs a potential therapeutic option for COVID-19 treatment. Recently, MSCs have been widely studied from basic research to clinical trials particularly for immune-mediated inflammatory diseases such as systemic lypus erythematous (SLE) and GVHD [125–127].
