2.2 Mesenchymal stem cells (MSCs)
MSCs, also known as mesenchymal stromal cells, are multipotent stem cells that can differentiate into numerous cells types such as osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells), and adipocytes (fat cells)(Ong, Ankrum, Dastidar, Levy, & Karp, 2014; Tonk, Witzler, Schulze, & Tobia Sc H, 2020). The morphology of MSCs is also characteristic, as MSCs have a small cell body with long and thin processes that are widely dispersed and populated in the adjacent extracellular matrix. In label-free live cell imaging, some organelles can be seen, and MSCs are clearly defined due to these distinct morphological features(Richmond, 1992). According to the International Society for Cellular Therapy (ISCT), MSCs are characterized by the following criteria: (1) expression of a specific set of clusters of differentiation CD markers (CD73, CD90, and CD105), (2) lack of expression of hematopoietic lineage CD markers [CD45, CD34, CD14 or CD11b, CD79a or CD19, human leukocyte antigen-antigen D related (HLA-DR)], (3) plastic adherence under standard culture conditions, (4) the ability to differentiate into osteoblasts, adipocytes, and chondroblasts in vitro (Fukumitsu & Suzuki, 2019).
Due to the clear definition, it is much easier to classify MSCs than EPCs. The most acknowledged classification is cell source, and the most common extraction sources are umbilical cord blood, amniotic fluid, adipose, and bone marrow, and different sources of MSCs possess different biological properties (Figure 2). The abundance and healing capacity of stem cells from umbilical cord blood are much higher as compared to amniotic fluid, and adipose and bone marrow stem cells. However, the replication and differentiation capacity not only correlate with the cell source, but also with the age of donors. Research shows that the doubling time and activity generation significantly decrease when age increases(Fraser, Wulur, Alfonso, & Hedrick, 2006; Pittenger et al., 1999).
The immunogenicity is also different between different cell sources. MSCs from bone marrow possess the highest immunogenicity because they have a higher expression level of HLA-DR under an inflammatory microenvironment (such as a high concentration of tumor necrosis factor-α (TNF-α) and interferon gamma (IFN-γ)), which will cause the immune cells to identify them and more rapidly eliminate them. The differentiation tendency is also different, as MSCs from umbilical cord blood tend to secrete additional hematopoietic factors such as G-CSF, GM-CSF, and HGF. Therefore, this type of MSC is more well-equipped to support the blood system. Additionally, MSCs from bone marrow can secrete a greater amount of VEGF than MSCs from umbilical cord blood, which enables MSCs from bone marrow to more easily form neovessels(Baksh, Yao, & Tuan, 2007; Hass, Kasper, Böhm, & Jacobs, 2011; Peng et al., 2008; Y.-Y. Shi, R. P. Nacamuli, A. Salim, & M. T. Longaker, 2005; Van Harmelen, Röhrig, & Hauner, 2004; Weiss et al., 2006).