Cell-based therapies

Over recent decades, regenerative medicine has made its name in the market with promising results, including tissue engineering, curing diseases associated with cardiovascular (Shafei et al., 2017; Liang et al., 2021), pulmonary (Cruz & Rocco, 2020; Li et al., 2016), renal (Missoum, 2019; Gao et al., 2020), etc. Mesenchymal stem cells (MSCs) and their derivatives (eg. exosome, extracellular vesicles, etc.) have recently been involved in treating COVID-19 (Khoury et al., 2020).

A) Mesenchymal stem cells (MSCs) and their sources

In 1970, non-hematopoietic MSCs were first isolated from bone marrow and described by Friedenstein et al. The term “mesenchymal stem cells” was being introduced and described as clonal, plastic adherent cells able to differentiate into osteoblasts, adipocytes, and chondrocytes (Gregory, Prockop & Spees, 2005). The International Society for Cellular Therapy has set three criteria for MSCs definition: (1) able to differentiate into osteoblasts, adipocytes, and chondrocytes; (2) plastic adherent under standard culture conditions; and (3) must express cell surface epitopes like CD73, CD90, and CD105, and must not express CD14/CD11b, CD34, CD45, CD79, and HLA-DR. Besides being able to differentiate into different cell lines, MSCs is also an immunomodulatory agent and exhibit antimicrobial activities (Krasnodembskaya et al., 2010). MSCs also used in allogeneic stem cell transplant with no rejection (Ryan et al., 2005). Sources of MSCs include bone marrow, adipose tissue, birth derived tissue, amniotic fluid and placenta, synovium and synovial fluid, mobilized peripheral blood, dental pulp, and olfactory tissue.

i) Bone marrow

Other sources of obtaining MSCs are more preferred than bone marrow (BM) due to the highly invasive procedure and may cause pain or infection. Potential of BM-MSCs to differentiate, its yield and longevity decrease with donor’s age with roughly 0.01 and 0.001% of the BM aspirated are MSCs (Choudhery et al., 2014; Salem & Thiemermann, 2010). Despite the challenges aforementioned, BM-MSCs are widely used due to ease of isolating from small aspirate of BM and short culture time (doubles 40 times in 8 – 10 weeks) (Salem & Thiemermann, 2010). According to Choudhery et al. (2014), BM-MSCs is the gold standard among other MSCs with the advantage of high multi-lineage differentiation and proliferation capacity.

ii) Adipose tissue

Second to BM-MSCs is adipose tissue MSCs (AT-MSCs). They have similar morphology, phenotypic and functional characteristic and AT-MSCs are stable in long-term cell culture (Choudhery et al., 2014). Main advantage of AT-MSCs over BM-MSCs is the ease of obtaining sample as human AT is easily access through liposuction.

iii) Birth-derived tissues

Birth-derived tissues like umbilical cord (UC) and umbilical cord blood (UCB) are considered as waste until early 1990s where it was shown to have therapeutic capability in treating patients with BM relate deficits (Weiss & Troyer, 2006). UC consists of two arteries and one vein wrapped around by gelatinous substance called Wharton’s jelly. UC-MSCs have more advantages over BM-MSCs due to several factors. Firstly, UC-MSCs are easier to collect and process. Collection of UC or UCB do not harm the mother or child and low risk of infecting donor (Broxmeyer, Farag & Rocha, 2015). Secondly, the cost of harvesting BM-MSCs is higher than UC-MSCs and number of stem cells collected per unit sample is less compared to UC. Thirdly, UC-MSCs has lower rate of graft-versus-host disease and are more tolerant to Human Leukocyte Antigen (HLA) compared to BM-MSCs. Lastly, UC-MSCs allow to be stored in a bank and use at later date as compared to BM-MSCs.

iv) Mobilized peripheral blood

By using GM-CSF, peripheral blood stem cells may be assembled from healthy individuals. Adhesion molecules that aid in binding of stem cells to BM are being interrupted, therefore releasing into the blood and larger quantity of blood can be collected compared to BM (Dabiri et al., 2018).

v) Synovium and synovial fluid

During formation of diarthrosis in human, cartilage and synovium are form from the same pool of cells. These synovia-derived MSCs has better in vitro differentiation potential and expandability as compared to AT-MSCs (Berebichez-Fridman & Montero-Olvera, 2018). Branquinho et al. (2018) reported that several studies had used synovia-derived MSCs in cell therapy, particularly in osteoarticular disorder due to their chondrogenic and proliferation potential.

vi) Dental pulp

Odontoblasts are cells that located between dental pulp and dentin. Dental pulp mesenchymal stem cell (DP-MSCs) is extracted through enzymatic digestive process or explant method (Coelho et al., 2020). They are easy to store and possess immunomodulatoy properties. Besides the classic tri-differentiation as mentioned, they are also able to differentiate into neuronal cells (Caseiro et al., 2019).

vii) Multipotency of MSCs

Stem cells have four stages of potency, namely totipotent, pluripotent, multipotent and unipotent. The first in the hierarchy is totipotent, it is described as a cell capable of forming all extraembryonic tissues and all tissues that constitute an organism (Baker & Pera, 2018). When a human egg is fertilized, cell division occurred into early blastomeres, these cells are called totipotent. When inner cell mass is formed, these cells are called pluripotent, they can form all cell types except for placenta and supporting tissues (Sobhani et al., 2017). Third in the hierarchy is multipotent stem cells, these are cells capable of differentiating into limited cell lineages depending on their location (Baker & Pera, 2018). At the bottom is unipotent stem cells, which can generate a specific cell type.

Benefits of MSCs

MSCs can induce angiogenesis and cell proliferation through the expression of growth factors and chemokines, making them to possess trophic ability. MSCs are also able to produce proteins like transforming growth factor α (TGF-α), TGF-β, hepatocyte growth factor (HGF), epithelial growth factor (EGF), fibroblast growth factor beta (FGF-β) and somatomedin C to boost division of fibroblast, epithelial and endothelial cells (Haynesworth, Baber & Caplan, 1996; Caplan & Bruder, 2001). MSCs also possessed anti-inflammatory, anti-apoptosis and immunomodulatory properties. A series of proteins associated to anti-inflammatory include IL-1, IL-2, IL-12, TNF-α and INF-g are produced (Aggarwal & Pittenger, 2005).