**2. MSCs and derivatives**

MSCs are cell populations with unique immune-privileged and hematopoietic properties, which are capable of differentiating into a variety of functional cells such as adipocytes, osteoblasts and chondrocytes, which thus have garnered increased interest for clinical translation in the last few decades [13, 14]. Therewith, MSCs have been considered as the uppermost components in the bone marrow microenvironment as well as splendid sources for regenerative medicine [15, 16]. Not until the year of 2006, International Society for Cellular Therapy (ISCT) released the basic criteria for MSC definition including spindle-shaped morphology, high expression of mesenchymal-associated biomarkers (CD73, CD90, CD105) whereas minimal expression of hematopoietic-associated biomarkers (CD31, CD34, CD45), *in vitro* differentiation towards adipocytes, osteoblasts and chondrocytes [17].

Since the 1970s, MSCs have been isolated from various adult tissues including bone marrow, adipose tissues, synovial fluid, periosteum and dental tissues (e.g., dental pulp, periodontium) [18–20]. After that, perinatal or fetal tissues including umbilical cord, placenta, amniotic member and amniotic fluid have also been reported for MSC isolation [21]. Distinguish from those derived from adult tissues, MSCs isolated from the "discarded" perinatal tissues have been considered with preferable immunoregulatory properties and long-term *in vitro* proliferative capacity, and in particular, release from ethical risks, invasiveness and pathogenic contamination [14, 21–23]. Notably, current studies have also put forward the feasibility of generating large-scale MSCs from induced pluripotent stem cells

### *Mesenchymal Stem Cell-based Cytotherapy for Osteoarthritis Management: State of the Art DOI: http://dx.doi.org/10.5772/intechopen.108258*

(iPSCs) or embryonic stem cells (ESCs) as well [24–26]. To date, MSCs with different origins have been involved in numerous refractory and relapse disease administration including acute-on-chronic liver failure (ACLF), acute myocardial infarction (AMI), aplastic anemia, premature ovarian failure (POF), fistulizing Crohn's disease, critical limb ischemia (CLI), cutaneous wounds, coronavirus disease 2019 (COVID-19)-induced acute lung injury and acute respiratory distress syndrome (ALI/ARDS) [26–32].

For decades, the derivatives generated from MSCs such as exosomes and relative microvesicles have been extensively investigated and regarded as the dominating factor during pathogenesis and disease treatment [20, 33]. Exosomes, also known as small extracellular vesicles (sEVs) or biological spherical lipid bilayer vesicles, are nano-sized extracellular vesicles secreted by various types of cells (e.g., MSCs, natural killer cells, T or B lymphocytes, epithelial cells, macrophages, dendritic cells, tumor cells) with partial sizes ranging from 20 to 200 nm according to the Minimal Information for Studies of Extracellular Vesicles 2018 (MISEV 2018) guidelines [34–36]. The plasma membrane-derived vesicles contain lipids, proteins (e.g., CD9, CD63, CD81, GTPases, HSP70, HSP90, Tsg101, Alix), nucleic acids (e.g., microRNAs, LncRNAs, mRNAs), and other bioactive substances, which thus play an important role in various physiological and pathological processes, and in particular, serving as intermediators for material exchange and intercellular communication via delivering a variety of the aforementioned bioactive substances [37, 38]. Numerous preclinical and clinical investigations including the International Society for Extracellular Vesicles (ISEV) have shown that MSC-derived extracellular vesicles (EVs) including exosomes and microvesicles (MV) are rich in growth factors, cytokines, mRNAs, signaling lipids and regulatory miRNAs, which are adequate to influence intercellular neighbors and tissue responses to infections, injuries, and diseases [39, 40]. However, the concomitant shortcomings of exosomes such as low purity, low yield, stability for storage and weak targeting collectively limit their preclinical investigation and clinical application. Therefore, there's still a long way to optimize the aforementioned problems and facilitate further exploration upon large-scale preparation (e.g., ultracentrifugation techniques, polymer precipitation, size-based isolation techniques, immunoaffinity chromatography, micro-vortex chips, commercial isolation kits) for translational purposes [41–43].
