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Mesenchymal stem cells (MSCs) are pluripotent stem cells found in the bone marrow and are important for making and repairing bone tissue such as cartilage, bone, and fat in the bone marrow. With age and disease, mesenchymal stem cells are primarily transformed into lipid-accumulating adipocytes.
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1. Bone Marrow-Derived MSCs (BM-MSCs)
Mohamed-Ahmed et al. exhibited the cellular yield, harvest, proliferation, and differentiation of BM-MSCs as negatively affected by the age of the donor [1]. BM-MSCs, having the higher expression of STRO-1, show a higher proliferation rate than Adipose tissue-derived MSCs (AD-MSCs) [1]. BM-MSCs exhibit early osteogenesis due to the formation of type 1 collagen, along with the higher expression of RUNX-2 and ALP activity on day 14 of the passage. In vitro studies stated that BM-MSCs possess a more increased osteogenic capacity than AD-MSCs due to the osteogenic gene expression and calcium deposition [1]. Due to an increased expression of aggrecan on day 28, BM-MSCs differentiate into the chondrocyte lineage more than AD-MSCs [2][3]. The cross-talk between BM-MSC-derived osteogenesis and adipogenesis is due to bone morphogenetic proteins(BMPs). BMP through BMPR-1A activates c/EBP-α and PPAR-γ via the Smad/p-38-MAPK pathways to differentiate MSC into adipocyte, whereas through BMPR-1B, it activates Runx-1, OSX, and PPAR-γ via the Smad/p-38-MAPK pathways to differentiate MSC into osteocyte. The mechanism of osteocyte differentiation of MSC by PPAR-γ is poorly understood [4]. PPAR-γ induction inhibits the β-catenin pathway during adipogenesis [5].
2. Adipose Tissue-Derived MSCs (AD-MSCs)
A study showed an elevated expression of CD34 and CD49d in AD-MSCs where CD34 expression is known to help in the prolonged cellular proliferation of MSCs [1]. AD-MSCs express Runx-1 and ALP activity after day fourteen on the passage. These expressions lead to a prolonged proliferation, maturation, and, finally, differentiation of AD-MSCs. The osteogenic differentiation of AD-MSCs is potentiated when AD-MSCs are subjected to mechanical stimulation along with osteogenic markers, such as vitamin D3, PDGF, and BMP-2 [6][7]. AD-MSCs are shown to activate adipogenesis through the induction of adiponectin, LPL, leptin, perilipin, and fatty acid-binding protein-1 by PPAR-γ and in addition, raised the lipid vesicle formation more than BM-MSCs [8]. Due to the reduced expression of TGF-β-R1, BMP-2, and BMP-4, the chondrogenic potential of AD-MSCs is decreased [9][10]. The chondrogenicity of AD-MSCs is characterized by the type 2 and 10 collagen, biglycan, aggrecan, and decorin genes expression in the differentiated cells [11]. AD-MSCs hold a potentially higher adipogenic differentiation than chondrogenic and/or osteogenic differentiation when compared with BM-MSCs [1][12][13].
3. Hematopoietic Stem Cells (HSCs)
Bone marrow contains MSCs and HSCs. HSCs are committed to hematopoietic lineages (erythropoiesis, leukopoiesis, and thrombopoiesis). HSCs are characterized by the presence of CD-45+, -34+, -31+, GATA-1+ and -3+, c-myb+, flk-1+/KDR+, and SCL+/TAL-1+ [14][15]. The homing effect of HSCs is maintained by stromal-derived factor -1 or the chemokine C-X-CR4 axis [16][17]. Upon the addition of specific lineage factors, HSCs differentiate into the particular lineage. HSC bound osteogenesis is mediated by BMP-2 and -6 through activation of PTH, Jagged-1 and -2, Delta-1 and -4, Hes-1 and -5, and Deltex ligand signaling [18][19][20]. Osteoblast trafficking in the HSC pool is maintained by osteopontin, angiopoietin-1, cysteine protease, cathepsin X, and C-X-CL-12 [21]. Chotinantakul et al. named osteoblasts and spindle-shaped N-cadherin+ osteoblastic cells as “Endosteal niche” [22]. The adipogenic potential of HSCs was poorly understood, yet the researchers have found that adipocyte is derived from monocyte/macrophage progenitor cells [23]. HSC-based adipogenic cells possess a Mac-1low cell surface marker [24]. Gavin et al. explained the transition of hematopoietic lineage to adipogenic differentiation of HSCs by the integration of integrin-β1 [25]. There is no available literature on the role of HSC in chondrogenesis.
4. Placental Derived MSCs (Pl-MSCs)
Though an immunologically temporary organ, the placenta being primitive and pluripotent, contains cellular components with stem cell-like activity and with higher potentiality for self-renewal and differentiation than other sources of MSCs [26][27][28][29]. Mesodermal (osteogenic, chondrogenic, and adipogenic) lineage differentiation has been demonstrated by human Wharton’s jelly (hWJ), decidua, and fetal membrane (FM)-derived MSC [29][30], whereas ectodermal (neurogenic) and endodermal (hepatogenic) lineages have been reported by FM-derived MSC and hWJ-MSC [31][32][33]. Pl-MSCs with CD-271+ differentiate into the osteogenic lineage [34]. Minimal oxygen tension inhibits Pl-MSC osteogenic differentiation. In addition, IGF-2 enhances differentiation through a relayed signaling cascade by IGF-1R/IR, PI3K, MEK1/2, and RUNX-2 phosphorylation more than IGF-1 [35]. Intraperitoneal injection of chorionic stem cells in a mouse model of osteogenesis imperfecta demonstrated a decreased number of fractures, as well as increased bone ductility and bone volume. Furthermore, the numbers of hypertrophic chondrocytes were increased and endochondral and intramembranous ossification-related endogenous genes were upregulated [36]. Increased secretion of glycosaminoglycans was observed when Pl-MSCs were seeded with the alginate/nCDHA/RGD mixed gel, which provides a 3D construct in the form of engineered cartilage tissue [37]. The TGF-β1-immobilized human fibroblast-derived extracellular matrix (ECM) with heparin provides a microenvironment for chondrogenic differentiation of Pl-MSCs in 3D collagen spheroid [38]. Chondrocyte ECM enriches the chondrogenesis of Pl-MSCs and is further enriched by preculture with chondrocyte-derived ECM [39].
5. Amniotic Fluid-Derived MSCs (Af-MSCs)
Af-MSC populations are a heterogeneous mixture with differentiated and undifferentiated progenitor cells derived from the fetus [40][41]. Af-MSCs are culture expandable and express CD-29, -44, -73, -90, -105, and SSEA4 with over 90% of the cells being positive for OCT-4 [40]. They express embryonic stems cell markers, such as TRA-1-60, TRA-1-81, SSEA3, and SSEA [42]. These fetal-derived cells retained their multi-differentiation capacities (adipogenic, chondrogenic, and osteogenic). They show a higher differentiation potential compared to adult stem cells [42]. Af-MSCs show similar characteristics with primordial germ cells expressing Sox17,c-Kit, STELLA, FGF-8, Nanos, DAZL, VASA, FRAGILIS, SSEA1, and Pum-2 [43]. Cloned lines of CD-117 selected Af-MSCs to modulate immune responses in chondrogenesis [44]. Compared to BM-MSCs, Af-MSCs cells generated less cartilaginous matrix after three weeks of TGF-β1 supplementation in pellet and alginate-based culture and hence, Af-MSCs have the ability to differentiate along the chondrogenic lineage [45]. Human Af-MSCs act as an important source for the induction of chitosan-based chondrogenesis [46]. Activation of calcium-sensing receptors by calcimimetic R-568 induces the osteogenic differentiation of Af-MSCs [47]. Wnt signaling acts as a key regulator in an osteogenic lineage of Af-MSCs by the upregulation of disheveled-2 expression, and the adipogenic lineage of Af-MSCs by the downregulation of disheveled-2 expression [48]. SOX-2 and ID-2 are the key targets of Nanog and POUSF-1, which are involved in the ossification and adipogenesis of Af-MSCs [49]. The exosome, miR-26a mediates the adipogenic lineage of Af-MSCs via PTEN, CyclinE1, and CDK6 [50].
6. Peripheral Blood-Derived MSCs (PB-MSCs)
PB-MSCs are obtained by mobilizing BM-MSCs to peripheral blood by giving G-CSF, which is called “blood mobilization” [51][52][53]. PB-MSCs constitute a heterogeneous population of cells containing MSCs, HSCs, immature blasts, and progenitor cells [54][55]. PB-MSCs possess CD-146 and 104b expression when compared with BM-MSCs [56]. The MSC count in PB-MSCs remains low when compared with other sources of MSCs. Though a higher cellular count prevails with BM-MSC, with 2 mL of peripheral blood, it is estimated that approximately 5 million cells PB-MSCs can be expanded in vitro for reparative procedures [57]. PB-MSCs express RUN-2, osterix, osteopontin, osteonectin, and COLIA1 during osteoblastic differentiation [58]. PB-MSCs upregulate the chondrogenic genes associated with the chondrogenic differentiation of MSCs present in the infrapatellar fat pad, increase the number of MSCs, cause native chondrocyte migration, and accelerate the rate of cellular movement [59]. Lyahyai et al. [60] and Spaas et al. [61] demonstrated that BM-MSCs possess a higher differentiation potential for osteogenic and chondrogenic lineages than PB-MSCs. Chong et al. reported that PB-MSCs possess higher adipogenic differentiation than BM-MSCs and similar chondrogenic differentiation than BM-MSCs [53]. In a rat model, while comparing with BM-MSCs, PB-MSCs possess a greater chondrogenic differentiation ability, whereas BM-MSCs possess greater osteogenic, adipogenic, and proliferative ability [62]. PB-MSCs seeded with hydroxyapatite polylactic-glycolic acid induce osteogenesis at a 4 mm calvarial bone defect in a rat model, which was evaluated by micro-CT [63].
7. Synovium-Derived MSCs (Sy-MSCs)
The minimally explored source of MSC in cellular therapy remains the synovium-derived MSCs. Literature reported that the synovium lining (the outer layer contains type A macrophage-like synoviocytes) of the knee joint provides an excellent source of Sy-MSCs [64][65][66][67]. These type A cells stain positive for CD-68 & -14, and collagen III, V & VI [66]. Due to limited senescence, Sy-MSCs have to be expanded in monolayer culture in vitro. Sy-MSCs possess superior chondrogenicity due to increased expression of CD-44, SOX-9, COMP, aggrecan, and collagen 1, 10, and 11 [66][68][69]. The cross-talks between ERK1/2 and SOX-9 stimulate the chondrogenic differentiation of Sy-MSCs [70][71][72]. In pellet culture media, Sy-MSCs regenerate an increased number of cartilage pellets when matched with BM-MSCs. A study reported that under in vitro conditions, the chondrogenic capability of Sy-MSCs was greater than that of periosteum-derived MSCs [73]. In six OA patients, Mizuno et al. observed a greater proliferation and chondrogenesis in the MSCs present in the perivascular region of the synovium, whereas poorer chondrogenesis was observed in the MSCs from the stromal part of the synovium [74]. In a rabbit model, Bami et al. demonstrated osteogenesis, chondrogenesis, myogenesis, and ethnogenesis with Sy-MSCs [75]. Fibrous synovium contains more MSCs than adipose synovium. Though retarded potential for adipogenesis, Katagiri et al. demonstrated adipogenesis of Sy-MSCs with the synovial tissue harvested during total knee arthroplasty [76].
8. Dental Tissue-Derived MSCs (D-MSCs)
Stem cells of dental origin (dental pulp, periodontal ligament, human exfoliated deciduous teeth, apical papilla, dental follicle, and gingiva) form a good therapeutic concept in regenerating tissues, cartilage, and bones. In addition to specific growth factors, ECM proteins, and transcriptional factors, dental pulp-derived MSCs (DP-MSCs) differentiate into multilineages, namely adipogenesis, osteogenesis, chondrogenesis, neurogenesis, and dentinogenesis [77][78]. D-MSCs possess immunophenotypes, such as CD-44, -73, -90, -105, -271, and STRO-1 like BM-MSCs, AD-MSCs, and Sy-MSCs [79][80][81]. Scaffold-assisted chondrogenesis by D-MSCs increases the procollagen type 2 and 10, alkaline phosphatase, aggrecan, and SOX-9 genes; in addition, decreases the Nanog, Slug, Twist, and Snail genes [82][83]. Distal-less homeobox 5 (DLX5) and C8 (HOXC8) boosted the chondrogenic differentiation of stem cells of the apical papilla (SCAPs). DLX5 and HOXC8 overexpression lead to upregulation of transcriptional activity of COL2, COL5, and SOX-9, which induces chondrogenesis [84]. The BMP-4/Smad signaling cascade is necessary for the osteogenic differentiation of DP-MSCs. This may be inhibited by tumor necrosis factor-inducible protein-6 (TSG-6) [85]. Amir et al. demonstrated a significant increase in DP-MSCs metabolism in 2 weeks of culture when added with chitosan, which is responsible for proliferation and early osteogenic differentiation of DP-MSCs [86]. Various studies demonstrated that DP-MSCs have regenerative potential to differentiate into functional osteoblasts in vitro and were able to produce extracellular matrix components [87][88]. Laino et al. demonstrated the differentiation of DP-MSCs into osteoblast precursors to living autologous fibrous bone (LAB) tissue [89]. Once the LAB tissue was transplanted, they were able to give rise to adult bone cells in immunocompromised rats [90][91].
9. Periosteum-Derived MSCs (P-MSCs)
The periosteum, an outer covering of bone, contains a cambium layer which is composed of mesenchymal progenitor cells, which are called periosteum-derived MSCs. P-MSCs hold prolonged proliferation and differentiation capacities, and a retention of differentiation ability in the in vitro culture condition as well as the in vivo condition [92][93]. P-MSCs from load-bearing sites have more osteogenic capability than flat bones [94]. After the fracture, the quiescent P-MSCs induce chondrogenesis and osteogenesis. In addition, they help in long-term integration together with native bone [95][96]. An analysis of the lineage of P-MSCs demonstrated that P-MSCs from the Prx-1 positive mesenchymal lineage add to cartilage and bone within the callus [97]. CD-90+ P-MSCs showed greater osteogenic potency than unsorted P-MSCs, either in vitro or in vivo [98]. Therefore, CD-90+ P-MSCs could be an ideal cell source with greater osteogenic potency for bone regeneration. Periosteal progenitors differentiate into chondrocytes in the presence of TGF-β3 along with atelocollagen, as evaluated by type 2 collagen staining [99]. TGF-β1 and IGF-1 improve in vitro cartilage regeneration, subperiosteal administration of TGF-β1 and IGF-1 in aged rabbits, the phenotypic stability, and cellular count in the cambium layer of periosteum [100].
This entry is adapted from the peer-reviewed paper 10.3390/ph15040386
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