Umbilical Cord Mesenchymal Stromal Cells for Cartilage Regeneration Applications

Russo, E.; Caprnda, M.; Kruzliak, P.; Conaldi, P. G.; Borlongan, C. V.; La Rocca, G.

doi:https://doi.org/10.1155/2022/2454168

Stem Cells International

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Current Status and Perspectives of Cartilage Regeneration

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Review Article | Open Access

Volume 2022 | Article ID 2454168 | https://doi.org/10.1155/2022/2454168

Umbilical Cord Mesenchymal Stromal Cells for Cartilage Regeneration Applications

E. Russo,¹M. Caprnda,²P. Kruzliak,³P. G. Conaldi,⁴C. V. Borlongan,⁵and G. La Rocca¹

Academic Editor: Andrea Ballini

Received18 Jun 2021

Revised13 Oct 2021

Accepted23 Nov 2021

Published06 Jan 2022

Abstract

Chondropathies are increasing worldwide, but effective treatments are currently lacking. Mesenchymal stromal cell (MSCs) transplantation represents a promising approach to counteract the degenerative and inflammatory environment characterizing those pathologies, such as osteoarthritis (OA) and rheumatoid arthritis (RA). Umbilical cord- (UC-) MSCs gained increasing interest due to their multilineage differentiation potential, immunomodulatory, and anti-inflammatory properties as well as higher proliferation rates, abundant supply along with no risks for the donor compared to adult MSCs. In addition, UC-MSCs are physiologically adapted to survive in an ischemic and nutrient-poor environment as well as to produce an extracellular matrix (ECM) similar to that of the cartilage. All these characteristics make UC-MSCs a pivotal source for a stem cell-based treatment of chondropathies. In this review, the regenerative potential of UC-MSCs for the treatment of cartilage diseases will be discussed focusing on in vitro, in vivo, and clinical studies.

1. Introduction

Chondropathies are a group of cartilage diseases that deviate from or interrupt the normal structure and function of cartilage, including osteoarthritis (OA), achondroplasia, spinal disc herniation (SDH), relapsing polychondritis, cartilage tumor (CT), and chondrocalcinosis [1]. There are over 100 types of arthritis. The most common forms are OA (degenerative joint disease) and rheumatoid arthritis (RA, autoimmune form of arthritis). OA is the most well-known chondropathy in the world, affecting the health of 343 million of people, while RA affects 14 million of people [2]. OA is a multifactorial and complex degenerative joint disease characterized by age-related “wear and tear,” chondrocytes’ poor response to growth factors, altered biomechanical properties of articular cartilage, mitochondrial dysfunction, oxidative stress, and inflammation [3]. The degenerative lesions in cartilage are secondary to inflammation associated with hyperplasia and chondrocyte apoptosis [4]. Increasing age is linked to a reduction in subchondral blood vessels resulting in cartilage-related physiological and biochemical anomalies [5]. This pathological process results in secondary joint fibrosis, stiffness, pain, and decreased function, leading to a poor quality of life. Risk factors for chondropathies include trauma, genetics, age, sex, obesity, and degenerative pathology. The biological mechanisms of chondropathies remain largely unknown, and there is no effective way to treat the cartilage damage because of its nature.

Cartilage is a supportive connective tissue, and it has a dense and highly organized extracellular matrix (ECM) embedding chondrocytes [6]. Three types of cartilage tissue are present throughout the body at various sites: hyaline, elastic, and fibrocartilaginous. Hyaline cartilage is the predominant form of cartilage and is present on the articular surfaces of synovial joints. Type II collagen is the main component in healthy articular cartilage. Other collagens of cartilage ECM are types III, VI, IX, X, XI, XII, and XIV. The main proteoglycan present in cartilage is aggrecan, but other proteoglycans found in cartilage include the syndecans, glypican, decorin, biglycan, fibromodulin, lumican, epiphycan, and perlecan. The chondrocytes are contained in cavities called lacunae embedded in the network of collagen fibrils and proteoglycans [6].

Cartilage has a decreased ability to self-repair because is avascular, resulting in a poor replicative capacity of chondrocytes. The lack of vascularity, along with the dense packing of ECM components, hinders the transport of drugs in the tissue, thus, challenging the treatments of cartilage diseases. In addition, cartilage also lacks nerve cells or endings and, therefore, cannot directly generate pain that is the main symptom of a chondropathy [7]. Therefore, symptoms usually occur only after the significant structural destruction of the cartilage ECM (with the damage affecting other tissues of the whole joint that do contain nociceptors), thus, making treatments difficult.

Current treatment of articular cartilage defects includes pharmacological management of pain, weight reduction, and exercises as well as intra-articular treatments with corticosteroid or hyaluronan and hylan derivatives injections [8]. Surgical options consist in bone marrow stimulation procedures such as subchondral drilling, microfracture, and abrasion arthroplasty, allowing endogenous mesenchymal stem cells (MSCs) to migrate into the lesion [9]. However, no treatment or procedure represents a cure for cartilaginous defects.

MSC-based therapy is beginning to show great potential in cartilage regeneration through several mechanisms including homing, angiogenesis, differentiation, and response to inflammatory condition. The most widely studied sources of MSCs are bone marrow (BM) and adipose tissue (AT). However, umbilical cord-derived MSCs (UC-MSCs) compared to AT- and BM-MSCs have many advantages such as higher proliferation rates, greater expansion ability, higher purity, and abundant supply along with no risks for the donor, since the UC is usually discarded after birth [10]. In Table 1 are listed the advantages and disadvantages of the different populations of stem/stromal cells used so far for cartilage regeneration purposes. UC-MSCs can be isolated from different regions of the UC stromal tissue called Wharton’s Jelly (WJ), and three different populations of UC-MSCs have been obtained: perivascular (PV-MSCs), intermediate WJ (WJ-MSCs), and subamniotic stromal region or cord lining (CL-MSCs) [11]. Notably, ECM components in WJ share several features with cartilage ECM. To this regard, UC-MSCs express aggrecan, type II collagen, and SOX-9 [12]. In addition, UC-MSCs express growth factors, chemokines, and cytokines at similar levels to those of cartilage [12]. Finally, since UC relies on only two arteries and one vein to supply oxygen and nutrients, without any capillary circulation, UC-MSCs are physiologically adapted to survive in a relatively hypoxic environment leading to the potential advantage to survive in cartilage. These results reinforce the concept of UC-MSCs as one of the best candidates for MSC-based therapy for cartilage regeneration.

2. Regeneration Mechanisms of UC-MSCs for Cartilage Diseases

There are two main concepts for UC-MSCs’ contribution to cartilage repair: preventing the degradation of cartilage, through the secretion of bioactive factors, and/or the differentiative potential of UC-MSCs to become chondrocytes. Several in vitro and in vivo studies indicated that UC-MSCs can play crucial roles in cartilage repair and regeneration by several mechanisms including (i) migration and homing, (ii) adaptation to cartilage hypoxic and nutrient-poor environment, (iii) chondrogenesis differentiation potential and promotion of survival, proliferation and differentiation of endogenous MSCs, (iv) synthesis and prevention of cartilage ECM degradation, and (v) anti-inflammatory and immunomodulatory properties.

2.1. Homing and Migration

MSCs exhibit certain capabilities of the homing of local mature leukocytes to inflammatory sites, such as rolling and adhesion [13]. Migration and homing ability into injured sites are considered as the primary steps for tissue repair in regenerative medicine. Different molecules mediate cell retention or mobilization such as adhesion molecules (E and P-selectin), integrins (particularly α4β1), stromal-derived factor 1 (SDF-1), and its receptor CXC chemokine receptor 4 (CXCR4) [13]. In addition, other factors play a key role in damaged joints homing such as CXCR1 and CXCR2, CC chemokine receptor 1 (CCR1), and monocyte chemoattractant protein 1 (MCP-1) through its receptor CCR2, vascular endothelial growth factor receptor 1 (Flt-1), platelet-derived growth factor receptor α (PDGFR-α, CD140a), PDGFR-β (CD140b), and their respective ligands IL-8, macrophage inflammatory protein 1α (MIP-1α), placenta growth factor (PlGF), and PDGF [14]. In Table 2, we reported different proteins involved in homing and migration of UC-MSCs in comparison with those expressed by BM- and AT-MSCs. In particular, BM- and AT-MSCs show similar expression pattern. On the other hand, based on the quantitative data reported in literature, UC-MSCs express higher levels of different proteins than BM- and AT-MSCs such as HGF, IL-8, IL-1RA, IGF-1, ICAM-1, bFGF, MCP-1, MIP-1β, PDGF-AA, PDGF-AB, PDGF-R, CXCR4, CCR2, VEGF-A, and VEGF-1. Interestingly, unlike cells from BM- and AT-MSCs, UC-MSCs express integrin α4 and MIP-1β suggesting their strong ability in homing and migration. In addition, UC-MSCs show less hematopoietic effects than BM- and AT-MSCs (low levels of SDF-1 and VCAM-1).

Increased levels of SDF-1, MCP-1, IL-8, MIP-1 α, PlGF, and PDGF were found in synovial fluid of OA and RA patients [14]. Shen et al. demonstrated that UC-MSCs secrete growth factors and chemokines which may contribute to a chemoattractive environment such as SDF-1, MCP-1, hepatocyte growth factor (HGF), vascular cell adhesion protein-1 (VCAM-1), IL-8, insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF) [15]. In addition, UC-MSCs express CXCR4, CCR2, and c-met receptors. Therefore, UC-MSCs are able to migrate in vitro and in vivo via the SDF-1/CXCR4 and MCP-1/CCR2 axes, and the secreted factors may induce the recruitment of cells from the surrounding tissues and promote regeneration of injured tissue [15]. To this regard, the SDF-1/CXCR4 axis has been shown to play a key role in endogenous and transplanted stem cell homing in the injured site promoting the regeneration of different tissues including cartilage [16, 17].

Another key player in cell adhesion is integrin α4β1 (very late antigen-4, VLA-4). It has been demonstrated a crucial link between the CXCR4/SDF-1 homing axis and the VLA-4/VCAM-1 (vascular cell adhesion molecule-1, CD106) adhesion axis [18]. In particular, SDF-1 (through CXCR4) increases VLA-4 adhesion to VCAM-1. VLA-4 is an integrin dimer composed of α4 (CD49d) and β1 (CD29) [19]. Although MSCs lack the expression of selectins, they express integrin β1. Interestingly, in contrast to BM-MSCs, UC-MSCs express integrin α4, VCAM-1, and intercellular adhesion molecule-1 (ICAM-1; CD54) supporting their stronger potential in homing [20].

One more ligand of integrin β1 is osteopontin (OPN), an osteogenic marker with several biological functions including migration, adhesion, and survival of MSCs [21]. On the other hand, OPN is also involved in regulation and propagation of inflammatory responses of macrophages, T-cells, and dendritic cells [22]. Notably, OPN is involved in different inflammatory pathologies including RA and OA pathogenesis [23, 24]. In a study of Schneider et al., UC-MSCs showed similar osteogenic and migration abilities compared to BM-MSCs with the lesser expression of OPN and the major expression of matrix metalloproteinases (MMP)-1 and -2 [25].

Moreover, extensive evidence found that growth factors play an important role in homing and migration of MSCs, as seen for basic fibroblast growth factor (bFGF), VEGF, HGF, IGF-1, PDGF, and transforming growth factor β1 (TGF-β1) [26]. In particular, UC-MSCs are able to migrate in vitro and in vivo, in response to chemotactic factors such as EGF, FGF-2, HGF, IGF-1, PDGF-BB, TGF-β, and VEGF, along with SDF-1, MCP-1, and VCAM-1 [15].

2.2. Capacity of Adaptation to Cartilage Hypoxic Environment

Because of the lack of vascularization, the physiological oxygen tension (physioxia) within human articular cartilage ranges between 2 and 5% [27]. Therefore, any MSC candidate for stem cell therapy of cartilage diseases should be able to adapt to a hypoxic environment with limited nutrient supply while maintaining its regenerative properties. Oxygen tension ranges from 1%-7% in bone marrow and from 10%-15% in adipose tissue [28, 29]. Regarding perinatal tissues such as the UC, oxygen tension within the mammalian female reproductive tract is low, between 1.5% and 8%, and lasts throughout the fetal development with dissolved oxygen in the fetal circulation rarely exceeding 5% [30]. Moreover, the UC is supplied by only two arteries and one vein and lacking in capillaries or lymphatics suggesting that UC-MSCs are physiologically adapted to survive in a hypoxic environment. It has been shown that low oxygen tension increases UC-MSC proliferation potential and matrix production and enhanced chondrogenic marker expression in UC-MSCs [31, 32]. This increased chondrogenic differentiation can lead to hypoxia-inducible factor-1 alpha (HIF-1α) and HIF-2α increased expression, NOTCH signaling activation, and the subsequent Sox-9 induction [33]. In addition, the UC-MSCs cultured under hypoxic conditions showed increased expression of energy metabolism-associated genes including GLUT-1, LDH, and PDK1 suggesting a switching of cell metabolism from oxidative phosphorylation to anaerobic glycolysis [32]. The yield of lactate production from glucose, however, is significantly lower in UC-MSCs than it has been reported in BM- and AT-MSCs in both hypoxic and normoxic conditions [32]. This finding could be explained by our recent study [34]. We demonstrated that all the three UC-MSC populations (PV-, WJ-, and CL-MSCs) exhibit low levels of mitochondrial and glycolytic activities. Moreover, PV-, WJ-, and CL-MSCs showed comparable mitochondrial respiration parameters in both normal and oxygen and glucose deprivation followed by reperfusion (OGD/R) conditions maintaining their proliferation capacity. Interestingly, PV-MSCs showed the highest oxygen consumption rate and OGD/R affected their metabolism but not their viability suggesting a superior mitochondrial activity compared to the other UC-MSC populations. While CL-MSCs were the cells least affected suggesting their robust survival in ischemic environment. These evidences taken together suggest that UC-MSCs may be a pivotal source for stem cell-based therapy of ischemic pathologies including chondropathies, brain, heart, and lung diseases [35–38]. Further investigations are needed to better understand whether these slight but significant differences among the three UC-MSCs are due to the specific region’s composition of different number of healthy mitochondria or improved adaptation of mitochondria to ischemic conditions.

2.3. Promotion of Survival, Proliferation, and Differentiation

MSCs secrete growth factors that are involved in several biological processes such as homing and migration as well as promotion of survival, proliferation, and differentiation. Some of growth factors with a key role in cartilage repair are bone morphogenetic proteins (BMPs), epidermal growth factor (EGF), HGF, IGF, PDGF, VEGF, FGF, and TGF families and UC-MSCs are a rich source of them [39].

EGF is one of the ligands of EGF receptor (EGFR) that plays a key role in joint homeostasis. In particular, EGFR stimulates chondrocyte proliferation and survival as well as maintenance of cartilage in adulthood. On one hand, EGFR signaling promotes the lubrication of the articular surface by increasing the boundary lubricants Prg4 and HA from superficial chondrocytes [40]. On the other hand, EGFR signaling also can play a catabolic action by inhibiting the expression of the chondrogenic master transcription factor Sox9, thereby suppressing the synthesis of cartilage matrix proteins, such as type II collagen (Col II) and aggrecan, as well as by stimulating the expression of MMPs involved in cartilage degradation, such as MMP-13 [41]. Interestingly, Zhang et al. recently showed the UC-MSCs release EGFR ligands TGF-α and EGF attenuating OA progression via EGFR signaling pathway of cartilage superficial layer cells [42]. In addition, UC-MSCs inhibited the apoptosis of chondrocytes, increased the expression of chondrogenesis-related genes (Col-2, Sox9), and reduced the expression of cartilage catabolism-related genes (MMP-13, ADAMTS-5) in vitro and in vivo [42].

HGF is a multifunctional growth factor that affects cell survival and proliferation, matrix metabolism, inflammatory response, and neurotrophic action playing an important role in normal bone and cartilage turnover [43]. In particular, HGF and VEGF can reduce tissue injury, inhibit fibrotic remodeling and apoptosis, promote angiogenesis, stimulate stem cell recruitment and proliferation, and reduce oxidative stress [44]. A recent comparative study showed that the secretion of HGF was three times higher in UC-MSCs compared to AT-MSCs and around nine times higher than in BM-MSCs [45]. In contrast, UC-MSCs secreted the lower levels of VEGF-A. This is probably due to the fact that VEGF-A and HGF signaling pathways reciprocally modulate each other [46].

IGF1 has been implicated in promotion of chondrogenesis and accumulation of cartilage-specific ECM molecules [47]. In addition, the synergy between TGF-β3 and IGF-1 promotes intervertebral disc regeneration [48]. WJ contains large amounts of IGF-I and IGF-I-binding proteins BP-3 and BP-1 suggesting a key role in stimulation of UC-MSCs to produce collagen and glycosaminoglycans (GAGs) in UC matrix as well as influencing the chondrogenic differentiation of these cells [49, 50].

TGF-β superfamily consists of about 30–35 different proteins including TGF-β proteins (TGF-β1-β2-β3), Bone Morphogenetic Proteins (BMPs), and Growth Differentiation Factors (GDFs) involved in chondrogenic differentiation and production of cartilage extracellular matrix as well as stimulation of cartilage repair [51]. TGF-β1, -β2, and -β3 play key roles in regulation of chondrocyte differentiation from early to terminal stages, including condensation, proliferation, terminal differentiation, and ECM synthesis as well as maintenance of articular chondrocytes [52]. All the three isoforms are expressed in mesenchymal condensations and secreted by UC-MSCs [53–55]. BMPs play important roles in bone and cartilage formation, including various aspects of embryonic development, such as skeletogenesis, and hematopoietic and epithelial cell differentiation [56]. Moreover, BMPs can induce protection against cartilage damage caused by inflammation or trauma, as well as stimulation of regenerative processes. BMPs are classified into subfamilies, including BMP subfamily (from BMP1 to BMP15), the osteogenic protein (OP) subfamily (OP1, OP2, and OP3 also known as BMP7, BMP8, and BMP8b, respectively), the GDF subfamily (GDF1, GDF2/BMP9, GDF3, GDF5/BMP14, GDF6/BMP13, GDF7/BMP12, GDF8, GDF9, GDF10, and GDF11/BMP11), and the cartilage-derived morphogenetic proteins (CDMP1/BMP14 and CDMP2/BMP13) [56]. BMP2, 4, 6, 7, and 9 have been reported to induce in vitro chondrogenesis of human MSCs [57]. UC-MSCs have been demonstrated to secrete BMP2 in vitro and to induce the increase of endogenous BMP4, 5, and 7 levels in vivo [58–60]. In addition, UC-MSCs induce overexpression of GDF5/BMP14/CDMP1, promoting chondrogenic differentiation in cocultures with fibroblast-like synoviocytes, thus, suggesting their potential in cartilage repair [61]. Moreover, UC-MSCs respond to BMP6 via decapentaplegic homolog (SMAD) signaling (SMAD 1/4/5, BMPR1A, and BMPR2 receptors) enhancing osteogenic differentiation [62]. In particular, BMP-2 stimulates osteogenesis as well as matrix synthesis, promoting cartilage repair (by upregulation of tissue inhibitors of metalloproteinases-1, TIMP-1) and reversing chondrocyte dedifferentiation [63]. BMP-7 promotes cartilage matrix synthesis by acting synergistically with other anabolic growth factors and also inhibits catabolic factors, such as matrix metalloproteinase-1 (MMP-1), MMP-13, IL-1, Il-6, and IL-8 [64].

2.4. Cartilage Extracellular Matrix Repair

UC-MSCs can increase the ECM synthesis and inhibit the cartilage ECM destruction supporting the tissue repair. UC stromal tissue shares a number of features with cartilage ECM: UC-MSCs are able to synthetize aggrecan, type II collagen, and express SOX-9 transcription factor [12]. The deposition of ECM molecules and regulation of MMPs and their inhibitors (TIMPs) are the main mechanisms involved in cartilage ECM synthesis. MSCs secrete high levels of TIMP-1 and TIMP-2, which inhibit MMP-9 and MMP-2, respectively, thus, suppressing cartilage ECM resorption [65]. UC-MSCs secrete MMP-2, -8, -9, and -13 as well as TIMP-1 and TIMP-2 suggesting a balance between protection of ECM and antifibrotic activity (Table 2) [66–68]. In addition, UC-MSCs secrete growth factors such as HGF, IGF-1, and TGF-β superfamily members that stimulate cartilage ECM synthesis. In particular, HGF has been involved in inhibition of the fibrosis and apoptosis of chondrocytes and increase ECM synthesis [65]. IGF-I and IGF-I-BP-3 and -BP-1 stimulate UC-MSCs to produce collagen and glycosaminoglycans (GAGs) [49]. BMP-2 increases TIMP-1 expression while BMP-7 inhibits MMP-1 and MMP-13 suppressing the ECM degradation [63, 64].

2.5. Anti-Inflammatory and Immunomodulatory Properties

The microenvironment of damaged articular cartilage is particularly challenging, due to hypoxia, insufficient blood supply, and concurrent inflammation. The latter contributes to the degeneration of the joints because it hampers the proliferation of chondrocytes and the deposition of cartilage matrix, resulting in low efficiency of repair. Immunomodulatory and anti-inflammatory properties of UC-MSCs have been widely described (Table 2) [69]. In particular, UC-MSCs express MHC class I (HLA-ABC) at low levels and lack MHC class II (HLA-DR, -DP, and -DQ). Moreover, they express other molecules belonging to noncanonical type I MHC such as HLA-G, HLA-E, and HLA-F [70–72]. Interestingly, HLA-G interacts with Ig-like transcript (ILT) receptors (ILT-2, ILT-3, and ILT-4), which are expressed by T and B lymphocytes, as well as natural killer (NK) cells and mononuclear phagocytes [69]. Through this interaction, HLA-G displays relevant immune functions which physiologically contribute to maternal-fetal immunotolerance. In addition, UC-MSCs lack CD40/CD40L, CD80, CD86, and B7 costimulatory antigens implicated in the activation of T and B cell responses and express coinhibitory molecules including B7-H3/CD276, CD73, Indolamine 2,3-dioxygenase-1 (IDO-1), Galectin-1 (Gal-1), and leukemia inhibitory factor (LIF) [73]. WJ-MSCs showed an immunosuppressive function by inhibiting the proliferative response of T helper cells (Th/CD4+) Type 1 (Th1) and Th17 and increasing Th2 and regulatory T cells (Tregs) [74]. UC-MSCs have been shown to be able to suppress the proliferation of both CD4 and CD8 cytotoxic T lymphocytes (Tc) and to decrease proinflammatory IFN-γ in activated peripheral blood mononuclear cells (PBMCs) [54, 75]. Moreover, secreted factors such as HGF and TGF-β1 may function as mediators for T cell suppression [76, 77]. UC-MSCs are also able to inhibit B-cells and natural killer (NK) cell proliferation as well as regulate monocyte/macrophage system by reducing the infiltration of macrophages in injured tissues and shifting macrophages toward a M2 anti-inflammatory phenotype [78, 79].

In the synovia of OA patients, various immune cells have been identified including M1 macrophages, T cells Th1, Th17 and Tc, and B cells, leading to chronic inflammation, exacerbation of arthritis, and tissue damage [80]. UC-MSCs have been shown to reduce synovial inflammatory cells infiltration, such as CD4+ T cells and macrophages, as well as significantly decrease the expression of interleukin- (IL-) 1β and tumor necrosis factor-α (TNF-α), while increasing anti-inflammatory factors TNF-α-induced protein 6 (TSG-6) and IL-1 receptor antagonist (IL-1RA) in rat OA models induced by monosodium iodoacetate (MIA) [81, 82]. In another study of MIA-induced OA in rabbits, UC-MSCs showed a prominent cartilage protective effect due to upregulation of growth factors FGF-2, TGF-β1, and IGF-1, secretion of ECM molecules (collagen type-I alpha-1 chain, collagen type-II alpha-1 chain, and aggrecan), reduction of the expression levels of proinflammatory cytokines Tnf-α, IL-1β, IL-6, and IL-17, and increase of anti-inflammatory cytokines TGF-β1, IL-10, and IL-1RA [83]. Interestingly, our group and others showed that UC-MSCs keep their hypoimmunogenic and immunomodulatory properties even when they had undergone in vitro chondrocyte differentiation [50, 84].

RA is a chronic inflammatory autoimmune disease characterized by chronic proliferation of synovial cells and progressive joint damage [85]. Fibroblast-like synoviocytes (FLS) play an important role in thickening of the synovium determining arthritis and cartilage degradation as well as inflammation and degradation of the joints. UC-MSCs inhibit Cadherin 11 expression in RA FLS by secreting IL-10. This event precludes the ability of FLS from RA patients to migrate and erode cartilage of other joints, thereby improving arthritis [86].

3. Preclinical and Clinical Studies of UC-MSCs for the Treatment of Cartilaginous Diseases

Thanks to their chondrogenic potential and immunomodulatory and anti-inflammatory properties, as well as their ability to promote endogenous repair mechanisms, UC-MSCs have been regarded as potential therapeutic agents against cartilage degradation. In particular, early evidences that emerged from in vitro studies on cell cultures (summarized in Table 3) have been confirmed in several in vivo animal models (listed in Table 4) and in recent clinical trials (reported in Table 5).

Preliminary in vitro studies investigated the chondrogenic potential of UC-MSCs, demonstrating their ability to achieve both hyaline, fibrous, and elastic cartilage phenotypes as well as nucleus pulposus-like cell differentiation capacity [87–90]. In addition, also the osteogenic, adipogenic, and myogenic differentiation potential have been reported suggesting UC-MSCs could be a pivotal stem cells source for tissue engineering applications in orthopaedics [91]. Comparative studies reported slightly differences in chondrogenesis between the UC-, BM-, and AT-MSCs. In particular, according to Danišovič et al., BM-MSCs showed the best chondrogenic potential while Hildner and coworkers showed that differentiated UC-MSCs present a more fibrous than hyaline cartilage phenotype compared to AT-MSCs suggesting their role in regeneration of fibrocartilage-like meniscus [87, 92]. Moreover, the results of Wu and coworkers indicate that, although nucleus pulposus stem/progenitor cells (D-NP-MSCs) isolated from degenerated intervertebral disc (IVD) shared the MSCs characteristics with UC-MSCs, the latter showed better proliferation capacity and differentiation potential, suggesting that UC-MSCs as a suitable source for regenerative therapy of IVD degeneration [93]. Furthermore, UC-MSCs may be an attractive alternative to condylar cartilage cells for temporomandibular joint tissue engineering applications [94]. Interestingly, UC-MSCs displayed superior anti-inflammatory, immunomodulatory, and trophic effects compared to adult MSCs including articular cartilage (AC), Hoffa’s fat pad (HFP), synovial membrane (SM), and maintain their immunomodulatory and anti-inflammatory properties after differentiation [50, 84, 95]. Moreover, coculture experiments of UC-MSCs and articular cartilage cells (ACs), fibroblast-like synoviocytes (FLSs), and nucleus pulposus cells (NPCs) showed their suitability for the treatment of arthritis, synovitis, and IVD degeneration [61, 96–98]. Finally, there are several cartilage tissue engineering studies that demonstrated the osteochondral differentiation capacity of UC-MSCs in different scaffold constituted by acellular cartilage extracellular matrix (ACECM), alginate enriched in hyaluronic acid (Alg/HA), polycaprolactone/collagen (PCL/Coll), polyglycolic acid (PGA), poly L-lactide/D-lactide/glycolide (PLGA), poly-L-lactic acid (PLLA), polyvinyl alcohol-polycaprolactone (PVA-PCL), and silk fibroin/hyaluronic acid (SF/HA).

In vivo studies in different animal models from mice to horses confirmed in vitro studies showing the feasibility of using UC-MSCs for the treatment of IVD degeneration, OA, RA, and cartilage defects repair. UC-MSC transplantation promotes chondrogenesis and improves the histology, cellularity, and ECM proteins content along with reduction of inflammation in a preclinical model of IVD degeneration. In the same way, UC-MSCs induce regeneration and repair of cartilage reducing its destruction, promote recovery from movement impairment, and reduce joint effusion and inflammation slowing down the progression of OA animal models. In addition, preclinical studies on RA treatment showed that UC-MSCs exerted the best therapeutic effect in reducing bone resorption, joint destruction, and inflammatory factor expression compared to BM-MSCs. Interestingly, several evidences support the regenerative potential of UC-MSCs in cartilage and osteochondral defects repair.

Following the promising in vitro and in vivo results, clinical applications have been attempted using UC-MSCs for the treatment of OA and RA (Table 5). In summary, clinical trials for the treatment of OA showed significant amelioration of pain and disability at 6 and 12 months of follow-up. No severe adverse events were reported. The main outcomes for RA patients treated with UC-MSCs were significant reduction of RA serological markers and improvement of health index and joint function index 1 year after treatment. No new or unexpected safety issues in 1-year follow-up. Despite the promising results of clinical trials, further basic and translational research investigations are needed to better understand the best stem cell candidate, scaffold materials, and/or best cellular derivatives which can be suitable for the different types of cartilage regeneration. In parallel, there is the need to increase the knowledge about underlying regenerative mechanisms. Finally, more research is needed to convert preclinical evidences obtained in animal models, to human-based clinical applications for cartilage regeneration. Consensus is still lacking in key points such as the methods to obtain the cell source, the use of scaffolds as well as bioactive molecules in parallel to the administration of stromal cells. As shown in the human studies reviewed so far, the achievement of amelioration of some parameters and confirmation of the safety of the overall procedure still needs more data generated on the interaction of the transplanted cells with the host tissue, their proper differentiation in vivo, as well as the long-term achievements of this cellular replacement strategy.

4. Conclusions

In conclusion, UC-MSCs represent a promising candidate for the therapy of chondropathies, as highlighted by the encouraging results emerged from in vitro and in vivo investigations and from the available results from clinical trials. UC-MSCs are characterized by several potential advantages such as a frank multilineage differentiation potential, immunomodulatory, and anti-inflammatory properties, as well as MSCs the ability to constitutively produce molecules that are involved in cartilage matrix biogenesis and in the trophic and reparative functions. In addition, UC-MSCs are able to migrate, home, and survive in an ischemic and nutrient-poor environment like cartilage as well as to produce an extracellular matrix (ECM) similar to that and induce endogenous repair mechanisms. We believe that these results warrant the need for further researches that can better define the criteria leading to the adoption of UC-MSCs in the stem cell-based therapy of cartilage diseases, as well as characterizing the mechanism of repair and increase the knowledge on the biomechanical properties of the regenerated cartilage tissue in vivo.

Conflicts of Interest

Prof. Giampiero La Rocca is member of the Scientific board of Auxocell Laboratories, Inc. The other authors report no conflicts.

Acknowledgments

GLR is a recipient of a PRIN 2017 fund by the Italian Ministry of University.

References

Y. Krishnan and A. J. Grodzinsky, “Cartilage diseases,” Matrix Biology, vol. 71-72, pp. 51–69, 2018.
View at: Publisher Site | Google Scholar
A. Cieza, K. Causey, K. Kamenov, S. W. Hanson, S. Chatterji, and T. Vos, “Global estimates of the need for rehabilitation based on the Global Burden of Disease study 2019: a systematic analysis for the Global Burden of Disease Study 2019,” The Lancet, vol. 396, no. 10267, pp. 2006–2017, 2021.
View at: Google Scholar
Y. P. Li, X. C. Wei, J. M. Zhou, and L. Wei, “The age-related changes in cartilage and osteoarthritis,” BioMed Research International, vol. 2013, Article ID 916530, 12 pages, 2013.
View at: Publisher Site | Google Scholar
N. Arden and M. Nevitt, “Osteoarthritis: epidemiology,” Best Practice & Research. Clinical Rheumatology, vol. 20, no. 1, pp. 3–25, 2006.
View at: Publisher Site | Google Scholar
W. M. Hopman, M. B. Harrison, H. Coo, E. Friedberg, M. Buchanan, and E. G. VanDenKerkhof, “Associations between chronic disease, age and physical and mental health status,” Chronic Diseases in Canada, vol. 29, no. 3, pp. 108–117, 2009.
View at: Publisher Site | Google Scholar
D. Umlauf, S. Frank, T. Pap, and J. Bertrand, “Cartilage biology, pathology, and repair,” Cellular and Molecular Life Sciences, vol. 67, no. 24, pp. 4197–4211, 2010.
View at: Publisher Site | Google Scholar
T. W. O’Neill and D. T. Felson, “Mechanisms of osteoarthritis (OA) pain,” Current Osteoporosis Reports, vol. 16, no. 5, pp. 611–616, 2018.
View at: Publisher Site | Google Scholar
M. C. Reid, R. Shengelia, and S. J. Parker, “Pharmacologic management of osteoarthritis-related pain in older adults,” HSS Journal, vol. 8, no. 2, pp. 159–164, 2012.
View at: Publisher Site | Google Scholar
P. Orth, A. Rey-Rico, J. K. Venkatesan, H. Madry, and M. Cucchiarini, “Current perspectives in stem cell research for knee cartilage repair,” Stem Cells Cloning, vol. 7, pp. 1–17, 2014.
View at: Google Scholar
D. L. Troyer and M. L. Weiss, “Concise review: Wharton’s jelly-derived cells are a primitive stromal cell population,” Stem Cells, vol. 26, no. 3, pp. 591–599, 2008.
View at: Publisher Site | Google Scholar
J. E. Davies, J. T. Walker, and A. Keating, “Concise review: Wharton's jelly: the rich, but enigmatic, source of mesenchymal stromal cells,” Stem Cells Translational Medicine, vol. 6, no. 7, pp. 1620–1630, 2017.
View at: Publisher Site | Google Scholar
S. Liu, K. D. Hou, M. Yuan et al., “Characteristics of mesenchymal stem cells derived from Wharton's jelly of human umbilical cord and for fabrication of non-scaffold tissue-engineered cartilage,” Journal of Bioscience and Bioengineering, vol. 117, no. 2, pp. 229–235, 2014.
View at: Publisher Site | Google Scholar
Y. Yin, X. Li, X. T. He, R. X. Wu, H. H. Sun, and F. M. Chen, “Leveraging stem cell homing for therapeutic regeneration,” Journal of Dental Research, vol. 96, no. 6, pp. 601–609, 2017.
View at: Publisher Site | Google Scholar
O. I. Eseonu and C. De Bari, “Homing of mesenchymal stem cells: mechanistic or stochastic? Implications for targeted delivery in arthritis,” Rheumatology, vol. 54, no. 2, pp. 210–218, 2015.
View at: Publisher Site | Google Scholar
C. Shen, P. Lie, T. Miao et al., “Conditioned medium from umbilical cord mesenchymal stem cells induces migration and angiogenesis,” Molecular Medicine Reports, vol. 12, no. 1, pp. 20–30, 2015.
View at: Publisher Site | Google Scholar
T. Kitaori, H. Ito, E. M. Schwarz et al., “Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model,” Arthritis and Rheumatism, vol. 60, no. 3, pp. 813–823, 2009.
View at: Publisher Site | Google Scholar
W. Zhang, J. Chen, J. Tao et al., “The use of type 1 collagen scaffold containing stromal cell-derived factor-1 to create a matrix environment conducive to partial-thickness cartilage defects repair,” Biomaterials, vol. 34, no. 3, pp. 713–723, 2013.
View at: Publisher Site | Google Scholar
J. M. Petty, C. C. Lenox, D. J. Weiss, M. E. Poynter, and B. T. Suratt, “Crosstalk between CXCR4/Stromal Derived Factor-1 and VLA-4/VCAM-1 pathways regulates neutrophil retention in the bone marrow,” The Journal of Immunology, vol. 182, no. 1, pp. 604–612, 2009.
View at: Publisher Site | Google Scholar
D. Cox, M. Brennan, and N. Moran, “Integrins as therapeutic targets: lessons and opportunities,” Nature Reviews Drug Discovery, vol. 9, no. 10, pp. 804–820, 2010.
View at: Publisher Site | Google Scholar
N. L. Payne, G. Sun, C. McDonald et al., “Distinct immunomodulatory and migratory mechanisms underpin the therapeutic potential of human mesenchymal stem cells in autoimmune demyelination,” Cell Transplantation, vol. 22, no. 8, pp. 1409–1425, 2013.
View at: Publisher Site | Google Scholar
C. Zou, Q. Luo, J. Qin et al., “Osteopontin promotes mesenchymal stem cell migration and lessens cell stiffness via integrin β1, FAK, and ERK pathways,” Cell Biochemistry and Biophysics, vol. 65, no. 3, pp. 455–462, 2013.
View at: Publisher Site | Google Scholar
S. A. Lund, C. M. Giachelli, and M. Scatena, “The role of osteopontin in inflammatory processes,” Journal of Cell Communication and Signaling, vol. 3, no. 3-4, pp. 311–322, 2009.
View at: Publisher Site | Google Scholar
F. Zhang, W. Luo, Y. Li, S. Gao, and G. Lei, “Role of osteopontin in rheumatoid arthritis,” Rheumatology International, vol. 35, no. 4, pp. 589–595, 2015.
View at: Publisher Site | Google Scholar
C. Cheng, S. Gao, and G. Lei, “Association of osteopontin with osteoarthritis,” Rheumatology International, vol. 34, no. 12, pp. 1627–1631, 2014.
View at: Publisher Site | Google Scholar
R. K. Schneider, A. Puellen, R. Kramann et al., “The osteogenic differentiation of adult bone marrow and perinatal umbilical mesenchymal stem cells and matrix remodelling in three-dimensional collagen scaffolds,” Biomaterials, vol. 31, no. 3, pp. 467–480, 2010.
View at: Publisher Site | Google Scholar
X. Fu, G. Liu, A. Halim, Y. Ju, Q. Luo, and G. Song, “Mesenchymal stem cell migration and tissue repair,” Cell, vol. 8, no. 8, p. 784, 2019.
View at: Publisher Site | Google Scholar
G. Pattappa, B. Johnstone, J. Zellner, D. Docheva, and P. Angele, “The importance of physioxia in mesenchymal stem cell chondrogenesis and the mechanisms controlling its response,” International Journal of Molecular Sciences, vol. 20, no. 3, p. 484, 2019.
View at: Publisher Site | Google Scholar
D. C. Chow, L. A. Wenning, W. M. Miller, and E. T. Papoutsakis, “Modeling pO₂ Distributions in the Bone Marrow Hematopoietic Compartment. I. Krogh's Model,” Biophysical Journal, vol. 81, no. 2, pp. 675–684, 2001.
View at: Publisher Site | Google Scholar
A. Bizzarri, H. Koehler, M. Cajlakovic et al., “Continuous oxygen monitoring in subcutaneous adipose tissue using microdialysis,” Analytica Chimica Acta, vol. 573-574, pp. 48–56, 2006.
View at: Publisher Site | Google Scholar
B. Fischer and B. D. Bavister, “Oxygen-tension in the oviduct and uterus of rhesus-monkeys, hamsters and rabbits,” Journal of Reproduction and Fertility, vol. 99, no. 2, pp. 673–679, 1993.
View at: Publisher Site | Google Scholar
A. Marmotti, S. Mattia, F. Castoldi et al., “Allogeneic umbilical cord-derived mesenchymal stem cells as a potential source for cartilage and bone regeneration: an in vitro study,” Stem Cells International, vol. 2017, Article ID 1732094, 16 pages, 2017.
View at: Publisher Site | Google Scholar
A. Lavrentieva, I. Majore, C. Kasper, and R. Hass, “Effects of hypoxic culture conditions on umbilical cord-derived human mesenchymal stem cells,” Cell Communication and Signaling: CCS, vol. 8, no. 1, p. 18, 2010.
View at: Publisher Site | Google Scholar
U. Nekanti, S. Dastidar, P. Venugopal, S. Totey, and M. Ta, “Increased proliferation and analysis of differential gene expression in human Wharton's jelly-derived mesenchymal stromal cells under hypoxia,” International Journal of Biological Sciences, vol. 6, no. 5, pp. 499–512, 2010.
View at: Publisher Site | Google Scholar
E. Russo, J. Y. Lee, H. Nguyen et al., “Energy metabolism analysis of three different mesenchymal stem cell populations of umbilical cord under normal and pathologic conditions,” Stem Cell Reviews and Reports, vol. 16, no. 3, pp. 585–595, 2020.
View at: Publisher Site | Google Scholar
Y. Kaneko, J. Y. Lee, N. Tajiri et al., “Translating intracarotid artery transplantation of bone marrow-derived NCS-01 cells for ischemic stroke: behavioral and histological readouts and mechanistic insights into stem cell therapy,” Stem Cells Translational Medicine, vol. 9, no. 2, pp. 203–220, 2020.
View at: Publisher Site | Google Scholar
E. G. Neal, M. G. Liska, T. Lippert et al., “An update on intracerebral stem cell grafts,” Expert Review of Neurotherapeutics, vol. 18, no. 7, pp. 557–572, 2018.
View at: Publisher Site | Google Scholar
B. Cozene, E. Russo, R. Anzalone, G. La Rocca, and C. Borlongan, “Mitochondrial activity of human umbilical cord mesenchymal stem cells,” Brain Circulation, vol. 7, no. 1, pp. 33–36, 2021.
View at: Google Scholar
E. Russo, T. Lippert, J. P. Tuazon, and C. V. Borlongan, “Advancing stem cells: new therapeutic strategies for treating central nervous system disorders,” Brain Circulation, vol. 4, no. 3, pp. 81–83, 2018.
View at: Google Scholar
K. Sobolewski, A. Małkowski, E. Bańkowski, and S. Jaworski, “Wharton's jelly as a reservoir of peptide growth factors,” Placenta, vol. 26, no. 10, pp. 747–752, 2005.
View at: Publisher Site | Google Scholar
L. Qin and F. Beier, “EGFR Signaling: friend or foe for cartilage?” JBMR Plus, vol. 3, no. 2, article e10177, 2019.
View at: Publisher Site | Google Scholar
D. L. Long, V. Ulici, S. Chubinskaya, and R. F. Loeser, “Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is increased in osteoarthritis and regulates chondrocyte catabolic and anabolic activities,” Osteoarthritis and Cartilage, vol. 23, no. 9, pp. 1523–1531, 2015.
View at: Publisher Site | Google Scholar
X. Zhang, S. Liu, Z. Wang et al., “Implanted 3D gelatin microcryogel enables low-dose cell therapy for osteoarthritis by preserving the viability and function of umbilical cord MSCs,” Chemical Engineering Journal, vol. 416, article 129140, 2021.
View at: Publisher Site | Google Scholar
H. Tonomura, M. Nagae, R. Takatori, H. Ishibashi, T. Itsuji, and K. Takahashi, “The potential role of hepatocyte growth factor in degenerative disorders of the synovial joint and spine,” International Journal of Molecular Sciences, vol. 21, no. 22, p. 8717, 2020.
View at: Publisher Site | Google Scholar
Y. Wang, M. Yuan, Q. Guo, S. Lu, and J. Peng, “Mesenchymal stem cells for treating articular cartilage defects and osteoarthritis,” Cell Transplantation, vol. 24, no. 9, pp. 1661–1678, 2015.
View at: Publisher Site | Google Scholar
Y. Petrenko, I. Vackova, K. Kekulova et al., “A comparative analysis of multipotent mesenchymal stromal cells derived from different sources, with a focus on neuroregenerative potential,” Scientific Reports, vol. 10, no. 1, p. 4290, 2020.
View at: Publisher Site | Google Scholar
E. Sulpice, S. Ding, B. Muscatelli-Groux et al., “Cross-talk between the VEGF-A and HGF signalling pathways in endothelial cells,” Biology of the Cell, vol. 101, no. 9, pp. 525–539, 2009.
View at: Publisher Site | Google Scholar
B. E. Bobick, F. H. Chen, A. M. Le, and R. S. Tuan, “Regulation of the chondrogenic phenotype in culture,” Birth Defects Research Part C: Embryo Today: Reviews, vol. 87, no. 4, pp. 351–371, 2009.
View at: Publisher Site | Google Scholar
Y. Tao, X. Zhou, C. Liang et al., “TGF-β3 and IGF-1 synergy ameliorates nucleus pulposus mesenchymal stem cell differentiation towards the nucleus pulposus cell type through MAPK/ERK signaling,” Growth Factors, vol. 33, no. 5-6, pp. 326–336, 2015.
View at: Publisher Site | Google Scholar
J. Palka, E. Bańkowski, and S. Jaworski, “An accumulation of IGF-I and IGF-binding proteins in human umbilical cord,” Molecular and Cellular Biochemistry, vol. 206, no. 1/2, pp. 133–139, 2000.
View at: Publisher Site | Google Scholar
G. La Rocca, M. Lo Iacono, T. Corsello, S. Corrao, F. Farina, and R. Anzalone, “Human Wharton's jelly mesenchymal stem cells maintain the expression of key immunomodulatory molecules when subjected to osteogenic, adipogenic and chondrogenic differentiation in vitro: new perspectives for cellular therapy,” Current Stem Cell Research & Therapy, vol. 8, no. 1, pp. 100–113, 2013.
View at: Publisher Site | Google Scholar
W. Wang, D. Rigueur, and K. M. Lyons, “TGFβ signaling in cartilage development and maintenance,” Birth Defects Research Part C: Embryo Today: Reviews, vol. 102, no. 1, pp. 37–51, 2014.
View at: Publisher Site | Google Scholar
A. S. Patil, R. B. Sable, and R. M. Kothari, “An update on transforming growth factor-β (TGF-β): sources, types, functions and clinical applicability for cartilage/bone healing,” Journal of Cellular Physiology, vol. 226, no. 12, pp. 3094–3103, 2011.
View at: Publisher Site | Google Scholar
G. Y. Liu, Y. Xu, Y. Li, L. H. Wang, Y. J. Liu, and D. Zhu, “Secreted galectin-3 as a possible biomarker for the immunomodulatory potential of human umbilical cord mesenchymal stromal cells,” Cytotherapy, vol. 15, no. 10, pp. 1208–1217, 2013.
View at: Publisher Site | Google Scholar
R. Donders, J. F. Bogie, S. Ravanidis et al., “Human Wharton's jelly-derived stem cells display a distinct immunomodulatory and proregenerative transcriptional signature compared to bone marrow-derived stem cells,” Stem Cells and Development, vol. 27, no. 2, pp. 65–84, 2018.
View at: Publisher Site | Google Scholar
I. B. Copland, S. L. Adamson, M. Post, S. J. Lye, and I. Caniggia, “TGF-β3 Expression During Umbilical Cord Development and its Alteration in Pre- eclampsia,” Placenta, vol. 23, no. 4, pp. 311–321, 2002.
View at: Publisher Site | Google Scholar
Z. H. Deng, Y. S. Li, X. Gao, G. H. Lei, and J. Huard, “Bone morphogenetic proteins for articular cartilage regeneration,” Osteoarthritis and Cartilage, vol. 26, no. 9, pp. 1153–1161, 2018.
View at: Publisher Site | Google Scholar
S. Scarfì, “Use of bone morphogenetic proteins in mesenchymal stem cell stimulation of cartilage and bone repair,” World Journal of Stem Cells, vol. 8, no. 1, pp. 1–12, 2016.
View at: Publisher Site | Google Scholar
M. Kosinski, A. Figiel-Dabrowska, W. Lech et al., “Bone defect repair using a bone substitute supported by mesenchymal stem cells derived from the umbilical cord,” Stem Cells International, vol. 2020, Article ID 1321283, 15 pages, 2020.
View at: Publisher Site | Google Scholar
J. Choi, T. Bae, N. Byambasuren et al., “CRISPR-Cpf1 Activation of Endogenous _BMP4_ Gene for Osteogenic Differentiation of Umbilical-Cord-Derived Mesenchymal Stem Cells,” Molecular Therapy - Methods & Clinical Development, vol. 17, pp. 309–316, 2020.
View at: Publisher Site | Google Scholar
D. B. Guo, X. Q. Zhu, Q. Q. Li et al., “Efficacy and mechanisms underlying the effects of allogeneic umbilical cord mesenchymal stem cell transplantation on acute radiation injury in tree shrews,” Cytotechnology, vol. 70, no. 5, pp. 1447–1468, 2018.
View at: Publisher Site | Google Scholar
J. Zeng, F. Wang, and M. Mao, “Co-culture of fibroblast-like synoviocytes with umbilical cord-mesenchymal stem cells inhibits expression of pro-inflammatory proteins, induces apoptosis and promotes chondrogenesis,” Molecular Medicine Reports, vol. 14, no. 4, pp. 3887–3893, 2016.
View at: Publisher Site | Google Scholar
Q. Wang, L. Xu, R. Willumeit-Römer, and B. J. Luthringer-Feyerabend, “Macrophage-derived oncostatin M/bone morphogenetic protein 6 in response to Mg-based materials influences pro-osteogenic activity of human umbilical cord perivascular cells,” Acta Biomaterialia, vol. 133, pp. 268–279, 2020.
View at: Google Scholar
S. R. Frenkel, P. B. Saadeh, B. J. Mehrara et al., “Transforming growth factor beta superfamily members: role in cartilage modeling,” Plastic and Reconstructive Surgery, vol. 105, no. 3, pp. 980–990, 2000.
View at: Publisher Site | Google Scholar
R. S. Tuan, A. F. Chen, and B. A. Klatt, “Cartilage regeneration,” The Journal of the American Academy of Orthopaedic Surgeons, vol. 21, no. 5, pp. 303–311, 2013.
View at: Publisher Site | Google Scholar
P. Kangari, T. Talaei-Khozani, I. Razeghian-Jahromi, and M. Razmkhah, “Mesenchymal stem cells: amazing remedies for bone and cartilage defects,” Stem Cell Research & Therapy, vol. 11, no. 1, p. 492, 2020.
View at: Publisher Site | Google Scholar
A. Mauro, M. Buscemi, and A. Gerbino, “Immunohistochemical and transcriptional expression of matrix metalloproteinases in full-term human umbilical cord and human umbilical vein endothelial cells,” Journal of Molecular Histology, vol. 41, no. 6, pp. 367–377, 2010.
View at: Publisher Site | Google Scholar
M. Lo Iacono, E. Russo, R. Anzalone et al., “Wharton's jelly mesenchymal stromal cells support the expansion of cord blood-derived CD34+Cells mimicking a hematopoietic niche in a direct cell-cell contact culture system,” Cell Transplantation, vol. 27, no. 1, pp. 117–129, 2018.
View at: Publisher Site | Google Scholar
A. Gupta, S. F. el-Amin III, H. J. Levy, R. Sze-Tu, S. E. Ibim, and N. Maffulli, “Umbilical cord-derived Wharton's jelly for regenerative medicine applications,” Journal of Orthopaedic Surgery and Research, vol. 15, no. 1, p. 49, 2020.
View at: Publisher Site | Google Scholar
M. Trapani, G. La Rocca, and O. Parolini, “Chapter 6. The immunomodulatory features of mesenchymal stromal cells derived from Wharton’s jelly, amniotic membrane, and chorionic villi: in vitro and in vivo data,” in Placenta: The Tree of Life, pp. 91–128, CRC Press, Boca Raton, FL, USA, 2016.
View at: Google Scholar
G. la Rocca, R. Anzalone, S. Corrao et al., “Isolation and characterization of Oct-4+/HLA-G+ mesenchymal stem cells from human umbilical cord matrix: differentiation potential and detection of new markers,” Histochemistry and Cell Biology, vol. 131, no. 2, pp. 267–282, 2009.
View at: Publisher Site | Google Scholar
G. La Rocca, S. Corrao, M. Lo Iacono, T. Corsello, F. Farina, and R. Anzalone, “Novel immunomodulatory markers expressed by human WJ-MSC: an updated review in regenerative and reparative medicine,” The Open Tissue Engineering and Regenerative Medicine Journal, vol. 5, no. 1, pp. 50–58, 2012.
View at: Publisher Site | Google Scholar
R. Anzalone, M. Lo Iacono, T. Loria et al., “Wharton's jelly mesenchymal stem cells as candidates for beta cells regeneration: extending the differentiative and immunomodulatory benefits of adult mesenchymal stem cells for the treatment of type 1 diabetes,” Stem Cell Reviews and Reports, vol. 7, no. 2, pp. 342–363, 2011.
View at: Publisher Site | Google Scholar
T. Corsello, G. Amico, S. Corrao et al., “Wharton's jelly mesenchymal stromal cells from human umbilical cord: a close-up on immunomodulatory molecules featured in situ and in vitro,” Stem Cell Reviews and Reports, vol. 15, no. 6, pp. 900–918, 2019.
View at: Publisher Site | Google Scholar
Q. Wang, Q. Yang, Z. Wang et al., “Comparative analysis of human mesenchymal stem cells from fetal-bone marrow, adipose tissue, and Warton's jelly as sources of cell immunomodulatory therapy,” Human Vaccines & Immunotherapeutics, vol. 12, no. 1, pp. 85–96, 2016.
View at: Publisher Site | Google Scholar
M. Najar, G. Raicevic, H. I. Boufker et al., “Mesenchymal stromal cells use PGE2 to modulate activation and proliferation of lymphocyte subsets: combined comparison of adipose tissue, Wharton's Jelly and bone marrow sources,” Cellular Immunology, vol. 264, no. 2, pp. 171–179, 2010.
View at: Publisher Site | Google Scholar
R. Anzalone, M. L. Iacono, S. Corrao et al., “New emerging potentials for human Wharton’s jelly mesenchymal stem cells: immunological features and hepatocyte-like differentiative capacity,” Stem Cells and Development, vol. 19, no. 4, pp. 423–438, 2010.
View at: Publisher Site | Google Scholar
M. di Nicola, C. Carlo-Stella, M. Magni et al., “Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli,” Blood, vol. 99, no. 10, pp. 3838–3843, 2002.
View at: Publisher Site | Google Scholar
L. Ma, Z. Zhou, D. Zhang et al., “Immunosuppressive function of mesenchymal stem cells from human umbilical cord matrix in immune thrombocytopenia patients,” Thrombosis and Haemostasis, vol. 107, no. 5, pp. 937–950, 2012.
View at: Publisher Site | Google Scholar
W. Li, Q. Zhang, M. Wang et al., “Macrophages are involved in the protective role of human umbilical cord- derived stromal cells in renal ischemia-reperfusion injury,” Stem Cell Research, vol. 10, no. 3, p. 405, 2013.
View at: Publisher Site | Google Scholar
X. Zhao, Y. Zhao, X. Sun, Y. Xing, X. Wang, and Q. Yang, “Immunomodulation of MSCs and MSC-derived extracellular vesicles in osteoarthritis,” Frontiers in Bioengineering and Biotechnology, vol. 8, article 575057, 2020.
View at: Publisher Site | Google Scholar
W. Tong, X. Zhang, Q. Zhang et al., “Multiple umbilical cord-derived MSCs administrations attenuate rat osteoarthritis progression via preserving articular cartilage superficial layer cells and inhibiting synovitis,” Journal of Orthopaedic Translation, vol. 23, pp. 21–28, 2020.
View at: Publisher Site | Google Scholar
Q. Zhang, E. Xiang, W. Rao et al., “Intra-articular injection of human umbilical cord mesenchymal stem cells ameliorates monosodium iodoacetate-induced osteoarthritis in rats by inhibiting cartilage degradation and inflammation,” Bone & Joint Research, vol. 10, no. 3, pp. 226–236, 2021.
View at: Publisher Site | Google Scholar
H. Kim, G. Yang, J. Park, J. Choi, E. Kang, and B. K. Lee, “Therapeutic effect of mesenchymal stem cells derived from human umbilical cord in rabbit temporomandibular joint model of osteoarthritis,” Scientific Reports, vol. 9, no. 1, article 13854, 2019.
View at: Publisher Site | Google Scholar
C. Voisin, G. Cauchois, L. Reppel et al., “Are the immune properties of mesenchymal stem cells from Wharton's jelly maintained during chondrogenic differentiation?” Journal of Clinical Medicine, vol. 9, no. 2, p. 423, 2020.
View at: Publisher Site | Google Scholar
D. Giannini, M. Antonucci, F. Petrelli, S. Bilia, A. Alunno, and I. Puxeddu, “One year in review 2020: pathogenesis of rheumatoid arthritis,” Clinical and Experimental Rheumatology, vol. 38, no. 3, pp. 387–397, 2020.
View at: Google Scholar
C. Zhao, L. Zhang, W. Kong et al., “Umbilical cord-derived mesenchymal stem cells inhibit cadherin-11 expression by fibroblast-like synoviocytes in rheumatoid arthritis,” Journal of Immunology Research, vol. 2015, Article ID 137695, 10 pages, 2015.
View at: Publisher Site | Google Scholar
F. Hildner, S. Wolbank, H. Redl, M. van Griensven, and A. Peterbauer, “How chondrogenic are human umbilical cord matrix cells? A comparison to adipose-derived stem cells,” Journal of Tissue Engineering and Regenerative Medicine, vol. 4, no. 3, pp. 242–245, 2010.
View at: Publisher Site | Google Scholar
D. Ruan, Y. Zhang, D. Wang et al., “Differentiation of human Wharton's jelly cells toward nucleus pulposus-like cells after coculture with nucleus pulposus CellsIn vitro,” Tissue Engineering. Part A, vol. 18, no. 1-2, pp. 167–175, 2012.
View at: Publisher Site | Google Scholar
B. H. Chon, E. J. Lee, L. Jing, L. A. Setton, and J. Chen, “Human umbilical cord mesenchymal stromal cells exhibit immature nucleus pulposus cell phenotype in a laminin-rich pseudo-three-dimensional culture system,” Stem Cell Research & Therapy, vol. 4, no. 5, p. 120, 2013.
View at: Google Scholar
M. Caballero, M. D. Skancke, A. E. Halevi et al., “Effects of connective tissue growth factor on the regulation of elastogenesis in human umbilical cord-derived mesenchymal stem cells,” Annals of Plastic Surgery, vol. 70, no. 5, pp. 568–573, 2013.
View at: Publisher Site | Google Scholar
A. Marmotti, S. Mattia, M. Bruzzone et al., “Minced umbilical cord fragments as a source of cells for orthopaedic tissue engineering: an in vitro study,” Stem Cells International, vol. 2012, Article ID 326813, 13 pages, 2012.
View at: Publisher Site | Google Scholar
L. Danišovič, M. Boháč, R. Zamborský et al., “Comparative analysis of mesenchymal stromal cells from different tissue sources in respect to articular cartilage tissue engineering,” General Physiology and Biophysics, vol. 35, no. 2, pp. 207–214, 2016.
View at: Publisher Site | Google Scholar
H. Wu, X. Zeng, J. Yu et al., “Comparison of nucleus pulposus stem/progenitor cells isolated from degenerated intervertebral discs with umbilical cord derived mesenchymal stem cells,” Experimental Cell Research, vol. 361, no. 2, pp. 324–332, 2017.
View at: Publisher Site | Google Scholar
M. M. Bailey, L. Wang, C. J. Bode, K. E. Mitchell, and M. S. Detamore, “A comparison of human umbilical cord matrix stem cells and temporomandibular joint condylar chondrocytes for tissue engineering temporomandibular joint condylar cartilage,” Tissue Engineering, vol. 13, no. 8, pp. 2003–2010, 2007.
View at: Google Scholar
A. Islam, I. Urbarova, J. A. Bruun, and I. Martinez-Zubiaurre, “Large-scale secretome analyses unveil the superior immunosuppressive phenotype of umbilical cord stromal cells as compared to other adult mesenchymal stromal cells,” European Cells & Materials, vol. 37, pp. 153–174, 2019.
View at: Google Scholar
Y. Zhang, S. Liu, W. Guo et al., “Coculture of hWJMSCs and pACs in oriented scaffold enhances hyaline cartilage regeneration in vitro,” Stem Cells International, vol. 2019, Article ID 5130152, 11 pages, 2019.
View at: Publisher Site | Google Scholar
X. Li, Y. Liang, X. Xu et al., “Cell-to-cell culture inhibits dedifferentiation of chondrocytes and induces differentiation of human umbilical cord-derived mesenchymal stem cells,” BioMed Research International, vol. 2019, Article ID 5871698, 11 pages, 2019.
View at: Publisher Site | Google Scholar
Z. Han, Y. Zhang, L. Gao, S. Jiang, and D. Ruan, “Human Wharton's jelly cells activate degenerative nucleus pulposus cells in vitro,” Tissue Engineering. Part A, vol. 24, no. 13-14, pp. 1035–1043, 2018.
View at: Google Scholar
W. S. Toh, E. H. Lee, and T. Cao, “Potential of human embryonic stem cells in cartilage tissue engineering and regenerative medicine,” Stem Cell Reviews and Reports, vol. 7, no. 3, pp. 544–559, 2011.
View at: Google Scholar
R. Castro-Viñuelas, C. Sanjurjo-Rodríguez, M. Piñeiro-Ramil et al., “Induced pluripotent stem cells for cartilage repair: current status and future perspectives,” European Cells & Materials, vol. 36, pp. 96–109, 2018.
View at: Publisher Site | Google Scholar
J. J. Hwang, Y. A. Rim, Y. Nam, and J. H. Ju, “Recent developments in clinical applications of mesenchymal stem cells in the treatment of rheumatoid arthritis and osteoarthritis,” Frontiers in Immunology, vol. 12, article 631291, 2021.
View at: Google Scholar
S. Jyothi Prasanna and V. Sowmya Jahnavi, “Wharton's jelly mesenchymal stem cells as off-the-shelf cellular therapeutics: a closer look into their regenerative and immunomodulatory properties,” The Open Tissue Engineering and Regenerative Medicine Journal, vol. 4, no. SPEC. ISSUE 1, pp. 28–38, 2011.
View at: Google Scholar
W. S. Khan, S. R. Tew, A. B. Adesida, and T. E. Hardingham, “Human infrapatellar fat pad-derived stem cells express the pericyte marker 3G5 and show enhanced chondrogenesis after expansion in fibroblast growth factor-2,” Arthritis Research & Therapy, vol. 10, no. 4, p. R74, 2008.
View at: Google Scholar
A. Hatakeyama, S. Uchida, H. Utsunomiya et al., “Isolation and characterization of synovial mesenchymal stem cell derived from hip joints: a comparative analysis with a matched control knee group,” Stem Cells International, vol. 2017, Article ID 9312329, 13 pages, 2017.
View at: Publisher Site | Google Scholar
P. R. Amable, M. V. Teixeira, R. B. Carias, J. M. Granjeiro, and R. Borojevic, “Protein synthesis and secretion in human mesenchymal cells derived from bone marrow, adipose tissue and Wharton’s jelly,” Stem Cell Research & Therapy, vol. 5, no. 2, p. 53, 2014.
View at: Google Scholar
G. Raicevic, M. Najar, B. Stamatopoulos et al., “The source of human mesenchymal stromal cells influences their TLR profile as well as their functional properties,” Cellular Immunology, vol. 270, no. 2, pp. 207–216, 2011.
View at: Publisher Site | Google Scholar
S. Balasubramanian, P. Venugopal, S. Sundarraj, Z. Zakaria, A. S. Majumdar, and M. Ta, “Comparison of chemokine and receptor gene expression between Wharton's jelly and bone marrow-derived mesenchymal stromal cells,” Cytotherapy, vol. 14, no. 1, pp. 26–33, 2012.
View at: Google Scholar
F. Mckinnirey, B. Herbert, G. Vesey, and S. McCracken, “Immune modulation via adipose derived mesenchymal stem cells is driven by donor sex in vitro,” Scientific Reports, vol. 11, no. 1, p. 12454, 2021.
View at: Google Scholar
S. Mohamed-Ahmed, I. Fristad, S. A. Lie et al., “Adipose-derived and bone marrow mesenchymal stem cells: a donor-matched comparison,” Stem Cell Research & Therapy, vol. 9, no. 1, p. 168, 2018.
View at: Publisher Site | Google Scholar
B. Mead, A. Logan, M. Berry, W. Leadbeater, and B. A. Scheven, “Paracrine-mediated neuroprotection and neuritogenesis of axotomised retinal ganglion cells by human dental pulp stem cells: comparison with human bone marrow and adipose-derived mesenchymal stem cells,” PLoS One, vol. 9, no. 10, article e109305, 2014.
View at: Google Scholar
A. K. Batsali, C. Pontikoglou, D. Koutroulakis et al., “Differential expression of cell cycle and WNT pathway-related genes accounts for differences in the growth and differentiation potential of Wharton’s jelly and bone marrow-derived mesenchymal stem cells,” Stem Cell Research & Therapy, vol. 8, no. 1, p. 102, 2017.
View at: Publisher Site | Google Scholar
C. Y. Li, X. Y. Wu, J. B. Tong et al., “Comparative analysis of human mesenchymal stem cells from bone marrow and adipose tissue under xeno-free conditions for cell therapy,” Stem Cell Research & Therapy, vol. 6, no. 1, p. 55, 2015.
View at: Publisher Site | Google Scholar
S. Shin, J. Lee, Y. Kwon et al., “Comparative proteomic analysis of the mesenchymal stem cells secretome from adipose, bone marrow, placenta and Wharton's jelly,” International Journal of Molecular Sciences, vol. 22, no. 2, p. 845, 2021.
View at: Publisher Site | Google Scholar
A. Heirani-Tabasi, S. Toosi, M. Mirahmadi et al., “Chemokine receptors expression in MSCs: comparative analysis in different sources and passages,” Tissue engineering and regenerative medicine, vol. 14, no. 5, pp. 605–615, 2017.
View at: Publisher Site | Google Scholar
M. Najar, G. Raicevic, F. Jebbawi et al., “Characterization and functionality of the CD200-CD200R system during mesenchymal stromal cell interactions with T-lymphocytes,” Immunology Letters, vol. 146, no. 1-2, pp. 50–56, 2012.
View at: Publisher Site | Google Scholar
E. Karaöz, P. C. Demircan, G. Erman, E. Güngörürler, and A. E. Sarıboyaci, “Comparative analyses of immunosuppressive characteristics of bone-marrow, Wharton’s jelly, and adipose tissue-derived human mesenchymal stem cells,” Turkish Journal of Haematology, vol. 34, no. 3, pp. 213–225, 2017.
View at: Google Scholar
B. Purandare, T. Teklemariam, L. Zhao, and B. M. Hantash, “Temporal HLA profiling and immunomodulatory effects of human adult bone marrow- and adipose-derived mesenchymal stem cells,” Regenerative Medicine, vol. 9, no. 1, pp. 67–79, 2014.
View at: Google Scholar
C. Mennan, J. Garcia, S. Roberts, C. Hulme, and K. Wright, “A comprehensive characterisation of large-scale expanded human bone marrow and umbilical cord mesenchymal stem cells,” Stem Cell Research & Therapy, vol. 10, no. 1, p. 99, 2019.
View at: Google Scholar
E. T. Camilleri, M. P. Gustafson, A. Dudakovic et al., “Identification and validation of multiple cell surface markers of clinical-grade adipose-derived mesenchymal stromal cells as novel release criteria for good manufacturing practice-compliant production,” Stem Cell Research & Therapy, vol. 7, no. 1, p. 107, 2016.
View at: Publisher Site | Google Scholar
A. K. Pappa, M. Caballero, R. G. Dennis et al., “Biochemical properties of tissue-engineered cartilage,” The Journal of Craniofacial Surgery, vol. 25, no. 1, pp. 111–115, 2014.
View at: Publisher Site | Google Scholar
A. T. Cashion, M. Caballero, A. Halevi, A. Pappa, R. G. Dennis, and J. A. van Aalst, “Programmable mechanobioreactor for exploration of the effects of periodic vibratory stimulus on mesenchymal stem cell differentiation,” BioResearch Open Access, vol. 3, no. 1, pp. 19–28, 2014.
View at: Publisher Site | Google Scholar
N. S. Remya and P. D. Nair, “Mechanoresponsiveness of human umbilical cord mesenchymal stem cells in in vitro chondrogenesis-a comparative study with growth factor induction,” Journal of Biomedical Materials Research. Part A, vol. 104, no. 10, pp. 2554–2566, 2016.
View at: Google Scholar
L. Zhao and M. S. Detamore, “Chondrogenic differentiation of stem cells in human umbilical cord stroma with PGA and PLLA scaffolds,” Journal of Biomedical Science and Engineering, vol. 3, no. 11, pp. 1041–1049, 2010.
View at: Google Scholar
C. Y. Fong, A. Subramanian, K. Gauthaman et al., “Human umbilical cord Wharton's jelly stem cells undergo enhanced chondrogenic differentiation when grown on nanofibrous scaffolds and in a sequential two-stage culture medium environment,” Stem Cell Reviews and Reports, vol. 8, no. 1, pp. 195–209, 2012.
View at: Publisher Site | Google Scholar
X. Chen, F. Zhang, X. He et al., “Chondrogenic differentiation of umbilical cord-derived mesenchymal stem cells in type I collagen-hydrogel for cartilage engineering,” Injury, vol. 44, no. 4, pp. 540–549, 2013.
View at: Publisher Site | Google Scholar
R. S. Nirmal and P. D. Nair, “Significance of soluble growth factors in the chondrogenic response of human umbilical cord matrix stem cells in a porous three dimensional scaffold,” European Cells & Materials, vol. 26, pp. 234–251, 2013.
View at: Google Scholar
B. Sridharan, S. M. Lin, A. T. Hwu, A. D. Laflin, and M. S. Detamore, “Stem cells in aggregate form to enhance chondrogenesis in hydrogels,” PLoS One, vol. 10, no. 12, article e0141479, 2015.
View at: Google Scholar
J. Jaipaew, P. Wangkulangkul, J. Meesane, P. Raungrut, and P. Puttawibul, “Mimicked cartilage scaffolds of silk fibroin/hyaluronic acid with stem cells for osteoarthritis surgery: morphological, mechanical, and physical clues,” Materials Science & Engineering. C, Materials for Biological Applications, vol. 64, pp. 173–182, 2016.
View at: Google Scholar
J. Wang, B. Sun, L. Tian et al., “Evaluation of the potential of rhTGF- β3 encapsulated P(LLA-CL)/collagen nanofibers for tracheal cartilage regeneration using mesenchymal stems cells derived from Wharton's jelly of human umbilical cord,” Materials Science & Engineering. C, Materials for Biological Applications, vol. 70, Part 1, pp. 637–645, 2017.
View at: Publisher Site | Google Scholar
E. Aleksander-Konert, P. Paduszyński, A. Zajdel, Z. Dzierżewicz, and A. Wilczok, “In vitro chondrogenesis of Wharton's jelly mesenchymal stem cells in hyaluronic acid-based hydrogels,” Cellular & Molecular Biology Letters, vol. 21, p. 11, 2016.
View at: Google Scholar
W. Zhang, J. Yang, Y. Zhu et al., “Extracellular matrix derived by human umbilical cord-deposited mesenchymal stem cells accelerates chondrocyte proliferation and differentiation potential in vitro,” Cell and Tissue Banking, vol. 20, no. 3, pp. 351–365, 2019.
View at: Publisher Site | Google Scholar
L. Wang, I. Tran, K. Seshareddy, M. L. Weiss, and M. S. Detamore, “A comparison of human bone marrow-derived mesenchymal stem cells and human umbilical cord-derived mesenchymal stromal cells for cartilage tissue engineering,” Tissue Engineering. Part A, vol. 15, no. 8, pp. 2259–2266, 2009.
View at: Publisher Site | Google Scholar
L. Wang, K. Seshareddy, M. L. Weiss, and M. S. Detamore, “Effect of initial seeding density on human umbilical cord mesenchymal stromal cells for fibrocartilage tissue engineering,” Tissue Engineering. Part A, vol. 15, no. 5, pp. 1009–1017, 2009.
View at: Google Scholar
L. Wang, L. Zhao, and M. S. Detamore, “Human umbilical cord mesenchymal stromal cells in a sandwich approach for osteochondral tissue engineering,” Journal of Tissue Engineering and Regenerative Medicine, vol. 5, no. 9, pp. 712–721, 2011.
View at: Google Scholar
L. Qi, R. Wang, Q. Shi, M. Yuan, M. Jin, and D. Li, “Umbilical cord mesenchymal stem cell conditioned medium restored the expression of collagen II and aggrecan in nucleus pulposus mesenchymal stem cells exposed to high glucose,” Journal of Bone and Mineral Metabolism, vol. 37, no. 3, pp. 455–466, 2019.
View at: Google Scholar
L. Penolazzi, M. Pozzobon, L. S. Bergamin et al., “Extracellular matrix from decellularized Wharton's jelly improves the behavior of cells from degenerated intervertebral disc,” Frontiers in Bioengineering and Biotechnology, vol. 8, p. 262, 2020.
View at: Publisher Site | Google Scholar
S. K. Leckie, G. A. Sowa, B. P. Bechara et al., “Injection of human umbilical tissue-derived cells into the nucleus pulposus alters the course of intervertebral disc degeneration in vivo,” The Spine Journal, vol. 13, no. 3, pp. 263–272, 2013.
View at: Publisher Site | Google Scholar
N. Beeravolu, J. Brougham, I. Khan, C. McKee, M. Perez-Cruet, and G. R. Chaudhry, “Human umbilical cord derivatives regenerate intervertebral disc,” Journal of Tissue Engineering and Regenerative Medicine, vol. 12, no. 1, pp. e579–e591, 2018.
View at: Google Scholar
M. Perez-Cruet, N. Beeravolu, C. McKee et al., “Potential of human nucleus pulposus-like cells derived from umbilical cord to treat degenerative disc disease,” Neurosurgery, vol. 84, no. 1, pp. 272–283, 2019.
View at: Publisher Site | Google Scholar
S. Ekram, S. Khalid, I. Bashir, A. Salim, and I. Khan, “Human umbilical cord-derived mesenchymal stem cells and their chondroprogenitor derivatives reduced pain and inflammation signaling and promote regeneration in a rat intervertebral disc degeneration model,” Molecular and Cellular Biochemistry, vol. 476, no. 8, pp. 3191–3205, 2021.
View at: Publisher Site | Google Scholar
N. Saulnier, E. Viguier, E. Perrier-Groult et al., “Intra-articular administration of xenogeneic neonatal mesenchymal stromal cells early after meniscal injury down-regulates metalloproteinase gene expression in synovium and prevents cartilage degradation in a rabbit model of osteoarthritis,” Osteoarthritis and Cartilage, vol. 23, no. 1, pp. 122–133, 2015.
View at: Publisher Site | Google Scholar
A. L. Raines, M. Shih, L. Chua, C. Su, S. C. Tseng, and J. O'Connell, “Efficacy of particulate amniotic membrane and umbilical cord tissues in attenuating cartilage destruction in an osteoarthritis model,” Tissue Engineering. Part A, vol. 23, no. 1-2, pp. 12–19, 2017.
View at: Google Scholar
H. S. Chang, K. C. Wu, H. W. Liu, T. Y. Chu, and D. C. Ding, “Human umbilical cord-derived mesenchymal stem cells reduce monosodium iodoacetate-induced apoptosis in cartilage,” Ci Ji Yi Xue Za Zhi, vol. 30, no. 2, pp. 71–80, 2018.
View at: Google Scholar
B. Y. Zhang, B. Y. Wang, S. C. Li et al., “Evaluation of the curative effect of umbilical cord mesenchymal stem cell therapy for knee arthritis in dogs using imaging technology,” Stem Cells International, vol. 2018, Article ID 1983025, 12 pages, 2018.
View at: Publisher Site | Google Scholar
S. E. Kim, A. Pozzi, J. C. Yeh et al., “Intra-articular umbilical cord derived mesenchymal stem cell therapy for chronic elbow osteoarthritis in dogs: a Double-Blinded, Placebo-Controlled Clinical Trial,” Frontiers in veterinary science, vol. 6, p. 474, 2019.
View at: Publisher Site | Google Scholar
Y. Geng, J. Chen, M. Alahdal et al., “Intra-articular injection of hUC-MSCs expressing miR-140-5p induces cartilage self-repairing in the rat osteoarthritis,” Journal of Bone and Mineral Metabolism, vol. 38, no. 3, pp. 277–288, 2020.
View at: Publisher Site | Google Scholar
K. C. Wu, Y. H. Chang, H. W. Liu, and D. C. Ding, “Transplanting human umbilical cord mesenchymal stem cells and hyaluronate hydrogel repairs cartilage of osteoarthritis in the minipig model,” Ci Ji Yi Xue Za Zhi, vol. 31, no. 1, pp. 11–19, 2019.
View at: Publisher Site | Google Scholar
C. Magri, M. Schramme, M. Febre et al., “Comparison of efficacy and safety of single versus repeated intra-articular injection of allogeneic neonatal mesenchymal stem cells for treatment of osteoarthritis of the metacarpophalangeal/metatarsophalangeal joint in horses: a clinical pilot study,” PLoS One, vol. 14, no. 8, article e0221317, 2019.
View at: Publisher Site | Google Scholar
J. Perry, H. S. McCarthy, G. Bou-Gharios et al., “Injected human umbilical cord-derived mesenchymal stromal cells do not appear to elicit an inflammatory response in a murine model of osteoarthritis,” Osteoarthritis and cartilage open, vol. 2, no. 2, article 100044, 2020.
View at: Publisher Site | Google Scholar
D. Xing, J. Wu, B. Wang et al., “Intra-articular delivery of umbilical cord-derived mesenchymal stem cells temporarily retard the progression of osteoarthritis in a rat model,” International Journal of Rheumatic Diseases, vol. 23, no. 6, pp. 778–787, 2020.
View at: Publisher Site | Google Scholar
X. D. Wang, X. C. Wan, A. F. Liu, R. Li, and Q. Wei, “Effects of umbilical cord mesenchymal stem cells loaded with graphene oxide granular lubrication on cytokine levels in animal models of knee osteoarthritis,” International Orthopaedics, vol. 45, no. 2, pp. 381–390, 2021.
View at: Publisher Site | Google Scholar
Y. Liu, R. Mu, S. Wang et al., “Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis,” Arthritis Research & Therapy, vol. 12, no. 6, p. R210, 2010.
View at: Publisher Site | Google Scholar
C. C. Wu, T. C. Wu, F. L. Liu, H. K. Sytwu, and D. M. Chang, “TNF-α inhibitor reverse the effects of human umbilical cord-derived stem cells on experimental arthritis by increasing immunosuppression,” Cellular Immunology, vol. 273, no. 1, pp. 30–40, 2012.
View at: Google Scholar
J. Gu, W. Gu, C. Lin et al., “Human umbilical cord mesenchymal stem cells improve the immune-associated inflammatory and prothrombotic state in collagen type-II-induced arthritic rats,” Molecular Medicine Reports, vol. 12, no. 5, pp. 7463–7470, 2015.
View at: Publisher Site | Google Scholar
Q. Zhang, Q. Li, J. Zhu et al., “Comparison of therapeutic effects of different mesenchymal stem cells on rheumatoid arthritis in mice,” PeerJ, vol. 7, p. e7023, 2019.
View at: Publisher Site | Google Scholar
D. Ma, K. Xu, G. Zhang et al., “Immunomodulatory effect of human umbilical cord mesenchymal stem cells on T lymphocytes in rheumatoid arthritis,” International Immunopharmacology, vol. 74, article 105687, 2019.
View at: Publisher Site | Google Scholar
M. Vohra, A. Sharma, R. Bagga, and S. K. Arora, “Human umbilical cord-derived mesenchymal stem cells induce tissue repair and regeneration in collagen-induced arthritis in rats,” Journal of Clinical and Translational Research, vol. 6, no. 6, pp. 203–216, 2020.
View at: Google Scholar
K. Xu, D. Ma, G. Zhang et al., “Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles ameliorate collagen-induced arthritis via immunomodulatory T lymphocytes,” Molecular Immunology, vol. 135, pp. 36–44, 2021.
View at: Publisher Site | Google Scholar
P. Zhao, S. Liu, Y. Bai et al., “hWJECM-derived oriented scaffolds with autologous chondrocytes for rabbit cartilage defect repairing,” Tissue Engineering. Part A, vol. 24, no. 11-12, pp. 905–914, 2018.
View at: Publisher Site | Google Scholar
Y. Zhang, S. Liu, W. Guo et al., “Human umbilical cord Wharton's jelly mesenchymal stem cells combined with an acellular cartilage extracellular matrix scaffold improve cartilage repair compared with microfracture in a caprine model,” Osteoarthritis and Cartilage, vol. 26, no. 7, pp. 954–965, 2018.
View at: Publisher Site | Google Scholar
Y. Zhang, C. Hao, W. Guo et al., “Co-culture of hWJMSCs and pACs in double biomimetic ACECM oriented scaffold enhances mechanical properties and accelerates articular cartilage regeneration in a caprine model,” Stem Cell Research & Therapy, vol. 11, no. 1, p. 180, 2020.
View at: Publisher Site | Google Scholar
L. Yan and X. Wu, “Exosomes produced from 3D cultures of umbilical cord mesenchymal stem cells in a hollow-fiber bioreactor show improved osteochondral regeneration activity,” Cell Biology and Toxicology, vol. 36, no. 2, pp. 165–178, 2020.
View at: Google Scholar
Z. Li, Y. Bi, Q. Wu et al., “A composite scaffold of Wharton's jelly and chondroitin sulphate loaded with human umbilical cord mesenchymal stem cells repairs articular cartilage defects in rat knee,” Journal of Materials Science. Materials in Medicine, vol. 32, no. 4, p. 36, 2021.
View at: Publisher Site | Google Scholar
N. H. Dormer, M. Singh, L. Zhao, N. Mohan, C. J. Berkland, and M. S. Detamore, “Osteochondral interface regeneration of the rabbit knee with macroscopic gradients of bioactive signals,” Journal of Biomedical Materials Research. Part A, vol. 100, no. 1, pp. 162–170, 2012.
View at: Google Scholar
S. Liu, Y. Jia, M. Yuan et al., “Repair of Osteochondral Defects Using Human Umbilical Cord Wharton’s Jelly- Derived Mesenchymal Stem Cells in a Rabbit Model,” BioMed Research International, vol. 2017, Article ID 8760383, 12 pages, 2017.
View at: Publisher Site | Google Scholar
S. Jiang, G. Tian, Z. Yang et al., “Enhancement of acellular cartilage matrix scaffold by Wharton's jelly mesenchymal stem cell-derived exosomes to promote osteochondral regeneration,” Bioactive Materials, vol. 6, no. 9, pp. 2711–2728, 2021.
View at: Publisher Site | Google Scholar
J. Matas, M. Orrego, D. Amenabar et al., “Umbilical cord-derived mesenchymal stromal cells (MSCs) for knee osteoarthritis: repeated MSC dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized phase I/II trial,” Stem Cells Translational Medicine, vol. 8, no. 3, pp. 215–224, 2019.
View at: Publisher Site | Google Scholar
I. H. Dilogo, A. F. Canintika, A. L. Hanitya, J. A. Pawitan, I. K. Liem, and J. Pandelaki, “Umbilical cord-derived mesenchymal stem cells for treating osteoarthritis of the knee: a single-arm, open-label study,” European Journal of Orthopaedic Surgery and Traumatology, vol. 30, no. 5, pp. 799–807, 2020.
View at: Google Scholar
O. G. Mead and L. P. Mead, “Intra-articular injection of amniotic membrane and umbilical cord particulate for the management of moderate to severe knee osteoarthritis,” Orthopedic Research and Reviews, vol. 12, pp. 161–170, 2020.
View at: Google Scholar
L. Wang, S. Huang, S. Li et al., “Efficacy and safety of umbilical cord mesenchymal stem cell therapy for rheumatoid arthritis patients: a prospective phase I/II study,” Drug Design, Development and Therapy, vol. Volume 13, pp. 4331–4340, 2019.
View at: Publisher Site | Google Scholar
T. Qi, H. Gao, Y. Dang, S. Huang, and M. Peng, “Cervus and cucumis peptides combined umbilical cord mesenchymal stem cells therapy for rheumatoid arthritis,” Medicine (Baltimore), vol. 99, no. 28, article e21222, 2020.
View at: Google Scholar
X. He, Y. Yang, M. Yao et al., “Combination of human umbilical cord mesenchymal stem (stromal) cell transplantation with IFN-γ treatment synergistically improves the clinical outcomes of patients with rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 79, no. 10, pp. 1298–1304, 2020.
View at: Publisher Site | Google Scholar

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