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Goh, D.; Yang, Y.; Lee, E.H.; Hui, J.H.P.; Yang, Z. Mesenchymal Stem Cells for Cartilage Regeneration. Encyclopedia. Available online: https://encyclopedia.pub/entry/42332 (accessed on 05 December 2025).
Goh D, Yang Y, Lee EH, Hui JHP, Yang Z. Mesenchymal Stem Cells for Cartilage Regeneration. Encyclopedia. Available at: https://encyclopedia.pub/entry/42332. Accessed December 05, 2025.
Goh, Doreen, Yanmeng Yang, Eng Hin Lee, James Hoi Po Hui, Zheng Yang. "Mesenchymal Stem Cells for Cartilage Regeneration" Encyclopedia, https://encyclopedia.pub/entry/42332 (accessed December 05, 2025).
Goh, D., Yang, Y., Lee, E.H., Hui, J.H.P., & Yang, Z. (2023, March 20). Mesenchymal Stem Cells for Cartilage Regeneration. In Encyclopedia. https://encyclopedia.pub/entry/42332
Goh, Doreen, et al. "Mesenchymal Stem Cells for Cartilage Regeneration." Encyclopedia. Web. 20 March, 2023.
Mesenchymal Stem Cells for Cartilage Regeneration
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This entry is adapted from the peer-reviewed paper 10.3390/bioengineering10030355

Articular cartilage defects commonly result from trauma and are associated with significant morbidity. Since cartilage is an avascular, aneural, and alymphatic tissue with a poor intrinsic healing ability, the regeneration of functional hyaline cartilage remains a difficult clinical problem. Mesenchymal stem cells (MSCs) are multipotent cells with multilineage differentiation potential, including the ability to differentiate into chondrocytes. Due to their availability and ease of ex vivo expansion, clinicians are increasingly applying MSCs in the treatment of cartilage lesions.

mesenchymal stem cells heterogeneity cartilage regeneration

1. Articular Cartilage Injury and Management

Articular cartilage is a highly specialised tissue found in synovial joints at the articulating surfaces of bones. It has a low density of chondrocytes, which produce and maintain a rich extracellular matrix (ECM) comprising collagens, proteoglycans, water, and ions [1]. The dense collagen network contributes to tensile strength and shear stiffness of articular cartilage [2]. The high proteoglycan content in cartilage enables articular cartilage to withstand compressive forces and allows for weight-bearing. With the secretion of lubricin by superficial zone chondrocytes, cartilage is coated by a lubricating layer and has a low coefficient of friction, providing a smooth surface for uninterrupted joint movement [3].
However, repeated high-intensity mechanical overloading and acute trauma can cause cartilage injury. Given its avascular, aneural, and alymphatic nature [4], articular cartilage has a limited intrinsic regenerative capacity and does not recover readily from injury. This is exacerbated by the low density of chondrocytes in articular cartilage [5] and the high density of cartilage ECM, which impedes the migration of local chondrocytes to the injury site [6]. If cartilage injury is allowed to progress, changes in load bearing and the release of inflammatory mediators [7] can result in cumulative cartilage degeneration with secondary synovitis, subchondral bone remodelling, and contractions in the surrounding ligaments, joint capsule, and muscles [8]. This predisposes the patient to developing osteoarthritis.
Current management of cartilage injury includes surgical debridement of the joint, bone marrow stimulation, and transplantation approaches. In surgical debridement, loose bodies and calcified cartilage are removed from the joint to avoid further deterioration and fragmentation of the articular surface [9]. Bone marrow stimulation techniques, such as drilling, microfracture, and abrasion chondroplasty, induce the migration of bone marrow cells into the cartilage defect by mechanically penetrating the underlying subchondral bone. A fibrin clot, containing extravasated bone marrow mesenchymal stem cells (BM-MSCs), forms in the defect. Mesenchymal stem cells (MSCs) then participate in cartilage regeneration [10]. However, repair after bone marrow stimulation mostly results in the formation of biomechanically inferior fibrocartilage containing type I collagen, instead of the desired hyaline cartilage with type II collagen [11]. The fibrocartilage repair tissue is poorly integrated into the native cartilage and deteriorates over time [12], leading to declining treatment effectiveness in long-term studies [13][14]. Bone marrow stimulation techniques also disrupt the integrity of the subchondral bone, leading to instability and the formation of subchondral cysts and osteophytes [15].
Alternatively, surgeons can consider transplantation techniques for the management of articular cartilage defects. Osteochondral autograft transfers, either with the osteochondral autograft transfer system (OATS), or Mosaicplasty, are indicated in smaller defects less than 4 cm2 [16]. They involve the transplantation of healthy osteochondral tissue from non-weight-bearing areas of the joint into the defect. However, these techniques are limited by donor site morbidity and the scarce amount of donor tissue that can be harvested. Non-weight-bearing donor cartilage may also have differences in mechanical properties and depth [17]. In larger defects, osteochondral allografting can be applied instead, which involves the transplantation of osteochondral tissue from a cadaveric source. Osteochondral allografting avoids donor-site morbidity and limitations in tissue size and structure. However, allografts are associated with high cost, and the risk of tissue rejection and disease transmission [18].
Autologous chondrocyte implantation (ACI) is the first application of cell therapy in orthopaedics. ACI is suited for defect sizes larger than 3 to 4 cm2 [19]. First-generation ACI is a two-stage procedure that consists of cartilage harvesting from the joint, in vitro isolation and expansion of chondrocytes, and subsequent reintroduction of chondrocytes into the chondral defect under a periosteal patch [20]. However, the periosteal patch is prone to hypertrophy, with more than 20% of patients requiring repeat arthroscopy with debridement. In second generation ACI, a collagen membrane replaces the periosteal patch for covering the defect. In third generation ACI, tissue engineering principles are applied to incorporate chondrocytes directly onto a three-dimensional (3D) scaffold for implantation. The scaffold allows for better graft stability and reduces dedifferentiation of chondrocytes, generating more hyaline-like cartilage [21][22]. Also known as matrix-induced autologous cartilage implantation (M-ACI), this technique has led to improved clinical outcomes in patients compared to microfracture [23].
Despite the promising clinical outcomes of cell therapy approaches, the use of autologous chondrocytes requires tissue harvesting from the non-weight-bearing areas of knee cartilage, resulting in donor site morbidity. Chondrocytes are also scarce, with only 10 cells available in every 0.22 mm2 of human knee articular cartilage [24], necessitating the extensive ex vivo expansion of limited chondrocytes after isolation from patient tissue. Yet, chondrocytes that are cultured for prolonged periods are prone to dedifferentiation, during which cells become fibroblastic with reduced expression of type II collagen, generating neo-cartilage of lower functional efficacy, with mechanically inferior ECM [25]. Clinicians have, hence, explored the use of stem cells, especially adult MSCs, as an alternative cell source for the treatment of cartilage lesions.

2. Mesenchymal Stem Cells (MSCs) for Cartilage Regeneration

MSCs are multipotent cells with a multilineage differentiation potential, including the ability to differentiate into chondrocytes and generate ECM containing type II collagen. The use of MSCs as an alternative cell source for cartilage regeneration confers numerous advantages. Firstly, autologous MSCs can be harvested relatively easily through less invasive means, without injuring existing healthy cartilage [26]. Various tissue sources are available for MSC harvest, including bone marrow, adipose tissue, umbilical cord blood, and synovial fluid [27][28]. Unlike chondrocytes, MSCs can undergo expansion in vitro without losing their phenotype through dedifferentiation [29]. Allogenic cells can also be used in tissue engineering, as MSCs have been shown to be immune-evasive [30].
As such, many pre-clinical studies and clinical trials have been conducted on the use of MSCs for cartilage regeneration [31]. In vivo, intra-articular implantation of MSCs has led to enhanced cartilage repair in both small and large animal models [32]. Clinically, seven years of extended follow up, after implantation of MSCs encapsulated within a hyaluronic acid hydrogel, have found MSCs to be safe and efficacious for the treatment of cartilage defects [33]. As an adjuvant treatment, a large multicentre prospective randomised clinical trial has recently found that the intra-articular injection of BM-MSCs after microfracture led to improved repair, and a trend towards improved clinical outcomes in articular cartilage injuries of the knee [34]. A single-stage cartilage repair procedure, employing allogenic MSCs and autologous chondrons in fibrin glue, has similarly reported good five-year safety outcomes and led to clinical improvement [35].
In addition to being capable of chondrogenic differentiation, MSCs exert trophic effects on the surrounding chondrocytes, secreting bioactive molecules that promote ECM formation [36]. The therapeutic potential of the MSC secretome has led to an increased focus on cell-free strategies to facilitate cartilage repair. A systematic review of pre-clinical research reports that MSC exosomes are effective in the treatment of articular cartilage injury, resulting in hyaline-like neocartilage formation, improved integration with native cartilage, and increased ECM deposition in the defect site [37]. Exosomes secreted by MSCs enhance cartilage regeneration through multiple pathways, including the activation of AKT and ERK signalling to promote chondrocyte proliferation [38]. CD73 found in MSC exosomes also initiate tissue repair by hydrolysing the post-injury extracellular pro-apoptotic ATP signal into the pro-survival adenosine signal, while exosomal miRNAs are involved in MSC chondrogenesis and matrix synthesis [39]. MSCs also promote a regenerative milieu in injured tissue, increasing the infiltration of regenerative M2 macrophages and inhibiting pro-inflammatory cytokines [38][40]. The MSC secretome further increases the anti-inflammatory IL-10 and TGF-β1 levels, and induces regulatory T cells through CCL18 signalling [39][41]. miRNAs found in MSC exosomes contribute to the immunomodulatory role of MSCs [42]. In an in vivo porcine model, the injection of MSC exosomes and hyaluronic acid has led to improved morphological, histological, and functional recovery after 4 months [43].

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Subjects: Cell & Tissue Engineering
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Doreen Goh
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Yanmeng Yang
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Eng Hin Lee
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James Hoi Po Hui
, Zheng Yang
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Revisions: 2 times (View History)
Update Date: 21 Mar 2023
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