Next Article in Journal
Molecular Characteristics and Pathogenicity of Staphylococcus aureus Exotoxins
Next Article in Special Issue
Controlled Stimulus-Responsive Delivery Systems for Osteoarthritis Treatment
Previous Article in Journal
Synovial Fluid from Patients with Osteoarthritis Shows Different Inflammatory Features Depending on the Presence of Calcium Pyrophosphate Crystals
Previous Article in Special Issue
Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 25
Issue 1
10.3390/ijms25010394
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Advances in Stem Cell-Based Therapies in the Treatment of Osteoarthritis

by
Ye Chen
1,2,3,†,
Rui-Juan Cheng
1,2,3,†,
Yinlan Wu
1,2,3,
Deying Huang
1,2,3,
Yanhong Li
1,2,3,* and
Yi Liu
1,2,3,*
1
Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China
2
Rare Diseases Center, West China Hospital, Sichuan University, Chengdu 610041, China
3
Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Chengdu 610041, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2024, 25(1), 394; https://doi.org/10.3390/ijms25010394
Submission received: 19 November 2023 / Revised: 16 December 2023 / Accepted: 21 December 2023 / Published: 28 December 2023
(This article belongs to the Special Issue Osteoarthritis 3.0: From Molecular Pathways to Therapeutic Advances)
Browse Figure
Review Reports Versions Notes

Abstract

:
Osteoarthritis (OA) is a chronic, degenerative joint disease presenting a significant global health threat. While current therapeutic approaches primarily target symptom relief, their efficacy in repairing joint damage remains limited. Recent research has highlighted mesenchymal stem cells (MSCs) as potential contributors to cartilage repair, anti-inflammatory modulation, and immune regulation in OA patients. Notably, MSCs from different sources and their derivatives exhibit variations in their effectiveness in treating OA. Moreover, pretreatment and gene editing techniques of MSCs can enhance their therapeutic outcomes in OA. Additionally, the combination of novel biomaterials with MSCs has shown promise in facilitating the repair of damaged cartilage. This review summarizes recent studies on the role of MSCs in the treatment of OA, delving into their advantages and exploring potential directions for development, with the aim of providing fresh insights for future research in this critical field.

1. Introduction

Osteoarthritis (OA) is a chronic degenerative joint disease that commonly occurs in elderly individuals, postmenopausal women, athletes, and individuals with metabolic disorders such as diabetes and hyperlipidemia [1,2]. Its clinical manifestations include pain, joint stiffness, swelling, deformity, crepitus, and restricted mobility [3]. OA not only significantly impacts patients’ quality of life, but also stands as a leading cause of disability in the elderly [4]. With the global trend of population aging, OA is becoming a significant threat to global health.
Current approaches to OA treatment encompass physical therapy, pharmaceutical interventions, and surgical procedures. Pharmaceutical interventions primarily aim at anti-inflammatory and analgesic effects, lacking the capacity to repair or reverse joint damage associated with OA [4]. In recent years, biologic agents such as interleukin-1 (IL-1) receptor antagonists and adalimumab (TNF antibodies) have been gradually incorporated into OA treatment; however, multiple clinical trials have failed to demonstrate significant improvements [5,6,7]. Moreover, the evidence supporting the efficacy of physical therapy in OA treatment remains inconclusive [8]. Surgical interventions, such as total joint replacement and joint arthroplasty, are viable options for advanced OA patients, offering pain relief and improved joint function [9]. Nevertheless, the limited lifespan and variable long-term outcomes of artificial implants, coupled with potential complications [10], underscore the absence of definitive therapeutic modalities for joint damage repair in OA patients.
Encouragingly, recent research has unveiled the potential therapeutic role of stem cells in OA. Mesenchymal stem cells (MSCs), possessing self-renewal capabilities and derived from the mesodermal germ layer, can be harvested from bone marrow, adipose tissue, synovium, umbilical cord, dental pulp, amniotic fluid, dermis, and peripheral blood [11,12,13]. MSCs exhibit multilineage differentiation potential into osteogenic and chondrogenic lineages and secrete immunomodulatory factors, cytokines, growth factors, extracellular vesicles (EVs), and other bioactive substances, thereby contributing to tissue homeostasis and regeneration [14,15], and exerting immunomodulatory functions [16]. Numerous preclinical and clinical studies currently support the significant improvement of clinical symptoms and the repair of damaged cartilage in OA animal models and patients following MSC-based interventions [17,18,19]. In this article, we discuss the recent progress in stem cell therapy for OA, elucidating the current status of stem cell therapy as a novel approach in the treatment of OA.

2. Mechanisms of OA

2.1. Pathological Process of OA

The onset of OA is closely associated with an imbalance in cartilage metabolism, subchondral bone sclerosis, and synovial inflammation, involving various cell types, such as macrophages, T cells, chondrocytes, osteoclasts, and fibroblasts. Factors such as aging, trauma, obesity, biomechanics, and alterations in circadian rhythms can lead to hypertrophy or apoptosis of chondrocytes, metabolic disorders, cellular senescence, and disruption of cartilage homeostasis, thereby promoting the occurrence of OA [20]. In the early stages of OA, mitochondrial dysfunction in chondrocytes results in the excessive generation of reactive oxygen species (ROS), inducing oxidative damage. This process triggers chondrocyte apoptosis through the activation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) and Caspase pathways [21,22]. Metabolic disturbances in chondrocytes, such as overexpression of glucose transporters (GLUT1), lead to increased glucose uptake and excessive production of advanced glycation end products, ultimately contributing to cartilage degradation [23]. Aberrations in lipid metabolism and cholesterol regulation also contribute to the pathogenesis of OA [24,25]. Cheng et al. observed a significant upregulation of receptor-interacting protein kinase 1 (RIP1) expression in the cartilage of OA patients and rat models, where RIP1, through downstream activation of bone morphogenetic protein 7 (BMP7), promoted necroptotic apoptosis in chondrocytes, contributing to OA onset [26]. Liang et al. found that downregulating RIP1 protects chondrocytes from IL-1β-induced inflammation and apoptosis [27]. Yao et al. discovered that, under inflammatory conditions, chondrocyte ferroptosis leads to increased matrix metallopeptidase 13 (MMP13) expression and downregulation of collagen II expression, contributing to OA development [28].
Various inflammatory and chemotactic factors, including colony-stimulating factors for granulocyte-macrophage (GM-CSF), IL-1, IL-6, IL-7, and IL-8, monocyte chemoattractant protein-1 (MCP-1), MCP-2, MMP1, MMP3, MMP10, and MMP13, can disrupt tissue regeneration induced by stem cells or progenitor cells, cause adjacent cell senescence, promote OA progression, and result in symptoms such as pain and impaired mobility [29].The recruitment and activation of inflammatory cells are crucial factors in the onset and development of OA. Monocyte/macrophage lineage cells, after differentiating into osteoclasts, accumulate at the subchondral plate, causing focal degeneration of subchondral bone and articular cartilage, leading to cartilage damage [30]. Activated macrophages aggregate in 76% of OA patients’ knee joints, and their quantity correlates with the severity of OA and joint symptoms such as pain, narrowed joint space, and osteophyte formation [31]. In OA animal models, Zhang et al. found that M1-polarized macrophages can secrete Rspo2 and activate β-catenin signaling in chondrocytes, exacerbating OA symptoms in mice model [32]. Additionally, macrophages can produce nerve growth factor (NGF), causing OA pain [33]. Macrophages secrete B-cell activating factor (BAFF), promoting proinflammatory cell responses (Th1 and Th17) and inhibiting anti-inflammatory cell responses (Th2) [34]. Synovial fibrosis in the late stages of OA is a critical factor leading to joint stiffness, synovial hyperplasia, and restricted functionality [35].

2.2. Mechanism of MSCs in the Treatment of OA

MSCs are multipotent stem cells with self-renewal capabilities originating from the mesoderm. They express surface markers, including CD73, CD90, and CD105, while lacking the expression of hematopoietic differentiation markers such as CD11b, CD14, CD34, CD45, CD19, CD79a, or HLA-DR [36,37]. It is essential to note species differences in MSC surface markers, with human MSCs commonly reported to express CD29, CD73, CD90, CD105, and CD106 [37]. Rat bone marrow-derived MSCs (BM-MSCs) express CD29, CD44, CD54, CD90, and CD166 [38]. Interestingly, the expression of MSC surface markers in mice varies slightly across strains. C57BL, DBA1, and FVBN mice express the SCA-1 surface marker [39], while BALB/C mice express SCA-1 [40]. MSCs are readily accessible and can be isolated from the stroma of almost all organs, with a relatively straight forward isolation process [41]. MSCs have demonstrated notable efficacy in the treatment of autoimmune diseases and tissue/organ repair. In the context of OA treatment, MSCs play a pivotal role in several aspects (Figure 1).

2.2.1. Cartilage Regeneration

MSCs have the capability to promote cartilage formation and repair. MSCs can achieve this by differentiating into chondrocytes or by stimulating the upregulation of chondrogenic hormones in existing chondrocytes [42]. In the context of OA, MSCs can migrate from the subchondral bone to damaged areas, differentiating into chondrocytes and osteoblasts to repair cartilage and subchondral bone tissues [43]. Additionally, OA chondrocytes can stimulate the expression of type II collagen (Col2), SRY-box transcription factor 9 (SOX-9), and aggrecan in umbilical cord-derived MSCs (UC-MSCs), thereby promoting cartilage formation in UC-MSCs. MSCs can activate the AKT and extracellular signal-regulated kinase (ERK) signaling pathways in receptor chondrocytes, thereby enhancing their proliferation and cartilage formation [44]. Studies by Prasadam et al. have reported that in a coculture system of BM-MSCs and chondrocytes, the expression of cartilage regeneration markers, including Col2, aggrecan, and SOX9, is significantly higher in the BM-MSC combined with chondrocyte pellet group, confirming the chondrogenic potential of BM-MSCs [45]. Zhi et al. discovered that coculturing BM-MSCs with articular chondrocytes significantly increases the proliferation rate of chondrocytes [46]. The exosomal long noncoding RNA (lncRNA) KLF1-AS2018 from MSCs has been found to enhance cartilage repair and chondrocyte proliferation in an OA model [47]. Furthermore, research has revealed that transforming growth factor-beta (TGF-β), as a growth factor involved in cell differentiation, proliferation, and migration, can activate the ERK/JNK signaling pathway, enhancing the function of vitamin D and subsequently promoting MSC proliferation and migration. This ultimately affects chondrocyte differentiation [48].

2.2.2. Anti-Inflammatory and Immunomodulatory Effects

A crucial aspect of the pathogenic mechanism in OA involves the relative antagonistic effects between pro-inflammatory cytokines and anti-inflammatory cytokines. Proinflammatory cytokines such as IL-1β and TNF-α can independently or synergistically drive inflammatory responses with other cytokines [49]. Under inflammatory stimulation, damaged synovial cells or other cells release IL-1β, IL-6, IL-8, TNF-α, and MMPs with a platelet-reactive protein domain and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) [50]. In animal models, post-MSC treatment significantly decreases the expression of serum MMP-13, MMP-3, IL-6, and IL-8. Zhao et al. found that after MSC treatment, the levels of inflammatory biomarkers in synovial fibroblasts of OA patients, including IL-6, TNF-α, and NF-κB, were significantly reduced, while IL-10 levels increased [51].
MSCs possess specific immunomodulatory properties, producing immunoregulatory substances that downregulate immune-inflammatory processes and promote tissue regeneration, alleviating arthritis inflammation [52]. In OA treatment, MSCs inhibit innate immune responses by suppressing the development of mature dendritic cells, inhibiting IL-2-induced natural killer (NK) cells proliferation, and reducing the cytotoxicity of NK cells [53]. MSCs inhibit cell apoptosis, slow the development of T cells and B cells, and regulate adaptive immunity [54]. MSCs promote the transformation of macrophages/microglia from an inflammatory (M1) phenotype to an anti-inflammatory (M2) phenotype [55]. Additionally, MSCs inhibit the inflammatory response of NK cells by secreting TGF-β and IL-6 [56].

2.2.3. Analgesic Effect of MSCs

Pain is a primary manifestation of OA and significantly impacts patients’ functionality and quality of life. In recent years, researchers have discovered that MSC therapy for OA not only promotes cartilage recovery but also significantly alleviates pain and improves function. The cyclooxygenase 2/prostaglandin E2 (PGE2) pathway has been implicated in the analgesic mechanism of BM-MSCs in OA [57]. Wang et al. also found that exosomes derived from MSCs modified with TGF-β1 alleviate cartilage damage and pain in OA by inhibiting angiogenesis and suppressing chondrocyte calcification and osteoclast activity [58]. Yang’s team reported the results of a clinical study involving UC-MSCs in the treatment of 44 cases of severe knee OA (KOA). The study showed that visual analog scale (VAS) scores, American Knee Society Score (AKS) joint scores, and AKS functional scores were significantly reduced at 3, 6, and 12 months after treatment, indicating that UC-MSC transplantation for severe OA can more rapidly, significantly, and persistently alleviate joint pain and improve joint function compared to hyaluronic acid sodium [59]. In a Phase I/IIa trial, late-stage KOA patients received a single intra-articular injection of 1, 10, or 50 thousand BM-MSCs. Patients demonstrated significant improvements in pain, symptoms, quality of life, and The Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores overall, compared to the baseline [60]. Centeno et al. observed, through 24-weeks of follow-up magnetic resonance imaging (MRI) monitoring, that autologous transplantation of BM-MSCs can stimulate cartilage growth and reduce degenerative joint pain [61].

3. Application of MSCs from Different Sources in OA Therapy

MSCs sourced from different origins exhibit distinct characteristics and possess unique advantages. Bone marrow and adipose tissue are the primary sources of therapeutic MSCs [62]. Among these, UC-MSCs have the highest content [63], and MSCs derived from the umbilical cord and amniotic membrane demonstrate stronger proliferative capacity. Additionally, MSCs from the umbilical cord, amniotic membrane, and adipose tissue exhibit higher immunomodulatory capabilities than BM-MSCs, with placental MSCs having the lowest immunomodulatory strength but the ability to secrete more cell growth factors [64].

3.1. BM-MSCs

BM-MSCs are the most widely used source of therapeutic MSCs, offering advantages such as easy accessibility, rapid cell proliferation, strong maintenance of differentiation capabilities, and minimal risk of immune rejection [37]. Hamdalla HM et al. found that BM-MSCs significantly alleviated inflammation in a monosodium iodoacetate (MIA)-induced KOA rat model, improving knee joint swelling. A single intra-articular injection of BM-MSCs markedly downregulated IL-1β, IL-6, and TNF-α while upregulating IL-10 and TGF-β [41]. Chahal J et al. observed a reduction in the levels of the proinflammatory factors IL-12 and p40, decreased proinflammatory monocyte and macrophage subpopulations, and decreased synovial inflammation in late-stage KOA patients after BM-MSC injection, leading to improved passive joint mobility [60].
In a clinical trial conducted by Lamo-Espinosa JM’s team, 55 patients undergoing partial meniscectomy were recruited, and both low-dose and high-dose allogeneic BM-MSCs were used in the treatment group. A 2-year follow-up revealed no clinical adverse reactions, and based on VAS and WOMAC scores, significant pain reduction was observed [65]. Analyzing the results of two pivotal trials using autologous BM-MSCs, it was found that WOMAC responses obtained at 1-year post cell application persisted at 2 and 4 years, providing evidence for the long-term efficacy of MSC therapy for OA [66].

3.2. Adipose-Derived MSCs (AD-MSCs)

AD-MSCs, commonly derived from adipose tissue, possess characteristics such as abundant availability, ease of collection, minimal trauma, low complication rates, and high proliferative potential. AD-MSCs secrete anti-inflammatory factors, such as IL-10 and IL-1, inhibiting inflammation or promoting the expression of CD4+ FOXP3+ T helper cells [57].They can inhibit synovial macrophage activation, reduce the secretion of inflammatory factors, and play a regulatory role in the immune system [67]. Huňáková K et al. injected AD-MSCs into the bilateral elbow joints of dogs with OA and observed a decrease in the concentrations of MMP-3, TIMP-1, IL-6, and TNF-α in the joint synovial fluid [68]. Both the meta-analyses conducted by Muthu S’s team and Jeyaraman M’s team concluded that compared to BM-MSCs, AD-MSC transplantation showed better effectiveness, safety, and superiority in the treatment of KOA [69,70]. In a randomized, controlled trial aiming to assess cartilage defect regeneration, functional improvement, and safety after intra-articular injection of AD-MSCs following medial open-wedge high tibial osteotomy (MOWHTO), 26 patients were divided into an ADMSC injection group (n = 13) and a control group (n = 13). The primary outcome was the continuous change in cartilage defects assessed by periodic MRI. Continuous MRI demonstrated significantly better cartilage regeneration in the AD-MSC group than in the control group. No treatment-related adverse events, serious adverse events, or postoperative complications occurred in any case, suggesting that intra-articular injection of AD-MSCs could be a promising therapeutic approach for disease improvement after MOWHTO [71].

3.3. UC-MSCs

UC-MSCs possess advantages such as cellular youthfulness, large yield, high proliferative characteristics, multilineage differentiation potential, and low immunogenicity [72]. UC-MSCs can downregulate the expression of cartilage-degrading enzymes, inhibit cartilage degradation, stimulate the proliferation of damaged chondrocytes, and prevent cartilage degeneration. They also suppress pro-inflammatory cytokines such as TNF-α, IL-1β, TNF-α-stimulated protein-6, and IL-1 receptor, thereby reducing inflammation and protecting joint cartilage [73]. Ragni et al. demonstrated that the therapeutic effect of UC-MSCs in treating OA is mediated through BMP6 [74]. Zhang Q et al. found that intra-articular injection of UC-MSCs in a rat OA model enhanced the expression of Col2 and ki67 in joint cartilage while increasing the expression of the anti-inflammatory factors TSG-6 and IL-1 receptor antagonist, and reducing the expression of IL-1β, TNF-α, MMP13, and ADAMTS-5 in joint cartilage [73]. Research by Ju Y et al. demonstrated that the proliferation of UC-MSCs is higher than that of AD-MSCs, and both types of cells significantly reduce the development of OA induced by ACLT surgery [75]. In a Phase I pilot study conducted in 2020 on patients with bilateral KOA, intra-articular injection of UC-MSCs led to improvements in VAS, SF-36, and WOMAC scores [76].

3.4. Other Sources of MSCs

In addition, synovial MSCs (SMSCs), embryonic stem cell-derived MSCs (ES-MSCs), and MSCs from other sources have also been studied as potential treatments for OA. In rats with OA, injection of ES-MSCs derived from embryos showed effects such as alleviating OA pain, protecting joint structures, and slowing OA progression [77]. Akgun et al. used a combination of SMSCs (treatment group) and chondrocytes (control group) with a I/III collagen membrane to treat patients with knee joint cartilage defects. A 2-year follow-up revealed significant improvements in knee joint flexion, extension, and straight-leg raise height in both groups [78]. The mechanisms of stem cell therapy for OA vary among different cell sources. However, these approaches may be applicable to the treatment needs of different situations, and further exploration is still needed to develop precise stem cell-based therapies for OA.

4. Derivatives of MSCs for OA

Increasing research has found that paracrine signaling is a key mechanism through which stem cells exert their effects [79]. MSCs can secrete various growth factors and nutrients, promoting their own differentiation into chondrocytes, stimulating the proliferation and growth of resident chondrocytes, and secreting anti-inflammatory and immunomodulatory factors to regulate the damaged tissue microenvironment and promote tissue regeneration [80,81]. The paracrine effects of MSCs are mediated by the secretion of EVs [82]. EVs encompass various membrane-bound vesicle structures released by cells. According to their size and biogenesis, EVs can be classified into three subtypes: exosomes, microvesicles, and apoptotic bodies [83]. Exosomes are one subtype, characterized as nanoscale (40–100 nm) vesicles spontaneously produced and secreted by various active cells in mammals [84].
Compared to MSCs, EVs retain similar biological characteristics but offer advantages such as biocompatibility, low immunogenicity, long-term stability, and ease of storage [85,86]. EVs derived from BM-MSCs can alleviate joint inflammation by inhibiting the NF-κB pathway [87]. Those from AD-MSCs can protect cartilage and alleviate inflammation by inhibiting the PI3K/Akt/mTOR pathway [88]. Studies have found that exosomal miR-92a-3p can promote the proliferation and differentiation of chondrocytes, reduce cartilage degradation, and activate MMPs, thereby improving OA [89]. Exosomal miRNAs can mediate cell-to-cell communication and gene regulation, including the regulation of cartilage formation and degeneration, making them ideal substitutes for cell-free MSC therapies for OA [90]. In addition to their ability to regenerate cartilage, EVs can prolong the survival of degenerative chondrocytes induced by IL-1β by increasing the expression of chondrocyte markers and simultaneously inhibiting the expression of degradation-related genes (including ADAMTS-5 and MMP-13). This helps in upregulating Col2 and resynthesizing the extracellular matrix (ECM), protecting cartilage, preventing chondrocyte hypertrophy, and avoiding chondrocyte dedifferentiation [91]. The powerful ability of EVs derived from MSCs to improve and protect joints from injury-induced degeneration has been confirmed in preclinical studies. For example, studies by Cosenza et al. demonstrated that EVs and exosomes derived from MSCs could enhance the expression of chondrocyte biomarkers (Col2 and aggrecan), reduce inflammatory mediators, protect chondrocytes from apoptosis, inhibit macrophage activity, and emphasize the equivalent protective role of EVs and exosomes in the pathogenesis of OA [92]. Research by Li K et al. indicated that EVs from UC-MSCs could provide therapeutically effective miRNAs. These miRNAs could promote the reprogramming of macrophages into the M2 type, induce the expression of IL-10, and effectively induce the PI3K-Akt signaling pathway, which could delay knee joint cartilage degeneration in OA [93]. Another characteristic of OA progression is chondrocyte apoptosis. Studies by Jin et al. found that BM-MSC-exosomes could reduce IL-1β levels through lncRNA MEG-3, alleviate chondrocyte apoptosis and senescence, and have the potential for cartilage protection and improvement of osteoporosis [94]. MiRNA-140 is specifically expressed and regulates ECM-degrading enzymes in cartilage. Research by Si HB’s team concluded that intra-articular injection of miRNA-140 could alleviate the progression of OA by regulating the extracellular homeostasis of rats [95]. As a carrier for delivering miR-140 to chondrocytes, exosomes have become a new treatment for OA. This targeted treatment, using exosomes as drug carriers, not only improves the efficacy of anti-OA but also reduces the cost of treatment for patients [96].
MSC-ECM is also a noncellular component that contains various large molecules secreted by MSCs. After removing cell components that trigger immune reactions such as DNA, the ECM retains natural biochemical and biophysical signals [97]. Platas J et al. found that conditioned medium from AD-MSCs could downregulate the production of IL-1β in OA chondrocytes [98].
Another noteworthy cell therapy is bone marrow aspirate concentrate (BMAC). This therapy stands out for its composition, which includes multiple cell fractions such as platelets, monocytes, and MSCs [99]. Clinically, BMAC is increasingly utilized as a regenerative therapy for musculoskeletal pathological conditions, although its evidence-based support remains limited. Multiple clinical trials have indicated the effectiveness of BMAC therapy in reducing OARSI intermittent and persistent joint pain, as well as bilateral knee VAS pain scores. Moreover, it has shown improvement in pain and patient-reported outcomes in KOA patients during short-term follow-up [100,101,102,103]. Additionally, a study followed up with 140 patients for 15 years and found that subchondral BMAC had a significant effect on pain, leading to the postponement or avoidance of total knee arthroplasty in the contralateral joint of patients [104]. Consequently, intra-articular autologous BMAC therapy has been deemed safe, effective in managing pain, and capable of ameliorating functionality in patients with symptomatic KOA [104,105,106].

5. Application of Novel Techniques for MSCs

5.1. Preconditioning

MSCs exhibit dynamic adaptability to their environment, adjusting their regulatory functions based on different conditions. To enhance MSC functions both in vitro and in vivo, essential strategies include preconditioning, genetic modification, and optimizing MSC culture conditions. The implementation of these procedures holds the promise of significantly improving the efficacy of MSC transplantation in tissue engineering and regenerative medicine [107].
During the tissue regeneration process, MSCs often encounter challenges such as low cell viability, poor differentiation, ineffective cell communication, suboptimal ECM formation, and slow migration [108]. Preconditioning of MSCs has been employed to enhance their capabilities in vascular induction, proliferation, survival, immunomodulation, and migration toward injured areas [109].
MSCs subjected to hypoxic preconditioning can secrete increased quantities of bioactive factors, including vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), and basic fibroblast growth factor (bFGF), leading to enhanced angiogenesis and osteogenic induction [110]. TGF-β1 stimulation induces CD24 expression in MSCs while concurrently reducing surface expression of MHC I and MHC II [111,112]. Wan Safwani WKZ and colleagues found that hypoxia improves the viability and proliferation rates of cryopreserved AD-MSCs. This process upregulates hypoxia-inducible factor 1 alpha (HIF-1α) and induces the expression of chondrogenic genes such as aggrecan, Col-2, and SOX-9 in AD-MSCs, promoting their proliferation, differentiation into chondrocytes, and facilitating cartilage repair [113].
Chemical or pharmaceutical preconditioning is another strategy employed. Toll-like receptor (TLR) activation plays a crucial role in immune responses and MSC differentiation. For instance, stimulation with LPS, a TLR4 agonist, does not impact the viability or morphology of BM-MSCs, nor does it alter the expression pattern of key cell surface markers. However, it does influence the immunomodulatory potential of MSCs [114,115]. Preconditioning with LPS improves the regenerative properties of MSCs, significantly promoting the proliferation and migration of chondrocytes while inhibiting chondrocyte apoptosis [116]. Research indicates that pretreatment with a p38/MAPK inhibitor (sb203580) leads to increased ECM expansion in the inflammatory environment, enhancing the ability of human SMSCs to regenerate cartilage [117]. Preconditioning with IL-3 promotes the upregulation of chemokine receptor 4 (CXCR4) expression in MSCs, increasing their migration and facilitating their differentiation into osteogenic cells [118].

5.2. Genetic Engineering

The utilization of gene editing techniques to knockout or silence genes inhibiting the osteogenic or chondrogenic differentiation of stem cells and the transfection of genes favoring osteogenic or chondrogenic differentiation has emerged as a novel research approach in the field of stem cell regenerative medicine. Transfection of human UC-MSCs induced with a recombinant pIRES2-EG-FP-hBMP-2 plasmid showed stable transcription of the hBMP-2 gene, indicating successful differentiation of stem cells into chondrocytic tissues [119]. Under conditions of hyperglycemia, the knockdown of NLRP3 demonstrates a protective effect on the paracrine function of AD-MSCs. This protection is achieved through the activation of anti-apoptotic and anti-ROS deposition mechanisms [120]. Studies have revealed that genetic synthesis modifications of certain miRNAs in MSC-exosomes can result in improved cartilage repair outcomes [47,121]. MAO et al. found that overexpression of miR-92a-3p in exosomes derived from BM-MSCs exhibited enhanced inhibition of early-stage OA progression in a collagen-induced mouse model [89].

5.3. MSC Transplantation and Novel Technologies

The combination of MSCs with biomaterials has demonstrated notable efficacy in the treatment of OA [122]. The key feature lies in the interaction between biomaterials and MSCs, guiding the differentiation of MSCs into specific cell lineages. Their combined application in OA models has been shown to promote hyaline-like cartilage regeneration, opening new avenues for diverse clinical applications of MSCs [123].
Biomaterials possess precise shapes and microstructures, exhibit stable performance, are nontoxic, and display excellent biocompatibility. When implanted into cartilage-deficient areas along with MSCs, these biomaterials degrade, aiding in the chondrogenic differentiation of MSCs and facilitating the formation of new cartilage [124]. Commonly used scaffold biomaterials include collagen gel, agarose, platelet-rich fibrin gel, and 3D scaffolds [125,126]. KIM et al. investigated the role of self-assembling peptide hydrogelen capsulated MSCs in treating rat OA models, demonstrating chondroprotective effects, suppressing inflammatory cytokine levels and apoptosis biomarker expression, along with reducing subchondral bone density [127]. Using a hyaluronic acid gel sponge as a carrier, Kayakabe M et al. effectively transplanted BM-MSCs into rabbit joints, leading to the successful repair of damaged articular cartilage [128]. In the first large-scale clinical trial conducted by WAKITANI et al., autologous BM-MSCs embedded in a collagen gel were implanted into the cartilage-deficient areas of OA patients, resulting in improved joint function in both the control and BM-MSC groups [129]. Haleem et al. suggested that intra-articular implantation of a fibrous gel cell scaffold containing autologous BM-MSCs and platelet-rich plasma might be a more effective treatment for repairing joint cartilage injuries [130]

6. Conclusions

MSCs have been extensively researched since entering the scientific spotlight, with their role in various diseases being widely explored. The positive impact of MSCs on OA treatment has been substantiated through clinical experiments. Several controlled, randomized Phase I/II trials have demonstrated that patients treated with UC-MSCs and BM-MSCs experienced significant improvements in pain and function, compared to the HA-treated group at 12 months from the baseline. Moreover, almost no adverse effects were reported after MSC administration or during short-term follow-up [105,131,132]. While the majority of studies support the positive effects of MSCs therapy in OA treatment, a randomized Phase 3 trial has shown no significant advantage of BM-MSC over corticosteroids in terms of reducing pain scores and improving MRI scores [133]. Moreover, EVs derived from MSCs have demonstrated promising therapeutic effects in multiple experiments involving OA animal models. While significant efforts are needed for advancements in both basic and clinical research frontiers, improved cell therapies hold the promise of becoming safer, more affordable, and more effective treatments for OA. The pretreatment of MSCs, genetic engineering enhancements, and their combination with biomaterials further amplify the advantages of MSC-based treatments for OA, providing additional avenues for the treatment of OA and potentially other diseases. In the future, we anticipate broader recognition and application of MSCs in the field of OA and beyond.

Author Contributions

Y.C. wrote the manuscript; R.-J.C. conceived the idea and structured the article; Y.W. and D.H. drew the figure; Y.L. (Yanhong Li) and Y.L. (Yi Liu) supervised the project. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Sichuan University West China Hospital Science and Technology Achievement Transformation Fund Project (project no. CGZH21005) to Y.L., and the Natural Science Foundation of Sichuan Province (project no. 2023NSFSC1752) to R.-J.C.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lo, C.W.T.; Tsang, W.W.N.; Yan, C.H.; Lord, S.R.; Hill, K.D.; Wong, A.Y.L. Risk factors for falls in patients with total hip arthroplasty and total knee arthroplasty: A systematic review and meta-analysis. Osteoarthr. Cartil. 2019, 27, 979–993. [Google Scholar] [CrossRef] [PubMed]
  2. Osani, M.C.; Vaysbrot, E.E.; Zhou, M.; McAlindon, T.E.; Bannuru, R.R. Duration of Symptom Relief and Early Trajectory of Adverse Events for Oral Nonsteroidal Antiinflammatory Drugs in Knee Osteoarthritis: A Systematic Review and Meta-Analysis. Arthritis Care Res. 2020, 72, 641–651. [Google Scholar] [CrossRef] [PubMed]
  3. Tuncay Duruöz, M.; Öz, N.; Gürsoy, D.E.; Hande Gezer, H. Clinical aspects and outcomes in osteoarthritis. Best Pract. Res. Clin. Rheumatol. 2023, 101855, in press. [Google Scholar] [CrossRef] [PubMed]
  4. Zhang, W.; Ouyang, H.; Dass, C.R.; Xu, J. Current research on pharmacologic and regenerative therapies for osteoarthritis. Bone Res 2016, 4, 15040. [Google Scholar] [CrossRef] [PubMed]
  5. Aitken, D.; Laslett, L.L.; Pan, F.; Haugen, I.K.; Otahal, P.; Bellamy, N.; Bird, P.; Jones, G. A randomised double-blind placebo-controlled crossover trial of HUMira (adalimumab) for erosive hand OsteoaRthritis—The HUMOR trial. Osteoarthr. Cartil. 2018, 26, 880–887. [Google Scholar] [CrossRef] [PubMed]
  6. Kloppenburg, M.; Peterfy, C.; Haugen, I.K.; Kroon, F.; Chen, S.; Wang, L.; Liu, W.; Levy, G.; Fleischmann, R.M.; Berenbaum, F.; et al. Phase IIa, placebo-controlled, randomised study of lutikizumab, an anti-interleukin-1α and anti-interleukin-1β dual variable domain immunoglobulin, in patients with erosive hand osteoarthritis. Ann. Rheum. Dis. 2019, 78, 413–420. [Google Scholar] [CrossRef]
  7. Fleischmann, R.M.; Bliddal, H.; Blanco, F.J.; Schnitzer, T.J.; Peterfy, C.; Chen, S.; Wang, L.; Feng, S.; Conaghan, P.G.; Berenbaum, F.; et al. A Phase II Trial of Lutikizumab, an Anti-Interleukin-1α/β Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients with Synovitis. Arthritis Rheumatol. 2019, 71, 1056–1069. [Google Scholar] [CrossRef]
  8. Ernst, E.; Posadzki, P. Complementary and alternative medicine for rheumatoid arthritis and osteoarthritis: An overview of systematic reviews. Curr. Pain Headache Rep. 2011, 15, 431–437. [Google Scholar] [CrossRef]
  9. Saris, D.B.; Vanlauwe, J.; Victor, J.; Haspl, M.; Bohnsack, M.; Fortems, Y.; Vandekerckhove, B.; Almqvist, K.F.; Claes, T.; Handelberg, F.; et al. Characterized chondrocyte implantation results in better structural repair when treating symptomatic cartilage defects of the knee in a randomized controlled trial versus microfracture. Am. J. Sports Med. 2008, 36, 235–246. [Google Scholar] [CrossRef]
  10. Grayson, C.W.; Decker, R.C. Total joint arthroplasty for persons with osteoarthritis. PM&R 2012, 4, S97–S103. [Google Scholar] [CrossRef]
  11. Lindroos, B.; Suuronen, R.; Miettinen, S. The potential of adipose stem cells in regenerative medicine. Stem Cell Rev. Rep. 2011, 7, 269–291. [Google Scholar] [CrossRef] [PubMed]
  12. Erices, A.; Conget, P.; Minguell, J.J. Mesenchymal progenitor cells in human umbilical cord blood. Br. J. Haematol. 2000, 109, 235–242. [Google Scholar] [CrossRef] [PubMed]
  13. Sessarego, N.; Parodi, A.; Podestà, M.; Benvenuto, F.; Mogni, M.; Raviolo, V.; Lituania, M.; Kunkl, A.; Ferlazzo, G.; Bricarelli, F.D.; et al. Multipotent mesenchymal stromal cells from amniotic fluid: Solid perspectives for clinical application. Haematologica 2008, 93, 339–346. [Google Scholar] [CrossRef] [PubMed]
  14. Ullah, I.; Subbarao, R.B.; Rho, G.J. Human mesenchymal stem cells—Current trends and future prospective. Biosci. Rep. 2015, 35, e00191. [Google Scholar] [CrossRef] [PubMed]
  15. Pittenger, M.F.; Mackay, A.M.; Beck, S.C.; Jaiswal, R.K.; Douglas, R.; Mosca, J.D.; Moorman, M.A.; Simonetti, D.W.; Craig, S.; Marshak, D.R. Multilineage potential of adult human mesenchymal stem cells. Science 1999, 284, 143–147. [Google Scholar] [CrossRef] [PubMed]
  16. Dunavin, N.; Dias, A.; Li, M.; McGuirk, J. Mesenchymal Stromal Cells: What Is the Mechanism in Acute Graft-Versus-Host Disease? Biomedicines 2017, 5, 39. [Google Scholar] [CrossRef]
  17. Akgun, I.; Unlu, M.C.; Erdal, O.A.; Ogut, T.; Erturk, M.; Ovali, E.; Kantarci, F.; Caliskan, G.; Akgun, Y. Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: A 2-year randomized study. Arch. Orthop. Trauma Surg. 2015, 135, 251–263. [Google Scholar] [CrossRef]
  18. Vega, A.; Martín-Ferrero, M.A.; Del Canto, F.; Alberca, M.; García, V.; Munar, A.; Orozco, L.; Soler, R.; Fuertes, J.J.; Huguet, M.; et al. Treatment of Knee Osteoarthritis with Allogeneic Bone Marrow Mesenchymal Stem Cells: A Randomized Controlled Trial. Transplantation 2015, 99, 1681–1690. [Google Scholar] [CrossRef]
  19. Gupta, P.K.; Chullikana, A.; Rengasamy, M.; Shetty, N.; Pandey, V.; Agarwal, V.; Wagh, S.Y.; Vellotare, P.K.; Damodaran, D.; Viswanathan, P.; et al. Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): Preclinical and clinical trial in osteoarthritis of the knee joint. Arthritis Res. Ther. 2016, 18, 301. [Google Scholar] [CrossRef]
  20. Lee, A.S.; Ellman, M.B.; Yan, D.; Kroin, J.S.; Cole, B.J.; van Wijnen, A.J.; Im, H.J. A current review of molecular mechanisms regarding osteoarthritis and pain. Gene 2013, 527, 440–447. [Google Scholar] [CrossRef]
  21. Mobasheri, A.; Batt, M. An update on the pathophysiology of osteoarthritis. Ann. Phys. Rehabil. Med. 2016, 59, 333–339. [Google Scholar] [CrossRef] [PubMed]
  22. Li, D.; Ni, S.; Miao, K.S.; Zhuang, C. PI3K/Akt and caspase pathways mediate oxidative stress-induced chondrocyte apoptosis. Cell Stress Chaperones 2019, 24, 195–202. [Google Scholar] [CrossRef] [PubMed]
  23. Qing-Xian, L.; Lin-Long, W.; Yi-Zhong, W.; Liang, L.; Hui, H.; Liao-Bin, C.; Hui, W. Programming changes in GLUT1 mediated the accumulation of AGEs and matrix degradation in the articular cartilage of female adult rats after prenatal caffeine exposure. Pharmacol. Res. 2020, 151, 104555. [Google Scholar] [CrossRef] [PubMed]
  24. Jónasdóttir, H.S.; Brouwers, H.; Kwekkeboom, J.C.; van der Linden, H.M.J.; Huizinga, T.; Kloppenburg, M.; Toes, R.E.M.; Giera, M.; Ioan-Facsinay, A. Targeted lipidomics reveals activation of resolution pathways in knee osteoarthritis in humans. Osteoarthr. Cartil. 2017, 25, 1150–1160. [Google Scholar] [CrossRef] [PubMed]
  25. Choi, W.S.; Lee, G.; Song, W.H.; Koh, J.T.; Yang, J.; Kwak, J.S.; Kim, H.E.; Kim, S.K.; Son, Y.O.; Nam, H.; et al. The CH25H-CYP7B1-RORα axis of cholesterol metabolism regulates osteoarthritis. Nature 2019, 566, 254–258. [Google Scholar] [CrossRef]
  26. Cheng, J.; Duan, X.; Fu, X.; Jiang, Y.; Yang, P.; Cao, C.; Li, Q.; Zhang, J.; Hu, X.; Zhang, X.; et al. RIP1 Perturbation Induces Chondrocyte Necroptosis and Promotes Osteoarthritis Pathogenesis via Targeting BMP7. Front. Cell Dev. Biol. 2021, 9, 638382. [Google Scholar] [CrossRef]
  27. Liang, S.; Wang, Z.G.; Zhang, Z.Z.; Chen, K.; Lv, Z.T.; Wang, Y.T.; Cheng, P.; Sun, K.; Yang, Q.; Chen, A.M. Decreased RIPK1 expression in chondrocytes alleviates osteoarthritis via the TRIF/MyD88-RIPK1-TRAF2 negative feedback loop. Aging 2019, 11, 8664–8680. [Google Scholar] [CrossRef]
  28. Yao, X.; Sun, K.; Yu, S.; Luo, J.; Guo, J.; Lin, J.; Wang, G.; Guo, Z.; Ye, Y.; Guo, F. Chondrocyte ferroptosis contribute to the progression of osteoarthritis. J. Orthop. Transl. 2021, 27, 33–43. [Google Scholar] [CrossRef]
  29. Coryell, P.R.; Diekman, B.O.; Loeser, R.F. Mechanisms and therapeutic implications of cellular senescence in osteoarthritis. Nat. Rev. Rheumatol 2021, 17, 47–57. [Google Scholar] [CrossRef]
  30. Bertuglia, A.; Lacourt, M.; Girard, C.; Beauchamp, G.; Richard, H.; Laverty, S. Osteoclasts are recruited to the subchondral bone in naturally occurring post-traumatic equine carpal osteoarthritis and may contribute to cartilage degradation. Osteoarthr. Cartil. 2016, 24, 555–566. [Google Scholar] [CrossRef]
  31. Kraus, V.B.; McDaniel, G.; Huebner, J.L.; Stabler, T.V.; Pieper, C.F.; Shipes, S.W.; Petry, N.A.; Low, P.S.; Shen, J.; McNearney, T.A.; et al. Direct in vivo evidence of activated macrophages in human osteoarthritis. Osteoarthr. Cartil. 2016, 24, 1613–1621. [Google Scholar] [CrossRef] [PubMed]
  32. Zhang, H.; Lin, C.; Zeng, C.; Wang, Z.; Wang, H.; Lu, J.; Liu, X.; Shao, Y.; Zhao, C.; Pan, J.; et al. Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2. Ann. Rheum. Dis. 2018, 77, 1524–1534. [Google Scholar] [CrossRef] [PubMed]
  33. Takano, S.; Uchida, K.; Inoue, G.; Miyagi, M.; Aikawa, J.; Iwase, D.; Iwabuchi, K.; Matsumoto, T.; Satoh, M.; Mukai, M.; et al. Nerve growth factor regulation and production by macrophages in osteoarthritic synovium. Clin. Exp. Immunol. 2017, 190, 235–243. [Google Scholar] [CrossRef] [PubMed]
  34. Chen, M.; Lin, X.; Liu, Y.; Li, Q.; Deng, Y.; Liu, Z.; Brand, D.; Guo, Z.; He, X.; Ryffel, B.; et al. The function of BAFF on T helper cells in autoimmunity. Cytokine Growth Factor Rev. 2014, 25, 301–305. [Google Scholar] [CrossRef] [PubMed]
  35. Zhang, L.; Xing, R.; Huang, Z.; Ding, L.; Zhang, L.; Li, M.; Li, X.; Wang, P.; Mao, J. Synovial Fibrosis Involvement in Osteoarthritis. Front. Med. 2021, 8, 684389. [Google Scholar] [CrossRef]
  36. Cheng, R.J.; Xiong, A.J.; Li, Y.H.; Pan, S.Y.; Zhang, Q.P.; Zhao, Y.; Liu, Y.; Marion, T.N. Mesenchymal Stem Cells: Allogeneic MSC May Be Immunosuppressive but Autologous MSC Are Dysfunctional in Lupus Patients. Front. Cell Dev. Biol. 2019, 7, 285. [Google Scholar] [CrossRef]
  37. Volarevic, V.; Gazdic, M.; Simovic Markovic, B.; Jovicic, N.; Djonov, V.; Arsenijevic, N. Mesenchymal stem cell-derived factors: Immuno-modulatory effects and therapeutic potential. BioFactors 2017, 43, 633–644. [Google Scholar] [CrossRef]
  38. Karaoz, E.; Aksoy, A.; Ayhan, S.; Sariboyaci, A.E.; Kaymaz, F.; Kasap, M. Characterization of mesenchymal stem cells from rat bone marrow: Ultrastructural properties, differentiation potential and immunophenotypic markers. Histochem. Cell Biol. 2009, 132, 533–546. [Google Scholar] [CrossRef]
  39. Peister, A.; Mellad, J.A.; Larson, B.L.; Hall, B.M.; Gibson, L.F.; Prockop, D.J. Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood 2004, 103, 1662–1668. [Google Scholar] [CrossRef]
  40. Ooi, Y.Y.; Rahmat, Z.; Jose, S.; Ramasamy, R.; Vidyadaran, S. Immunophenotype and differentiation capacity of bone marrow-derived mesenchymal stem cells from CBA/Ca, ICR and Balb/c mice. World J. Stem Cells 2013, 5, 34–42. [Google Scholar] [CrossRef]
  41. Hamdalla, H.M.; Ahmed, R.R.; Galaly, S.R.; Ahmed, O.M.; Naguib, I.A.; Alghamdi, B.S.; Abdul-Hamid, M. Assessment of the Efficacy of Bone Marrow-Derived Mesenchymal Stem Cells against a Monoiodoacetate-Induced Osteoarthritis Model in Wistar Rats. Stem Cells Int. 2022, 2022, 1900403. [Google Scholar] [CrossRef] [PubMed]
  42. Dickinson, S.C.; Sutton, C.A.; Brady, K.; Salerno, A.; Katopodi, T.; Williams, R.L.; West, C.C.; Evseenko, D.; Wu, L.; Pang, S.; et al. The Wnt5a Receptor, Receptor Tyrosine Kinase-Like Orphan Receptor 2, Is a Predictive Cell Surface Marker of Human Mesenchymal Stem Cells with an Enhanced Capacity for Chondrogenic Differentiation. Stem Cells 2017, 35, 2280–2291. [Google Scholar] [CrossRef] [PubMed]
  43. Wang, S.; Lei, B.; Zhang, E.; Gong, P.; Gu, J.; He, L.; Han, L.; Yuan, Z. Targeted Therapy for Inflammatory Diseases with Mesenchymal Stem Cells and Their Derived Exosomes: From Basic to Clinics. Int. J. Nanomed. 2022, 17, 1757–1781. [Google Scholar] [CrossRef] [PubMed]
  44. Wang, H.; Yan, X.; Jiang, Y.; Wang, Z.; Li, Y.; Shao, Q. The human umbilical cord stem cells improve the viability of OA degenerated chondrocytes. Mol. Med. Rep. 2018, 17, 4474–4482. [Google Scholar] [CrossRef] [PubMed]
  45. Prasadam, I.; Akuien, A.; Friis, T.E.; Fang, W.; Mao, X.; Crawford, R.W.; Xiao, Y. Mixed cell therapy of bone marrow-derived mesenchymal stem cells and articular cartilage chondrocytes ameliorates osteoarthritis development. Lab. Investig. 2018, 98, 106–116. [Google Scholar] [CrossRef] [PubMed]
  46. Zhi, Z.; Zhang, C.; Kang, J.; Wang, Y.; Liu, J.; Wu, F.; Xu, G. The therapeutic effect of bone marrow-derived mesenchymal stem cells on osteoarthritis is improved by the activation of the KDM6A/SOX9 signaling pathway caused by exposure to hypoxia. J. Cell Physiol. 2020, 235, 7173–7182. [Google Scholar] [CrossRef] [PubMed]
  47. Liu, Y.; Zou, R.; Wang, Z.; Wen, C.; Zhang, F.; Lin, F. Exosomal KLF3-AS1 from hMSCs promoted cartilage repair and chondrocyte proliferation in osteoarthritis. Biochem. J. 2018, 475, 3629–3638. [Google Scholar] [CrossRef]
  48. Jiang, X.; Huang, B.; Yang, H.; Li, G.; Zhang, C.; Yang, G.; Lin, F.; Lin, G. TGF-β1 is Involved in Vitamin D-Induced Chondrogenic Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells by Regulating the ERK/JNK Pathway. Cell. Physiol. Biochem. 2017, 42, 2230–2241. [Google Scholar] [CrossRef]
  49. Clockaerts, S.; Bastiaansen-Jenniskens, Y.M.; Feijt, C.; De Clerck, L.; Verhaar, J.A.; Zuurmond, A.M.; Stojanovic-Susulic, V.; Somville, J.; Kloppenburg, M.; van Osch, G.J. Cytokine production by infrapatellar fat pad can be stimulated by interleukin 1β and inhibited by peroxisome proliferator activated receptor α agonist. Ann. Rheum. Dis. 2012, 71, 1012–1018. [Google Scholar] [CrossRef]
  50. Li, H.; Xie, S.; Qi, Y.; Li, H.; Zhang, R.; Lian, Y. TNF-α increases the expression of inflammatory factors in synovial fibroblasts by inhibiting the PI3K/AKT pathway in a rat model of monosodium iodoacetate-induced osteoarthritis. Exp. Ther. Med. 2018, 16, 4737–4744. [Google Scholar] [CrossRef]
  51. Zhao, C.; Chen, J.Y.; Peng, W.M.; Yuan, B.; Bi, Q.; Xu, Y.J. Exosomes from adipose-derived stem cells promote chondrogenesis and suppress inflammation by upregulating miR-145 and miR-221. Mol. Med. Rep. 2020, 21, 1881–1889. [Google Scholar] [CrossRef] [PubMed]
  52. Lv, Z.; Cai, X.; Bian, Y.; Wei, Z.; Zhu, W.; Zhao, X.; Weng, X. Advances in Mesenchymal Stem Cell Therapy for Osteoarthritis: From Preclinical and Clinical Perspectives. Bioengineering 2023, 10, 195. [Google Scholar] [CrossRef] [PubMed]
  53. Spaggiari, G.M.; Capobianco, A.; Becchetti, S.; Mingari, M.C.; Moretta, L. Mesenchymal stem cell-natural killer cell interactions: Evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood 2006, 107, 1484–1490. [Google Scholar] [CrossRef] [PubMed]
  54. Benvenuto, F.; Ferrari, S.; Gerdoni, E.; Gualandi, F.; Frassoni, F.; Pistoia, V.; Mancardi, G.; Uccelli, A. Human mesenchymal stem cells promote survival of T cells in a quiescent state. Stem Cells 2007, 25, 1753–1760. [Google Scholar] [CrossRef] [PubMed]
  55. Zhong, Z.; Chen, A.; Fa, Z.; Ding, Z.; Xiao, L.; Wu, G.; Wang, Q.; Zhang, R. Bone marrow mesenchymal stem cells upregulate PI3K/AKT pathway and down-regulate NF-κB pathway by secreting glial cell-derived neurotrophic factors to regulate microglial polarization and alleviate deafferentation pain in rats. Neurobiol. Dis. 2020, 143, 104945. [Google Scholar] [CrossRef]
  56. Petri, R.M.; Hackel, A.; Hahnel, K.; Dumitru, C.A.; Bruderek, K.; Flohe, S.B.; Paschen, A.; Lang, S.; Brandau, S. Activated Tissue-Resident Mesenchymal Stromal Cells Regulate Natural Killer Cell Immune and Tissue-Regenerative Function. Stem Cell Rep. 2017, 9, 985–998. [Google Scholar] [CrossRef] [PubMed]
  57. Manferdini, C.; Maumus, M.; Gabusi, E.; Piacentini, A.; Filardo, G.; Peyrafitte, J.A.; Jorgensen, C.; Bourin, P.; Fleury-Cappellesso, S.; Facchini, A.; et al. Adipose-derived mesenchymal stem cells exert antiinflammatory effects on chondrocytes and synoviocytes from osteoarthritis patients through prostaglandin E2. Arthritis Rheum. 2013, 65, 1271–1281. [Google Scholar] [CrossRef] [PubMed]
  58. Wang, R.; Xu, B. TGFβ1-modified MSC-derived exosome attenuates osteoarthritis by inhibiting PDGF-BB secretion and H-type vessel activity in the subchondral bone. Acta Histochem. 2022, 124, 151933. [Google Scholar] [CrossRef]
  59. Yang, X.; Jiang, F.; Zhang, F.; Shi, X.; Liu, L.; Xu, Z. Therapeutic effect of human umbilical cord-derived mesenchymal stem cells for severe knee osteoarthritis. Chin. J. Clin. Pharmacol. Ther. 2017, 22, 305–311. [Google Scholar]
  60. Chahal, J.; Gómez-Aristizábal, A.; Shestopaloff, K.; Bhatt, S.; Chaboureau, A.; Fazio, A.; Chisholm, J.; Weston, A.; Chiovitti, J.; Keating, A.; et al. Bone Marrow Mesenchymal Stromal Cell Treatment in Patients with Osteoarthritis Results in Overall Improvement in Pain and Symptoms and Reduces Synovial Inflammation. Stem Cells Transl. Med. 2019, 8, 746–757. [Google Scholar] [CrossRef]
  61. Centeno, C.J.; Busse, D.; Kisiday, J.; Keohan, C.; Freeman, M.; Karli, D. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician 2008, 11, 343–353. [Google Scholar] [PubMed]
  62. Zhu, C.; Wu, W.; Qu, X. Mesenchymal stem cells in osteoarthritis therapy: A review. Am. J. Transl. Res. 2021, 13, 448–461. [Google Scholar] [PubMed]
  63. Somoza, R.A.; Welter, J.F.; Correa, D.; Caplan, A.I. Chondrogenic differentiation of mesenchymal stem cells: Challenges and unfulfilled expectations. Tissue Eng. Part B Rev. 2014, 20, 596–608. [Google Scholar] [CrossRef] [PubMed]
  64. Saghahazrati, S.; Ayatollahi, S.A.M.; Kobarfard, F.; Minaii Zang, B. The Synergistic Effect of Glucagon-Like Peptide-1 and Chamomile Oil on Differentiation of Mesenchymal Stem Cells into Insulin-Producing Cells. Cell J. 2020, 21, 371–378. [Google Scholar] [CrossRef] [PubMed]
  65. Lamo-Espinosa, J.M.; Mora, G.; Blanco, J.F.; Granero-Moltó, F.; Nuñez-Córdoba, J.M.; Sánchez-Echenique, C.; Bondía, J.M.; Aquerreta, J.D.; Andreu, E.J.; Ornilla, E.; et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: Multicenter randomized controlled clinical trial (phase I/II). J. Transl. Med. 2016, 14, 246. [Google Scholar] [CrossRef] [PubMed]
  66. Lamo-Espinosa, J.M.; Prósper, F.; Blanco, J.F.; Sánchez-Guijo, F.; Alberca, M.; García, V.; González-Vallinas, M.; García-Sancho, J. Long-term efficacy of autologous bone marrow mesenchymal stromal cells for treatment of knee osteoarthritis. J. Transl. Med. 2021, 19, 506. [Google Scholar] [CrossRef] [PubMed]
  67. Schelbergen, R.F.; van Dalen, S.; ter Huurne, M.; Roth, J.; Vogl, T.; Noël, D.; Jorgensen, C.; van den Berg, W.B.; van de Loo, F.A.; Blom, A.B.; et al. Treatment efficacy of adipose-derived stem cells in experimental osteoarthritis is driven by high synovial activation and reflected by S100A8/A9 serum levels. Osteoarthr. Cartil. 2014, 22, 1158–1166. [Google Scholar] [CrossRef]
  68. Huňáková, K.; Hluchý, M.; Špaková, T.; Matejová, J.; Mudroňová, D.; Kuricová, M.; Rosocha, J.; Ledecký, V. Study of bilateral elbow joint osteoarthritis treatment using conditioned medium from allogeneic adipose tissue-derived MSCs in Labrador retrievers. Res. Vet. Sci. 2020, 132, 513–520. [Google Scholar] [CrossRef]
  69. Jeyaraman, M.; Muthu, S.; Ganie, P.A. Does the Source of Mesenchymal Stem Cell Have an Effect in the Management of Osteoarthritis of the Knee? Meta-Analysis of Randomized Controlled Trials. Cartilage 2021, 13, 1532s–1547s. [Google Scholar] [CrossRef]
  70. Muthu, S.; Patil, S.C.; Jeyaraman, N.; Jeyaraman, M.; Gangadaran, P.; Rajendran, R.L.; Oh, E.J.; Khanna, M.; Chung, H.Y.; Ahn, B.C. Comparative effectiveness of adipose-derived mesenchymal stromal cells in the management of knee osteoarthritis: A meta-analysis. World J. Orthop. 2023, 14, 23–41. [Google Scholar] [CrossRef]
  71. Kim, J.H.; Kim, K.I.; Yoon, W.K.; Song, S.J.; Jin, W. Intra-articular Injection of Mesenchymal Stem Cells After High Tibial Osteotomy in Osteoarthritic Knee: Two-Year Follow-up of Randomized Control Trial. Stem Cells Transl. Med. 2022, 11, 572–585. [Google Scholar] [CrossRef] [PubMed]
  72. Ding, D.C.; Chou, H.L.; Chang, Y.H.; Hung, W.T.; Liu, H.W.; Chu, T.Y. Characterization of HLA-G and Related Immunosuppressive Effects in Human Umbilical Cord Stroma-Derived Stem Cells. Cell Transpl. 2016, 25, 217–228. [Google Scholar] [CrossRef] [PubMed]
  73. Zhang, Q.; Xiang, E.; Rao, W.; Zhang, Y.Q.; Xiao, C.H.; Li, C.Y.; Han, B.; Wu, D. Intra-articular injection of human umbilical cord mesenchymal stem cells ameliorates monosodium iodoacetate-induced osteoarthritis in rats by inhibiting cartilage degradation and inflammation. Bone Jt. Res. 2021, 10, 226–236. [Google Scholar] [CrossRef] [PubMed]
  74. Ragni, E.; Perucca Orfei, C.; De Luca, P.; Colombini, A.; Viganò, M.; de Girolamo, L. Secreted Factors and EV-miRNAs Orchestrate the Healing Capacity of Adipose Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis. Int. J. Mol. Sci. 2020, 21, 1582. [Google Scholar] [CrossRef] [PubMed]
  75. Ju, Y.; Yi, L.; Li, C.; Wang, T.; Zhang, W.; Chai, W.; Yin, X.; Weng, T. Comparison of biological characteristics of human adipose- and umbilical cord- derived mesenchymal stem cells and their effects on delaying the progression of osteoarthritis in a rat model. Acta Histochem. 2022, 124, 151911. [Google Scholar] [CrossRef] [PubMed]
  76. Lu, L.; Dai, C.; Du, H.; Li, S.; Ye, P.; Zhang, L.; Wang, X.; Song, Y.; Togashi, R.; Vangsness, C.T.; et al. Intra-articular injections of allogeneic human adipose-derived mesenchymal progenitor cells in patients with symptomatic bilateral knee osteoarthritis: A Phase I pilot study. Regen. Med. 2020, 15, 1625–1636. [Google Scholar] [CrossRef]
  77. Almahasneh, F.; Abu-El-Rub, E.; Khasawneh, R.R. Mechanisms of analgesic effect of mesenchymal stem cells in osteoarthritis pain. World J. Stem Cells 2023, 15, 196–208. [Google Scholar] [CrossRef]
  78. Jones, K.J.; Cash, B.M. Matrix-Induced Autologous Chondrocyte Implantation with Autologous Bone Grafting for Osteochondral Lesions of the Femoral Trochlea. Arthrosc. Tech. 2019, 8, e259–e266. [Google Scholar] [CrossRef]
  79. Qi, H.; Liu, D.P.; Xiao, D.W.; Tian, D.C.; Su, Y.W.; Jin, S.F. Exosomes derived from mesenchymal stem cells inhibit mitochondrial dysfunction-induced apoptosis of chondrocytes via p38, ERK, and Akt pathways. In vitro cellular & developmental biology. Animal 2019, 55, 203–210. [Google Scholar] [CrossRef]
  80. Toh, W.S.; Foldager, C.B.; Pei, M.; Hui, J.H. Advances in mesenchymal stem cell-based strategies for cartilage repair and regeneration. Stem Cell Rev. Rep. 2014, 10, 686–696. [Google Scholar] [CrossRef]
  81. Meirelles Lda, S.; Fontes, A.M.; Covas, D.T.; Caplan, A.I. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 2009, 20, 419–427. [Google Scholar] [CrossRef] [PubMed]
  82. Yu, D.D.; Wu, Y.; Shen, H.Y.; Lv, M.M.; Chen, W.X.; Zhang, X.H.; Zhong, S.L.; Tang, J.H.; Zhao, J.H. Exosomes in development, metastasis and drug resistance of breast cancer. Cancer Sci. 2015, 106, 959–964. [Google Scholar] [CrossRef] [PubMed]
  83. Doyle, L.M.; Wang, M.Z. Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells 2019, 8, 727. [Google Scholar] [CrossRef] [PubMed]
  84. Xu, J.F.; Wang, Y.P.; Zhang, S.J.; Chen, Y.; Gu, H.F.; Dou, X.F.; Xia, B.; Bi, Q.; Fan, S.W. Exosomes containing differential expression of microRNA and mRNA in osteosarcoma that can predict response to chemotherapy. Oncotarget 2017, 8, 75968–75978. [Google Scholar] [CrossRef] [PubMed]
  85. Foo, J.B.; Looi, Q.H.; Chong, P.P.; Hassan, N.H.; Yeo, G.E.C.; Ng, C.Y.; Koh, B.; How, C.W.; Lee, S.H.; Law, J.X. Comparing the Therapeutic Potential of Stem Cells and their Secretory Products in Regenerative Medicine. Stem Cells Int. 2021, 2021, 2616807. [Google Scholar] [CrossRef]
  86. Görgens, A.; Corso, G.; Hagey, D.W.; Jawad Wiklander, R.; Gustafsson, M.O.; Felldin, U.; Lee, Y.; Bostancioglu, R.B.; Sork, H.; Liang, X.; et al. Identification of storage conditions stabilizing extracellular vesicles preparations. J. Extracell. Vesicles 2022, 11, e12238. [Google Scholar] [CrossRef]
  87. Zhou, L.; Ye, H.; Liu, L.; Chen, Y. Human Bone Mesenchymal Stem Cell-Derived Exosomes Inhibit IL-1β-Induced Inflammation in Osteoarthritis Chondrocytes. Cell J. 2021, 23, 485–494. [Google Scholar] [CrossRef]
  88. Wu, J.; Kuang, L.; Chen, C.; Yang, J.; Zeng, W.N.; Li, T.; Chen, H.; Huang, S.; Fu, Z.; Li, J.; et al. miR-100-5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis. Biomaterials 2019, 206, 87–100. [Google Scholar] [CrossRef]
  89. Mao, G.; Zhang, Z.; Hu, S.; Zhang, Z.; Chang, Z.; Huang, Z.; Liao, W.; Kang, Y. Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A. Stem Cell Res. Ther. 2018, 9, 247. [Google Scholar] [CrossRef]
  90. Herrmann, I.K.; Wood, M.J.A.; Fuhrmann, G. Extracellular vesicles as a next-generation drug delivery platform. Nat. Nanotechnol. 2021, 16, 748–759. [Google Scholar] [CrossRef]
  91. Kwon, D.G.; Kim, M.K.; Jeon, Y.S.; Nam, Y.C.; Park, J.S.; Ryu, D.J. State of the Art: The Immunomodulatory Role of MSCs for Osteoarthritis. Int. J. Mol. Sci. 2022, 23, 1618. [Google Scholar] [CrossRef] [PubMed]
  92. Cosenza, S.; Ruiz, M.; Toupet, K.; Jorgensen, C.; Noël, D. Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Sci. Rep. 2017, 7, 16214. [Google Scholar] [CrossRef] [PubMed]
  93. Li, K.; Yan, G.; Huang, H.; Zheng, M.; Ma, K.; Cui, X.; Lu, D.; Zheng, L.; Zhu, B.; Cheng, J.; et al. Anti-inflammatory and immunomodulatory effects of the extracellular vesicles derived from human umbilical cord mesenchymal stem cells on osteoarthritis via M2 macrophages. J. Nanobiotechnol. 2022, 20, 38. [Google Scholar] [CrossRef] [PubMed]
  94. Jin, Y.; Xu, M.; Zhu, H.; Dong, C.; Ji, J.; Liu, Y.; Deng, A.; Gu, Z. Therapeutic effects of bone marrow mesenchymal stem cells-derived exosomes on osteoarthritis. J. Cell. Mol. Med. 2021, 25, 9281–9294. [Google Scholar] [CrossRef] [PubMed]
  95. Si, H.B.; Zeng, Y.; Liu, S.Y.; Zhou, Z.K.; Chen, Y.N.; Cheng, J.Q.; Lu, Y.R.; Shen, B. Intra-articular injection of microRNA-140 (miRNA-140) alleviates osteoarthritis (OA) progression by modulating extracellular matrix (ECM) homeostasis in rats. Osteoarthr. Cartil. 2017, 25, 1698–1707. [Google Scholar] [CrossRef] [PubMed]
  96. Liang, Y.; Xu, X.; Li, X.; Xiong, J.; Li, B.; Duan, L.; Wang, D.; Xia, J. Chondrocyte-Targeted MicroRNA Delivery by Engineered Exosomes toward a Cell-Free Osteoarthritis Therapy. ACS Appl. Mater. Interfaces 2020, 12, 36938–36947. [Google Scholar] [CrossRef] [PubMed]
  97. Golebiowska, A.A.; Intravaia, J.T.; Sathe, V.M.; Kumbar, S.G.; Nukavarapu, S.P. Decellularized extracellular matrix biomaterials for regenerative therapies: Advances, challenges and clinical prospects. Bioact. Mater. 2024, 32, 98–123. [Google Scholar] [CrossRef] [PubMed]
  98. Platas, J.; Guillén, M.I.; del Caz, M.D.; Gomar, F.; Mirabet, V.; Alcaraz, M.J. Conditioned media from adipose-tissue-derived mesenchymal stem cells downregulate degradative mediators induced by interleukin-1β in osteoarthritic chondrocytes. Mediat. Inflamm. 2013, 2013, 357014. [Google Scholar] [CrossRef]
  99. Shammaa, R.; El-Kadiry, A.E.; Abusarah, J.; Rafei, M. Mesenchymal Stem Cells Beyond Regenerative Medicine. Front. Cell Dev. Biol. 2020, 8, 72. [Google Scholar] [CrossRef]
  100. Shapiro, S.A.; Kazmerchak, S.E.; Heckman, M.G.; Zubair, A.C.; O’Connor, M.I. A Prospective, Single-Blind, Placebo-Controlled Trial of Bone Marrow Aspirate Concentrate for Knee Osteoarthritis. Am. J. Sports Med. 2017, 45, 82–90. [Google Scholar] [CrossRef]
  101. Keeling, L.E.; Belk, J.W.; Kraeutler, M.J.; Kallner, A.C.; Lindsay, A.; McCarty, E.C.; Postma, W.F. Bone Marrow Aspirate Concentrate for the Treatment of Knee Osteoarthritis: A Systematic Review. Am. J. Sports Med. 2022, 50, 2315–2323. [Google Scholar] [CrossRef] [PubMed]
  102. Dulic, O.; Rasovic, P.; Lalic, I.; Kecojevic, V.; Gavrilovic, G.; Abazovic, D.; Maric, D.; Miskulin, M.; Bumbasirevic, M. Bone Marrow Aspirate Concentrate versus Platelet Rich Plasma or Hyaluronic Acid for the Treatment of Knee Osteoarthritis. Medicina 2021, 57, 1193. [Google Scholar] [CrossRef] [PubMed]
  103. Anil, U.; Markus, D.H.; Hurley, E.T.; Manjunath, A.K.; Alaia, M.J.; Campbell, K.A.; Jazrawi, L.M.; Strauss, E.J. The efficacy of intra-articular injections in the treatment of knee osteoarthritis: A network meta-analysis of randomized controlled trials. Knee 2021, 32, 173–182. [Google Scholar] [CrossRef] [PubMed]
  104. Hernigou, P.; Delambre, J.; Quiennec, S.; Poignard, A. Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: A prospective randomized study versus contralateral arthroplasty at a mean fifteen year follow-up. Int. Orthop. 2021, 45, 365–373. [Google Scholar] [CrossRef] [PubMed]
  105. Bastos, R.; Mathias, M.; Andrade, R.; Amaral, R.; Schott, V.; Balduino, A.; Bastos, R.; Miguel Oliveira, J.; Reis, R.L.; Rodeo, S.; et al. Intra-articular injection of culture-expanded mesenchymal stem cells with or without addition of platelet-rich plasma is effective in decreasing pain and symptoms in knee osteoarthritis: A controlled, double-blind clinical trial. Knee Surg. Sports Traumatol. Arthrosc. 2020, 28, 1989–1999. [Google Scholar] [CrossRef] [PubMed]
  106. El-Kadiry, A.E.; Lumbao, C.; Salame, N.; Rafei, M.; Shammaa, R. Bone marrow aspirate concentrate versus platelet-rich plasma for treating knee osteoarthritis: A one-year non-randomized retrospective comparative study. BMC Musculoskelet. Disord. 2022, 23, 23. [Google Scholar] [CrossRef] [PubMed]
  107. Hu, C.; Li, L. Preconditioning influences mesenchymal stem cell properties in vitro and in vivo. J. Cell. Mol. Med. 2018, 22, 1428–1442. [Google Scholar] [CrossRef]
  108. Francis, K.R.; Wei, L. Human embryonic stem cell neural differentiation and enhanced cell survival promoted by hypoxic preconditioning. Cell Death Dis. 2010, 1, e22. [Google Scholar] [CrossRef]
  109. Pasha, Z.; Wang, Y.; Sheikh, R.; Zhang, D.; Zhao, T.; Ashraf, M. Preconditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium. Cardiovasc. Res. 2008, 77, 134–142. [Google Scholar] [CrossRef]
  110. Fan, L.; Zhang, C.; Yu, Z.; Shi, Z.; Dang, X.; Wang, K. Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and osteogenesis in rabbit femoral head osteonecrosis. Bone 2015, 81, 544–553. [Google Scholar] [CrossRef]
  111. Guan, X.; Ma, X.; Zhang, L.; Feng, H.; Ma, Z. Evaluation of CD24 as a marker to rapidly define the mesenchymal stem cell phenotype and its differentiation in human nucleus pulposus. Chin. Med. J. 2014, 127, 1474–1481. [Google Scholar] [PubMed]
  112. Berglund, A.K.; Fisher, M.B.; Cameron, K.A.; Poole, E.J.; Schnabel, L.V. Transforming Growth Factor-β2 Downregulates Major Histocompatibility Complex (MHC) I and MHC II Surface Expression on Equine Bone Marrow-Derived Mesenchymal Stem Cells without Altering Other Phenotypic Cell Surface Markers. Front. Vet. Sci. 2017, 4, 84. [Google Scholar] [CrossRef] [PubMed]
  113. Wan Safwani, W.K.Z.; Choi, J.R.; Yong, K.W.; Ting, I.; Mat Adenan, N.A.; Pingguan-Murphy, B. Hypoxia enhances the viability, growth and chondrogenic potential of cryopreserved human adipose-derived stem cells. Cryobiology 2017, 75, 91–99. [Google Scholar] [CrossRef] [PubMed]
  114. Evaristo-Mendonça, F.; Sardella-Silva, G.; Kasai-Brunswick, T.H.; Campos, R.M.P.; Domizi, P.; Santiago, M.F.; de Melo Reis, R.A.; Mendez-Otero, R.; Ribeiro-Resende, V.T.; Pimentel-Coelho, P.M. Preconditioning of Rat Bone Marrow-Derived Mesenchymal Stromal Cells with Toll-Like Receptor Agonists. Stem Cells Int. 2019, 2019, 7692973. [Google Scholar] [CrossRef] [PubMed]
  115. Hwang, S.H.; Cho, H.K.; Park, S.H.; Lee, W.; Lee, H.J.; Lee, D.C.; Oh, J.H.; Park, S.H.; Kim, T.G.; Sohn, H.J.; et al. Toll like receptor 3 & 4 responses of human turbinate derived mesenchymal stem cells: Stimulation by double stranded RNA and lipopolysaccharide. PLoS ONE 2014, 9, e101558. [Google Scholar] [CrossRef]
  116. Duan, A.; Shen, K.; Li, B.; Li, C.; Zhou, H.; Kong, R.; Shao, Y.; Qin, J.; Yuan, T.; Ji, J.; et al. Extracellular vesicles derived from LPS-preconditioned human synovial mesenchymal stem cells inhibit extracellular matrix degradation and prevent osteoarthritis of the knee in a mouse model. Stem Cell Res. Ther. 2021, 12, 427. [Google Scholar] [CrossRef] [PubMed]
  117. Zhang, Y.; Pizzute, T.; Li, J.; He, F.; Pei, M. sb203580 preconditioning recharges matrix-expanded human adult stem cells for chondrogenesis in an inflammatory environment—A feasible approach for autologous stem cell based osteoarthritic cartilage repair. Biomaterials 2015, 64, 88–97. [Google Scholar] [CrossRef] [PubMed]
  118. Barhanpurkar-Naik, A.; Mhaske, S.T.; Pote, S.T.; Singh, K.; Wani, M.R. Interleukin-3 enhances the migration of human mesenchymal stem cells by regulating expression of CXCR4. Stem Cell Res. Ther. 2017, 8, 168. [Google Scholar] [CrossRef]
  119. Li, D.; Yi, S.; Jiang, C.; Cong, W.; Zhang, H. Research on human umbilical cord bloodmesenchymal stem cells transfected with the gene of humanbone morphogenetic protein-2. Chin. J. Geriatr. Orthop. Rehabil. 2019, 5, 75–81. [Google Scholar] [CrossRef]
  120. Luo, C.; Peng, Y.; Zhou, X.; Fan, J.; Chen, W.; Zhang, H.; Wei, A. NLRP3 downregulation enhances engraftment and functionality of adipose-derived stem cells to alleviate erectile dysfunction in diabetic rats. Front. Endocrinol. 2022, 13, 913296. [Google Scholar] [CrossRef]
  121. Tao, S.C.; Yuan, T.; Zhang, Y.L.; Yin, W.J.; Guo, S.C.; Zhang, C.Q. Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics 2017, 7, 180–195. [Google Scholar] [CrossRef] [PubMed]
  122. Zhang, S.; Xie, D.; Zhang, Q. Mesenchymal stem cells plus bone repair materials as a therapeutic strategy for abnormal bone metabolism: Evidence of clinical efficacy and mechanisms of action implied. Pharmacol. Res. 2021, 172, 105851. [Google Scholar] [CrossRef] [PubMed]
  123. Abdelrazik, H.; Giordano, E.; Barbanti Brodano, G.; Griffoni, C.; De Falco, E.; Pelagalli, A. Substantial Overview on Mesenchymal Stem Cell Biological and Physical Properties as an Opportunity in Translational Medicine. Int. J. Mol. Sci. 2019, 20, 5386. [Google Scholar] [CrossRef] [PubMed]
  124. Glowacki, J.; Mizuno, S. Collagen scaffolds for tissue engineering. Biopolymers 2008, 89, 338–344. [Google Scholar] [CrossRef] [PubMed]
  125. Kon, E.; Filardo, G.; Di Matteo, B.; Perdisa, F.; Marcacci, M. PRP-Augmented Scaffolds for Cartilage Regeneration: A Systematic Review. Oper. Tech. Sports Med. 2013, 21, 108–115. [Google Scholar] [CrossRef]
  126. Johnstone, B.; Alini, M.; Cucchiarini, M.; Dodge, G.R.; Eglin, D.; Guilak, F.; Madry, H.; Mata, A.; Mauck, R.L.; Semino, C.E.; et al. Tissue engineering for articular cartilage repair--the state of the art. Eur. Cells Mater. 2013, 25, 248–267. [Google Scholar] [CrossRef]
  127. Kim, J.E.; Lee, S.M.; Kim, S.H.; Tatman, P.; Gee, A.O.; Kim, D.H.; Lee, K.E.; Jung, Y.; Kim, S.J. Effect of self-assembled peptide-mesenchymal stem cell complex on the progression of osteoarthritis in a rat model. Int. J. Nanomed. 2014, 9 (Suppl. 1), 141–157. [Google Scholar] [CrossRef] [PubMed]
  128. Kayakabe, M.; Tsutsumi, S.; Watanabe, H.; Kato, Y.; Takagishi, K. Transplantation of autologous rabbit BM-derived mesenchymal stromal cells embedded in hyaluronic acid gel sponge into osteochondral defects of the knee. Cytotherapy 2006, 8, 343–353. [Google Scholar] [CrossRef]
  129. Wakitani, S.; Mitsuoka, T.; Nakamura, N.; Toritsuka, Y.; Nakamura, Y.; Horibe, S. Autologous bone marrow stromal cell transplantation for repair of full-thickness articular cartilage defects in human patellae: Two case reports. Cell Transpl. 2004, 13, 595–600. [Google Scholar] [CrossRef]
  130. Haleem, A.M.; Singergy, A.A.; Sabry, D.; Atta, H.M.; Rashed, L.A.; Chu, C.R.; El Shewy, M.T.; Azzam, A.; Abdel Aziz, M.T. The Clinical Use of Human Culture-Expanded Autologous Bone Marrow Mesenchymal Stem Cells Transplanted on Platelet-Rich Fibrin Glue in the Treatment of Articular Cartilage Defects: A Pilot Study and Preliminary Results. Cartilage 2010, 1, 253–261. [Google Scholar] [CrossRef]
  131. Matas, J.; Orrego, M.; Amenabar, D.; Infante, C.; Tapia-Limonchi, R.; Cadiz, M.I.; Alcayaga-Miranda, F.; González, P.L.; Muse, E.; Khoury, M.; 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 Transl. Med. 2019, 8, 215–224. [Google Scholar] [CrossRef] [PubMed]
  132. Lamo-Espinosa, J.M.; Mora, G.; Blanco, J.F.; Granero-Moltó, F.; Núñez-Córdoba, J.M.; López-Elío, S.; Andreu, E.; Sánchez-Guijo, F.; Aquerreta, J.D.; Bondía, J.M.; et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: Long-term follow up of a multicenter randomized controlled clinical trial (phase I/II). J. Transl. Med. 2018, 16, 213. [Google Scholar] [CrossRef] [PubMed]
  133. Mautner, K.; Gottschalk, M.; Boden, S.D.; Akard, A.; Bae, W.C.; Black, L.; Boggess, B.; Chatterjee, P.; Chung, C.B.; Easley, K.A.; et al. Cell-based versus corticosteroid injections for knee pain in osteoarthritis: A randomized phase 3 trial. Nat. Med. 2023, 29, 3120–3126. [Google Scholar] [CrossRef] [PubMed]
Ijms 25 00394 g001
Figure 1. Different sources of mesenchymal stem cells (MSCs)—including derivatives, pretreated MSCs, and transgenic MSCs, as well as biomaterials combined with MSCs—contribute to cartilage regeneration, anti-inflammatory response, immune regulation, and analgesic effects. These versatile applications position MSCs as potential therapeutic agents for osteoarthritis (OA), offering the prospect of slowing down the progression of OA.
Figure 1. Different sources of mesenchymal stem cells (MSCs)—including derivatives, pretreated MSCs, and transgenic MSCs, as well as biomaterials combined with MSCs—contribute to cartilage regeneration, anti-inflammatory response, immune regulation, and analgesic effects. These versatile applications position MSCs as potential therapeutic agents for osteoarthritis (OA), offering the prospect of slowing down the progression of OA.
Ijms 25 00394 g001
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Chen, Y.; Cheng, R.-J.; Wu, Y.; Huang, D.; Li, Y.; Liu, Y. Advances in Stem Cell-Based Therapies in the Treatment of Osteoarthritis. Int. J. Mol. Sci. 2024, 25, 394. https://doi.org/10.3390/ijms25010394

AMA Style

Chen Y, Cheng R-J, Wu Y, Huang D, Li Y, Liu Y. Advances in Stem Cell-Based Therapies in the Treatment of Osteoarthritis. International Journal of Molecular Sciences. 2024; 25(1):394. https://doi.org/10.3390/ijms25010394

Chicago/Turabian Style

Chen, Ye, Rui-Juan Cheng, Yinlan Wu, Deying Huang, Yanhong Li, and Yi Liu. 2024. "Advances in Stem Cell-Based Therapies in the Treatment of Osteoarthritis" International Journal of Molecular Sciences 25, no. 1: 394. https://doi.org/10.3390/ijms25010394

APA Style

Chen, Y., Cheng, R. -J., Wu, Y., Huang, D., Li, Y., & Liu, Y. (2024). Advances in Stem Cell-Based Therapies in the Treatment of Osteoarthritis. International Journal of Molecular Sciences, 25(1), 394. https://doi.org/10.3390/ijms25010394

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop