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Open access peer-reviewed chapter

Mesenchymal Stem Cell-based Cytotherapy for Osteoarthritis Management: State of the Art

Written By

Leisheng Zhang, Zhihai Han, Zhongchao Han and Hui Cai

Submitted: May 14th, 2022 Reviewed: September 23rd, 2022 Published: October 23rd, 2022

DOI: 10.5772/intechopen.108258

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Arthroplasty Advanced Techniques and Future Perspectives Edited by Alessandro Rozim Zorzi

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Arthroplasty

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Abstract

Osteoarthritis (OA), a principal and challenging disorder of articular cartilage, has been regarded as the most frequent and prevalent chronic disease of degenerative joints, which is caused by multiple factors including aging, trauma, overweight, joint deformity and congenital abnormality, together with the increase in life expectancy. In spite of considerable improvements that have been obtained by conducting multidisciplinary therapies such as surgical procedures and anti-inflammatory drugs, the pathogenesis and efficacy of OA with functional losses and degeneration are still elusively complicated for ascertainment. Mesenchymal stem/stromal cells (MSCs), also termed as multipotent mesenchymal progenitor/precursor cells, skeletal stem cells, or medicinal signaling cells, are heterogeneous cell populations with hematopoietic-supporting and immunomodulatory properties, together with multilineage differentiation property. For decades, investigators have illuminated the application of the advantaged and promising sources with/without remarkable biomaterials for the treatment of recurrent and refractory disorders including OA. In this chapter, we mainly concentrate on the current progress of MSC-based cytotherapy in both preclinical study and clinical practice as well as the promising prospective and critical challenges in the field, which will conformably benefit the administration of OA in future.

Keywords

  • osteoarthritis
  • mesenchymal stem cells
  • cytotherapy
  • biomaterials
  • tissue engineering

1. Introduction

Osteoarthritis (OA) is a whole organ disease characterized by the destruction or degeneration of articular cartilage, which is one of the most widespread and frequent chronic diseases and public health issues worldwide [1, 2]. During the course of OA, inflammatory response is a pivotal factor resulting in cartilage destruction or exacerbation of symptoms [2, 3, 4]. As satisfactory osteochondral repair, it’s of great importance for the zonal restoration of adjacent cartilage and the subchondral bone [5]. For the past decades, despite the significant number of progress have been achieved by multidisciplinary strategies such as surgeries (e.g., microfracture, mosaicplasty), autologous chondrocyte implantation (ACI), joint lubricants (e.g., hyaluronic acid), antiinflammatory drugs (e.g., NSAIDs) as well as cytotherapies (e.g., autologous chondrocyte implantation), the inherent limitations of regeneration and self-repair capacity in OA individuals still largely hinder the remission of the degeneration of articular cartilage [4, 6, 7, 8]. For example, even though joint replacement serves as an effective remedy for symptomatic end-stage disease including OA, most of the functional outcomes in patients are unsatisfactory and the lifespan of prosthesis is also largely limited [2, 9]. Distinguishing from the traditional remedies, cell-based strategies have emerged as an alternative with promising prospective in the treatment of OA and cartilage defects [10, 11].

State-of-the-art updates have turned to MSC-based cytotherapy for OA management both clinically and preclinically [5, 12]. The multifaceted superiorities of MSCs including multidirectional differentiation, high portability property, and low immunogenicity have made themselves ideal seed cells for OA treatment [3]. Meanwhile, MSCs or the derivatives are often encapsulated into natural or synthetic hydrogels, which can function by providing tunable biodegradability, and biocompatibility or enhancing cell vitality and functionality [10].

Herein, we mainly focus on the recent literatures relating to the application of MSCs for OA treatment based on the chondrogenic differentiation, and antiinflammatory and immunomodulatory effects of MSCs with or without biological scaffolds for cartilage regeneration. Meanwhile, we further discuss the promising prospective and formidable challenges of MSC-based cytotherapy in cartilage repair and regeneration as well.

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2. MSCs and derivatives

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

Since the 1970s, MSCs have been isolated from various adult tissues including bone marrow, adipose tissues, synovial fluid, periosteum and dental tissues (e.g., dental pulp, periodontium) [18, 19, 20]. After that, perinatal or fetal tissues including umbilical cord, placenta, amniotic member and amniotic fluid have also been reported for MSC isolation [21]. Distinguish from those derived from adult tissues, MSCs isolated from the “discarded” perinatal tissues have been considered with preferable immunoregulatory properties and long-term in vitro proliferative capacity, and in particular, release from ethical risks, invasiveness and pathogenic contamination [14, 21, 22, 23]. Notably, current studies have also put forward the feasibility of generating large-scale MSCs from induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs) as well [24, 25, 26]. To date, MSCs with different origins have been involved in numerous refractory and relapse disease administration including acute-on-chronic liver failure (ACLF), acute myocardial infarction (AMI), aplastic anemia, premature ovarian failure (POF), fistulizing Crohn’s disease, critical limb ischemia (CLI), cutaneous wounds, coronavirus disease 2019 (COVID-19)-induced acute lung injury and acute respiratory distress syndrome (ALI/ARDS) [26, 27, 28, 29, 30, 31, 32].

For decades, the derivatives generated from MSCs such as exosomes and relative microvesicles have been extensively investigated and regarded as the dominating factor during pathogenesis and disease treatment [20, 33]. Exosomes, also known as small extracellular vesicles (sEVs) or biological spherical lipid bilayer vesicles, are nano-sized extracellular vesicles secreted by various types of cells (e.g., MSCs, natural killer cells, T or B lymphocytes, epithelial cells, macrophages, dendritic cells, tumor cells) with partial sizes ranging from 20 to 200 nm according to the Minimal Information for Studies of Extracellular Vesicles 2018 (MISEV 2018) guidelines [34, 35, 36]. The plasma membrane-derived vesicles contain lipids, proteins (e.g., CD9, CD63, CD81, GTPases, HSP70, HSP90, Tsg101, Alix), nucleic acids (e.g., microRNAs, LncRNAs, mRNAs), and other bioactive substances, which thus play an important role in various physiological and pathological processes, and in particular, serving as intermediators for material exchange and intercellular communication via delivering a variety of the aforementioned bioactive substances [37, 38]. Numerous preclinical and clinical investigations including the International Society for Extracellular Vesicles (ISEV) have shown that MSC-derived extracellular vesicles (EVs) including exosomes and microvesicles (MV) are rich in growth factors, cytokines, mRNAs, signaling lipids and regulatory miRNAs, which are adequate to influence intercellular neighbors and tissue responses to infections, injuries, and diseases [39, 40]. However, the concomitant shortcomings of exosomes such as low purity, low yield, stability for storage and weak targeting collectively limit their preclinical investigation and clinical application. Therefore, there’s still a long way to optimize the aforementioned problems and facilitate further exploration upon large-scale preparation (e.g., ultracentrifugation techniques, polymer precipitation, size-based isolation techniques, immunoaffinity chromatography, micro-vortex chips, commercial isolation kits) for translational purposes [41, 42, 43].

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3. Biomaterials/MSC-based composites for osteoarthritis management

Biomaterials of different categories and characteristics have attracted great concerns of investigators in the field of MSC-based regenerative medicine, and thus allow the utilization of unique scaffolds to promote the expansion of MSCs and facilitate their differentiation into appropriate lineages [24, 44]. Biomaterials with highly biocompatible properties are adequate to act as splendid scaffolds for cell attachment and supply preferable microenvironment for the maintenance, differentiation, and biofunction of the encapsulated MSCs, which collectively benefit the in situ tissue engineering and translational medicine [45, 46, 47]. To date, a series of biomaterials with discrete advantages and disadvantages have been developed and combined with MSCs for regenerative purposes such as the highly biocompatible natural (e.g., collagen, chitosan) and synthetic (e.g., poly-ethylene-glycol, polycaprolactone) biomaterials [44, 46].

3.1 Hydrogel/MSC-based scaffolds for OA management

Hydrogels are splendid biomaterials with unique physical and chemical properties for both soft and hard tissue engineering and regenerative medicine, which largely attributes to the feasibility of orchestrating the critical properties (e.g., elasticity, water content, bioactivity, mechanical stiffness, degradation) rationally and conveniently [48, 49, 50]. For decades, hydrogels alone or in combination with appropriate biomaterials have been extensively investigated in various osteoarticular disorders such as OA and meniscus injury [51, 52, 53]. For example, our groups recently reported the reinforced efficacy upon OA rabbits by hyaluronic acid (HA) hydrogel and PSC-MSCs composite (HA/PSC-MSCs) compared to those with HA hydrogel or PSC-MSCs alone [24]. Instead, Chung and colleagues systematically compared the efficacy by implanting various hydrogels/UC-MSCs composites in rats such as alginate, chitosan, pluronic, hyaluronic acid (HA), and verified that HA/hUC-MSCs composites rather than relative hydrogels resulted in preferable cartilage repair and achieved collagen organization pattern and cellular arrangements much similar to the adjacent uninjured articular cartilage [54].

Recently, Yang and colleagues further reported the utilization of an injectable and biocompatible Diels-Alder crosslinked hyaluronic acid/PEG (DAHP) hydrogel for OA treatment, which was found with considerable improvement by controlling the release of MSC-derived small extracellular vesicles (MSC-sEVs) [55]. Similarly, Heirani-Tabasi et al. confirmed the enhanced chondrogenic differentiation capacity of adipose-derived MSCs (AD-MSCs) after incubation with an injectable chitosan-hyaluronic acid (CS-HA) hydrogel [56]. Additionally, Tang et al. demonstrated that sEVs derived from umbilical cord MSCs (UC-MSC-sEVs) revealed comparable therapeutic effects for OA but with upregulated proteins mostly involved in extracellular matrix (ECM) organization, immune effector process, PI3K-AKT and Rap1 signaling pathways [57]. Collectively, MSCs or derivatives (e.g., exosomes, sEVs) in combination with injectable hydrogels have attracted considerable attention in OA management for their advantaged chondrogenic differentiation capacity [51, 56, 58].

3.2 Hydroxyapatite (HAP)/MSCs scaffolds for OA management

State-of-the-art renewals have also highlighted the combination of HAP-based biomaterials with MSCs for OA administration and bone regeneration. For instance, Ji and colleagues recently took advantage of a novel hybrid scaffold composed of nano-hydroxyapatite (nHA)/poly ε-caprolactone (PCL) and thermosensitive hydroxypropyl chitin hydrogel (HPCH) for bone defect repair via a mechanism of enhancing vascularization and osteogenesis of encapsulated MSCs [59].

Instead, Shimomura et al. took advantage of a scaffold-free tissue-engineered construct (TEC) and a HAP artificial bone for the treatment of a rabbit osteochondral defect model, and found that osteochondral defects treated with the synovial MSC-derived TEC and HAP composite revealed more rapid and efficient subchondral bone repair coupled with cartilaginous tissues as well as good tissue integration to adjacent host cartilage. Moreover, the combined MSC-based implants significantly accelerated postoperative rehabilitation and sustained the longer-term durability of repaired osteochondral lesions in patients with OA [5]. Similarly, with the aid of bone marrow-derived MSCs (BM-MSCs) and an interconnected porous hydroxyapatite ceramic (IP-CHA), the large osteochondral defect of the knee in a 21-year-old man was effectively alleviated, and cartilage-like regeneration and bone formation were observed as well [12]. Additionally, we recently also reported the preferable outcomes of OA by conducting multidimensional optimization of MSC-based formulation in combination with the advantageous HA/PG biomaterials, which showed evaluated therapeutic efficacy over HA alone in ameliorating osteoarthritis progression [60, 61].

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4. Molecular mechanism of MSC-based cytotherapy for OA management

Generally, MSCs function mainly via orchestrating a series of mode of action including compositional microenvironment, immunoregulation, autocrine, paracrine, and direct- or trans-differentiation into functional cells [15, 62, 63]. In particular, the unique immunomodulatory property and paracrine manner have prompted the enthusiasm for allogenic transplantation of the “off-the-shelf” MSC products in both preclinical and clinical practices in the field of regenerative medicine.

4.1 Compositional microenvironment

In the bone marrow microenvironment, MSCs function as dominating component and stromal cells for the homeostasis and regeneration of hematopoietic stem cells (HSCs) and the concomitant derived cells [30, 64, 65]. In the context of physiological hematogenesis, MSCs are competent for the maintenance or replenishment of the stem cell pool in damaged tissues, and thus help reconstruct the microenvironment for the subsequent hematopoietic reconstitution [22, 30]. As to OA, by conducting MSC infusion into the articular cavity, the hyperactivated inflammatory response caused by inflammatory cytokines is supposed to be effectively suppressed by the released anti-inflammatory factors, extracellular organelles, and vesicles in the microenvironment [24, 66]. As to OA, the roles of MSCs are to orchestrate the spatiotemporal balance between the inflammation and cartilage tissue reconstruction via providing the damaged tissues including bone tissue and cartilage tissue with a relatively desirable environment for tissue repair [24, 67].

4.2 Immunomodulatory effect

To date, extensive literatures have demonstrated the therapeutic or ameliorative effects of MSCs on refractory and recurrent diseases via a bidirectional immunomodulatory approach [14, 25]. Notably, a variety of antiinflammatory factors and cytokines have been reported to play a pivotal role during inflammatory reactions such as interleukins (e.g., IL-6, IL-8, IL-10), transforming growth factor (TGF), stromal cell-derived factor 1 (SDF-1), and vascular endothelial growth factor (VEGF) [22, 68, 69]. The underlying molecular mechanism lies in the sensitive response of MSCs toward the concentration gradient of inflammatory cytokines and chemokines [70]. As to OA, low-grade inflammation has been demonstrated critically in the pathogenesis, which therefore hinders the deposition of cartilage matrix at the damaged sites, delays the proliferation of osteoblast and chondrocytes, and thus resulting in low efficiency of articular cartilage repair [71, 72]. Currently, various kinds of immune cells have been observed in the synovium of OA, including the classically activated and proinflammatory macrophages (M1Mφ), antiinflammatory macrophages (M2Mφ), and T cells. For example, as the major counterparts of immune cells in the joints, Mφ can be hyperactivated by proinflammatory factors in OA patients such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and even the pathogen-associated molecular patterns [73]. Therefore, the efficient treatment of OA should also pay close attention to the regulation of the local inflammatory microenvironment. As mentioned above, MSC with multilineage differentiation potential and effective immunomodulatory properties have been supposed as an alternative remedy in the administration of cartilage degradation [74]. In detail, MSCs are purposefully recruited to the site of the damaged cartilage and initiate the therapeutic effects upon osteochondral defects, and thus accelerating the reconstruction of articular surface in OA patients [70]. MSCs have been demonstrated involved in the regulation of M1Mφ towards M2Mφ via releasing growth and angiogenic factors as well as down-regulating inflammation and accelerating the remodeling of damaged tissue in OA. Additionally, the immunoregulatory effect of MSCs or MSC-derived EVs upon T cell subsets has also been extensively and in-detail described during the Th1/Th2 cell transformation, Th17 cell and Treg cell generation, and the apoptosis of hyperactivated T cells [75, 76, 77, 78, 79]. Similarly, state-of-the-art renewal has also indicated the immunomodulatory effect of MSCs upon CD24+CD38+ B cells partially via soluble secreted factors. Interestingly, the role of MSC-derived EVs in mediating B-cell immunoregulation merit seems contradictory and still needs further investigation [67, 80].

4.3 Autocrine and paracrine

Autocrine and paracrine play a critical role in intercellular communications among MSCs and the adjacent osteochondral defects, which are at the cornerstone of regenerative medicine for MSC-based cytotherapy [81, 82]. The secreted substances such as cytokines and anti-inflammatory factors are responsible for the majority of the ascribed bioremediation via promoting the survival and proliferation of adjacent damaged cells and tissues. For example, mediators (e.g., VEGF, bFGF, IL-6, IL-8) in the conditioned media have been considered to play an important role in influencing the differentiation capacity of MSCs or cocultured cells through an autocrine loop [22, 23, 83]. Interestingly, Lee and colleagues have demonstrated that MSC-secreted PGE-2 plays a key role in the maintenance of self-renewal via EP2 receptor [84].

Of the indicated mode of action, the paracrine phenomenon has been widely recognized as the main benefit of MSC therapy based on the secreted factors acting on MSCs and the neighboring cells. Up to now, a variety of key factors have been isolated and verified including SDF-1, TGF, VEGF, prostaglandin E2 (PGE2), hepatocyte growth factor (HGF), and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the diversity in the constitutive secretome has also been put forward by pioneering investigators in the field [23, 84, 85, 86]. As to OA, MSC-derived exosomes or sEVs are supposed to effectively avoid the inherent risks of MSCs and thus hold rosy prospects in clinical applications [87, 88]. However, the inherent disadvantages such as low efficacy in preparations, rapid degradation and clearance still need sustained efforts for further improvement [33, 80].

4.4 Direct- or trans-differentiation

For the past decades, the differentiation potential including direct-differentiation and tans-differentiation has been recognized as the key avenue for MSC-based repair [81]. Of note, the differentiation of MSCs into osteoblasts and chondrocytes has been extensively reported as achievable according to the ISCT guidelines [17]. However, current updates in the field indicate that it is likely that paracrine rather than the direct-differentiation or trans-differentiation play a core role in cartilage repair of OA after MSC delivery because intrathecal injection has presented limited MSC retention and engraftment. For example, aw we previously reviewed, initial attempts upon the molecular mechanisms for disease treatment with MSC transplantation focused on seeking direct evidence for generating functional cells during the rehabilitation of damaged tissues, whereas it was found to be difficult by most investigators when considering the insufficiency of effective retention rate (<5%) [89]. Instead, based on the unique homing property, MSCs mainly migrate to the damaged tissues and perform the restorative function through an orchestration of modulation, which is further verified with the aid of fluorescence in situ hybridization [90].

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5. Clinical trials of MSC-based cytotherapy for OA management

In recent years, MSC-based cytotherapy has also aroused the intense interest of clinicians in OA treatment. According to the Clinicaltrials.gov database, a total number of 128 clinical trials have been registered worldwide to explore the safety and effectiveness of MSC-based remedies for OA treatment, and in particular, for knee OA and hip OA (Figure 1). Of the aforementioned clinical trials, 22 were respectively registered in China and the United States (USA) and followed by 10 in Korea and 9 in Iran (Table 1). Meanwhile, we noticed that most of the registered clinical trials were in Phase 1 and/or Phase 2 stage(s), and a total number 13 trials were in the Phase 3 stage instead (Table 1). For instance, by conducting a two-year follow-up visit (NCT number: NCT01183728), Orozco and colleagues reported a significant improvement in cartilage quality in 11 of the 12 enrolled knee OA patients with autologous MSC intervention according to the Visual Analogue Scale (VAS) measurements and the pain relief–versus–initial pain score plot [91, 92]. Furthermore, the pain improvement was maintained without significant modifications during the 2-year follow-up, and no serious adverse effects were observed in the aforementioned patients as they previously reported [93].

Figure 1.

Clinical trials upon MSC-based cytotherapy for OA administration.

RankNCT No.AgePhasesEnrollmentLocation
1NCT0516083118–70Not Applicable50
2NCT0395671915–65Not Applicable8China
3NCT0150446418–65Phase 240Iran
4NCT03383081≤70Phase 260China
5NCT0435193218–70Phase 354Ecuador
6NCT0145964018–70Phase 250Malaysia
7NCT0316408325–65Phase 20Iran
8NCT0413010040–70Early Phase 160China
9NCT0380081030–80Early Phase 19Indonesia
10NCT0180976940–70Phase 1, Phase 218China
11NCT0120766118–65Phase 16Iran
12NCT0149905618–65Phase 16Iran
13NCT0254480250–70Phase 14China
14NCT0335757518–75Not Applicable14
15NCT0223784618–80Phase 1, Phase 20Panama
16NCT0316686530–70Phase 1, Phase 260China
17NCT0420864640–75Phase 2108China
18NCT0296372742–75Phase 110Jordan
19NCT0386922930–75Phase 1, Phase 2100Poland
20NCT0296695142–75Phase 110Jordan
21NCT0158631218–75Phase 1, Phase 230Spain
22NCT0198563340–75Phase 1, Phase 224India
23NCT0264186018–70Phase 122China
24NCT0118372818–76Phase 1, Phase 212Spain
25NCT0396968040–70Not Applicable60China
26NCT0421272840–70Not Applicable60China
27NCT0432698518–65Early Phase 120China
28NCT0145373840–70Phase 260India
29NCT0212336850–80Phase 1, Phase 230Spain
30NCT0360287235–65Phase 10Mexico
31NCT0236514240–80Phase 1, Phase 238Spain
32NCT0335865418–75Not Applicable9
33NCT0144843420–70Phase 272Malaysia
34NCT0189541325–65Phase 1, Phase 210Brazil
35NCT0143605818–65Phase 16Iran
36NCT0216269318–70Phase 253China
37NCT0386633030–75Phase 1, Phase 2100Poland
38NCT0347794218–60Phase 116USA
39NCT0200313118–80Phase 1, Phase 20Panama
40NCT04368806≥18Phase 2, Phase 3140USA
41NCT04448106≥18Phase 2300USA
42NCT0295826740–70Phase 232USA
43NCT0528872518–80Phase 1, Phase 2120USA
44NCT0486318330–75Phase 1, Phase 230
45NCT05147675Phase 120Antigua and Barbuda
46NCT0489317440–90Phase 16China
47NCT0085018745–60Phase 16Iran
48NCT0452094530–70Phase 2100Malaysia
49NCT0431466155–70Phase 1, Phase 215Indonesia
50NCT0130059818–75Phase 1, Phase 218Korea
51NCT0277694318–70Phase 1, Phase 220
52NCT0501601118–65Phase 250Malaysia
53NCT0335777018–75Not Applicable9
54NCT03589287≥40Phase 1, Phase 218China
55NCT0534956541–70Not Applicable26Pakistan
56NCT0187362510–65Phase 2, Phase 360Iran
57NCT0508693918–75Phase 3120Spain
58NCT0424087320–80Phase 1, Phase 224Korea
59NCT0229192618–75Phase 120China
60NCT0381873740–70Phase 3480USA
61NCT0502758140–80Phase 270China
62NCT0211851940–68Phase 213Jordan
63NCT0395549718–70Phase 1, Phase 230China
64NCT01879046≥18Not Applicable35France
65NCT0399080520–100Phase 3260Korea
66NCT0300071220–80Not Applicable26Korea
67NCT03509025≥18Phase 211Korea
68NCT0301403718–70Not Applicable35USA
69NCT0333724350–85Not Applicable60USA
70NCT0285507318–70Phase 228China
71NCT04037345≥19Phase 112Korea
72NCT0534415740–75Phase 1, Phase 254Australia
73NCT05182034≥19Phase 290
74NCT0267439922–60Phase 228USA
75NCT0089150115–55Phase 2, Phase 325Egypt
76NCT0302842840–75Phase 21
77NCT0394357640–80Phase 1, Phase 230China
78NCT04339504≥19Phase 112Korea
79NCT03648463Not Applicable20
80NCT0115989930–75Early Phase 150France
81NCT04427930≥20Phase 3260Korea
82NCT04825730≥20Not Applicable14
83NCT02468492≥40Early Phase 118USA
84NCT0528000240–80Phase 230Bangladesh
85NCT0055763518–65Phase 250
86NCT0193100718–99Phase 125USA
87NCT01041001≥18Phase 3104Korea
88NCT0330800645–65Phase 218Saudi Arabia
89NCT02658344≥18Phase 224Korea
90NCT03379168≥18Not Applicable100USA
91NCT0269687616–55Not Applicable20United Kingdom
92NCT04230902≥45Phase 348Lebanon
93NCT0500059330–75Not Applicable60China
94NCT04604288USA
95NCT0258069518–70Phase 1, Phase 230Chile
96NCT0379018935–75Not Applicable25Italy
97NCT0306787017–75Phase 1100
98NCT01626677≥18Phase 3103Korea
99NCT04821102≥20Not Applicable21
100NCT0471680345–75Not Applicable10USA
101NCT0192632718–65Phase 3150Iran
102NCT0423441230–65Not Applicable10
103NCT03788265≥18Not Applicable60China
104NCT0235101140–65Phase 1, Phase 212Canada
105NCT02582489≥18Not Applicable100USA
106NCT0122769418–65Phase 1, Phase 215Spain
107NCT0499012818–65Phase 3100USA
108NCT0527689540–80Phase 1, Phase 260
109NCT03048773≥20Not Applicable40China
110NCT0296414350–80Not Applicable306
111NCT04749758≥18Not Applicable77Andorra
112NCT0431085240–7025Italy
113NCT0519387755–85Not Applicable60Iraq
114NCT0341035516–60Not Applicable6Canada
115NCT0445311118–75Phase 1, Phase 245Ukraine
116NCT0430821335–75Not Applicable30Italy
117NCT0530583318–65Phase 1, Phase 220Turkey
118NCT0404381918–80Phase 1125USA
119NCT0508192140–70Phase 1, Phase 2200Poland
120NCT0173950418–80Not Applicable10USA
121NCT0141306118–80Not Applicable140USA
122NCT0422214025–60Not Applicable40USA
123NCT04223622≥1824Italy
124NCT0158585750–75Phase 118Germany
125NCT0360857918–65Phase 124USA
126NCT0283806945–75Phase 2153France
127NCT0103859650–9030Germany
128NCT01733186≥18Phase 1, Phase 212USA

Table 1.

MSC-based clinical trials for OA management.

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6. Conclusions

MSCs and concomitant derivatives have emerged as advantaged and alternative sources for OA administration and cartilage repair. MSC- or MSC-exo/sEVs- laden biomaterial systems have supplied overwhelming new tissue-engineering platforms to sequentially improve the osteochondral interface and alleviate the full-thickness articular cartilage defects, which collectively accelerates the reestablishment of osteochondral and cartilage tissues (Table 2). Of note, injecting MSCs into joints with an inflammatory environment may elevate the risk of ectopic calcification and osteoproliferation in patients with OA. Therefore, systematic and detailed investigations are urgently needed to ensure the maintenance of the intra-articular environment for cartilage repair before large-scale application in clinical practice. In spite of the tremendous progresses in the field of OA management and MSC-based regenerative medicine, it still remains challenging and there’s a long way to go to efficiently and cost-effectively repair the full-thickness articular cartilage defects and osteochondral interface via achieving efficient osteogenesis and chondrogenesis.

Cell typeStageOutcomeRef.
UC-MSCsClinical trialsSafe and superior to active comparator in knee OAMatas, et al. [94]
AD-MSC/BM-MSC/UC-MSC/AD-MSCsClinical trialsSubjective improvements in knee function and pain reductionBuzaboon, et al. [95]
BM-MSCs/S-MSCs/AD-MSCsClinical trialsPain relief and functional improvementCui, et al. [96]
HA hydrogel/
hPSC-MSCs		Preclinical studyPreferable restorative and ameliorative function on OA rabbitsZhang, et al. [24]
HA hydrogel/UC-MSCsPreclinical studySignificant gross and histological improvements in hyaline cartilage regenerationWu, et al. [97]
Hydrogel/MSCsPreclinical studyThe defects significantly better histologic scores with morphologic characteristics of hyaline cartilageZscharnack, et al. [98]
DAHP hydrogel/MSC-sEVsPreclinical studyEnhanced efficacy for OA improvementYang, et al. [55]

Table 2.

Advances in MSC-based cytotherapy for OA.

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Acknowledgments

The authors would like to thank the members of the Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province & NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, and the Institute of Biology & Hefei Institute of Physical Science, Chinese Academy of Sciences for their kind suggestions. This study was supported by grants from the National Natural Science Foundation of China (82260031), the project Youth Fund funded by Shandong Provincial Natural Science Foundation (ZR2020QC097), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT320005), Science and technology projects of Guizhou Province (QKH-J-ZK[2021]-107), The 2021 Central-Guided Local Science and Technology Development Fund (ZYYDDFFZZJ-1), Gansu Key Laboratory of molecular diagnosis and precision treatment of surgical tumors (18JR2RA033), Natural Science Foundation of Jiangxi Province (20212BAB216073), Key project funded by Department of Science and Technology of Shangrao City (2020AB002, 2020 K003, 2021F013, 2022AB003), Jiangxi Provincial Key New Product Incubation Program Funded by Technical Innovation Guidance Program of Shangrao (2020G002), Natural Science Foundation of Gansu Province (21JR11RA186, 20JR10RA415), Key talent project of Gansu Province of the Organization Department of Gansu provincial Party committee (2020RCXM076).

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Conflict of interest

The authors declare no conflict of interest.

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Abbreviation

Nomenclature

MSCs

mesenchymal stem/stromal cells

OA

osteoarthritis

POF

premature ovarian failure

AMI

acute myocardial infarction

ACLF

acute-on-chronic liver failure

P-MSCs

placental-derived MSCs

DPSCs

dental pulp-derived stem cells

UC-MSCs

umbilical cord-derived MSCs

AD-MSCs

adipose-derived MSCs

sEVs

small extracellular vesicles

PSC-MSCs

pluripotent stem cell-derived MSCs

ESCs

embryonic stem cells

iPSCs

induced pluripotent stem cells

ECM

extracellular matrix

TEC

tissue-engineered construct

PCL

poly ε-caprolactone

HA

hyaluronic acid

nHA

nano-hydroxyapatite

HAP

hydroxyapatite

BM-MSCs

bone marrow-derived MSCs

HPCH

hydroxypropyl chitin hydrogel

MV

microvesicles

MISEV

Minimal Information for Studies of Extracellular Vesicles

COVID-19

corona virus disease 2019

CLI

critical limb ischemia

ALI/ARDS

acute lung injury and acute respiratory distress syndrome

ACI

autologous chondrocyte implantation

ISCT

International Society for Cellular Therapy

CS-HA

chitosan-hyaluronic acid

BM-MSCs

bone marrow-derived MSCs

IP-CHA

interconnected porous hydroxyapatite ceramic

SDF-1

stromal cell-derived factor 1

TGF

transforming growth factor

HSCs

hematopoietic stem cells

VEGF

vascular endothelial growth factor

GM-CSF

granulocyte-macrophage colony-stimulating factor

Mφ

macrophages

PGE2

prostaglandin E2

HGF

hepatocyte growth factor

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Notes/thanks/other declarations

Not applicable.

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Written By

Leisheng Zhang, Zhihai Han, Zhongchao Han and Hui Cai

Submitted: May 14th, 2022 Reviewed: September 23rd, 2022 Published: October 23rd, 2022

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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