Table 4.
In vivo studies of cartilage repair with UC-MSCs or their secretome.
| Pathology | Source | Host | Study design | Results | Ref. |
|---|---|---|---|---|---|
| IVD degeneration | Human UC-MSCs | Rabbit | 1 × 105 UC-MSCs injected into degenerated IVD | Increase in cellularity and a relative preservation of architecture | Leckie et al., 2013 [137] |
| Human UC-MSCs | Rabbit | 1 × 106 UC-MSCs or 1 × 106 UC-MSC-derived CPCs injected into degenerated IVD | Improvement in the histology, cellularity, ECM proteins, water, and GAGs contents and higher expression of NP specific markers SOX9, ACAN, COL2, FOXF1, and KRT19 with CPCs | Beeravolu et al., 2018 [138] | |
| Human UC-MSCs | Rabbit | 1 × 106 UC-MSC-derived NPCs injected into degenerated IVD | Improvement in the histology, cellularity, sulfated GAGs, and water contents of the NP. Expression of SOX9, ACAN, COL2, FOXF1, KRT19, PAX6, CA12, and COMP | Perez-Cruet et al., 2019 [139] | |
| Human UC-MSCs | Rat | 1 × 106 UC-MSCs or UC-MSC-derived CPCs injected into degenerated IVD | Expression of chondrogenic markers and downregulation of pain and inflammatory genes. Differentiation of transplanted UC-MSCs and CPCs in functional NPCs. Better survival, homing, and distribution in IVD with CPCs. | Ekram et al., 2021 [140] | |
| OA | Equine UC-MSCs | Rabbit | Early (day 3) or delayed (day 15) intra-articular injection of 3,5.106 UC-MSCs | Early IA injection of UC-MSCs exerted better anti-inflammatory and anticatabolic effects (reduction of MMPs -1, -3, -13, and TNF-a) | Saulnier et al., 2015 [141] |
| AM/UC particulate | Rat | Intra-articular injection of 50 or 100 μg/μL AM/UC particulate decellularized | Attenuation of cartilage destruction, significant increase in cartilage thickness and volume, significant decrease in total lesion area with high dose at 4 weeks postinjection | Raines et al., 2017 [142] | |
| Human UC-MSCs | Mouse | Intra-articular injection of 1 × 105 UC-MSCs | Regeneration and repair of cartilage, recovery from movement impairment, amelioration of cartilage apoptosis via caspase 3 pathway | Chang et al., 2018 [143] | |
| CanineUC-MSCs | Dog | Intra-articular injection of 1 × 106 UC-MSCs on days 1 and 3 | Repair of cartilage and patella, improvement of the healing of the surrounding tissue, reduction of joint effusion and inflammation (reduction of TNF-α, IL-6, and IL-7 blood levels) | Zhang et al., 2018 [144] | |
| Canine UC-MSCs | Dog | Intra-articular injection of 7 × 106 UC-MSCs | Improvement of clinical signs related to OA in treated dogs | Kim et al., 2019 [145] | |
| Human UC-MSCs | Rabbit | Intra-articular injection of 1 × 105, 5 × 105 or 1 × 106 UC-MSCs | Chondrogenesis induction, upregulation of the expression of growth factors, ECM markers, and anti-inflammatory cytokines, and reduced expression of proinflammatory cytokines. Medium dose exerted the best effects | Kim et al., 2019 [83] | |
| Human UC-MSCs | Rat | Intra-articular injection of 1 × 107 UC-MSCs overexpressing miR-140-5p | UC-MSCs overexpressing miR-140-5p significantly enhanced articular cartilage self-repairing in comparison to normal UC-MSCs | Geng et al., 2019 [146] | |
| Human UC-MSCs | Minipig | Intra-articular injection of a UC-MSCs (5 × 106 cells) and HA composite (4%) | Significant gross and histological improvements in hyaline cartilage regeneration | Wu et al., 2019 [147] | |
| Equine UC-MSCs | Horse | 1 or 2 intra-articular injections (at 1-month interval) of 10 × 106 UC-MSCs | improvement of lameness and total clinical score. No apparent clinical benefit of repeated intra-articular administration | Magri et al., 2019 [148] | |
| Human UC-MSCs | Mouse | Intra-articular injection of 5 × 105 UC-MSCs at 3 or 6 weeks | Significantly reduction of the loss of joint space and no evidence of an inflammatory response | Perry et al., 2020 [149] | |
| Human UC-MSCs | Rat | Single (day 1) or three (on days 1, 7 and 14) intra-articular injections of 2.5 x 105 UC-MSCs | Amelioration of cartilage erosion, alleviation of inflammatory cells infiltration and hyperplasia of the synovium by repeated injections. Increase number of SFCs on the articular cartilage surface | Tong et al., 2020 [81] | |
| Human UC-MSCs | Rat | Intra-articular injection of 1 × 106 UC-MSCs in 100 μL HA | Temporary effects that decelerate the progression of cartilage degeneration, but may not inhibit OA progression in the long-term. | Xing et al., 2020 [150] | |
| Human UC-MSCs | Mouse | Intra-articular injection of low-dose UC-MSCs or UC-MSC-loaded GMs (3 × 104 cells) or high-dose UC-MSCs (3 × 105 cells) | UC-MSC-GMs promoted cartilage regeneration and inhibited macrophage-mediated synovitis better than low-dose and similar to high-dose UC-MSCs | Zhang et al., 2021 [42] | |
| Human UC-MSCs | Rat | intra-articular injection of 2.5 × 105 UC-MSCs once a week for 3 weeks | UC-MSCs prevent cartilage degradation, restore the proliferation of chondrocytes, and inhibit the inflammatory response | Zhang et al., 2021 [82] | |
| Human UC-MSCs | Rabbit | Intra-articular injection of UC-MSCs with GO granular lubricant | UC-MSCs loaded with the GO granular lubricant reduce the inflammatory level and improve the level of biochemical environment in the joint | Wang et al., 2021 [151] | |
| RA | Human UC-MSCs | Mouse | Intraperitoneal injection of 1 × 106 UC-MSCs each day for 5 days | Reduction of the severity of RA, reduced levels of proinflammatory cytokines and chemokines (TNF-α, IL-6, and MCP-1) and increased levels of the anti-inflammatory cytokine (IL-10), Th1/Th2 type responses shifting and Tregs induction | Liu et al., 2010 [152] |
| Human UC-MSCs | Mouse | Intra-articular injection of 1 × 106 UC-MSCs and/or 100 μg/mL TNF-α inhibitor | Inhibition of TNF-α decreases cartilage destruction by suppressing the immunogenicity of UC-MSCs | Wu et al., 2012 [153] | |
| Human UC-MSCs | Rat | Tail vein injection of 1 × 106 UC-MSCs | Markedly increased percentage of Tregs and antithrombin levels, decrease of IL-1, IL-17, TNF-α, VEGF, and tissue factor levels | Gu et al., 2015 [154] | |
| Human UC-MSCs | Mouse | Tail vein injection of 1 × 106 UC-MSCs or BM-MSCs or SHED | UC-MSCs exert the best therapeutic effect in reducing bone resorption, joint destruction, and inflammatory factor expression | Zhang et al. 2019 [155] | |
| Human UC-MSCs | Rat | Intravenous injection of 2 × 106 UC-MSCs | Improvement arthritis, delay of radiological progression, and inhibition of synovial hyperplasia by downregulation of RORγt and upregulation of Foxp3 expression, inhibition of IL-17 and promotion of TGF-β expression, inhibition of proliferation and promotion of apoptosis in T lymphocytes and increased Tregs ratio | Ma et al., 2019 [156] | |
| Human UC-MSCs | Rat | Intraperitoneal injection of 2 × 106 UC-MSCs | Slow down the progression of disease activity and reversal of arthritic processes along with triggering of joint tissue repair mechanisms | Vohra et al., 2020 [157] | |
| Human UC-MSC-sEVs | Rat | ND | Ameliorate arthritis and inhibit synovial hyperplasia in a dose-dependent manner by inhibiting T lymphocyte proliferation and promoting their apoptosis, decreasing Th17 cell proportion and increasing that of Tregs, decreasing serum IL-17, and enhanced IL-10 and TGF-β expression, decreasing RORγt and increased FOXP3 expression | Xu et al., 2021 [158] | |
| Cartilage defects | Human WJ- ECM | Rabbit | 1 × 106 rabbit chondrocytes seeded in decellularized WJ-ECM scaffold inserted into the cartilage defects | All defects were filled completely with repaired tissue, and most of which were hyaline cartilage compared to WJ-ECM alone in which the defects filled partially with repaired tissue | Zhao et al., 2018 [159] |
| Human WJ-MSCs | Goat | 1 × 106 WJ-MSCs seeded in ACECM-oriented scaffold implanted into the articular cartilage defect | The WJ-MSCs-ACECM scaffold complex achieved better quality repair and regeneration of hyaline cartilage compared to microfracture (predominant clinical treatment strategy for damaged cartilage) | Zhang et al., 2018 [160] | |
| Human WJ-MSCs | Goat | 1 × 107 WJ-MSCs and pACs mixed in 3 ratios: 100:0, 0:100 and 50:50 and seeded into ACECM-oriented scaffolds implanted into the articular cartilage defect | 50:50 ratio was more similar to native cartilage and better integrated with the surrounding tissue, more abundant cartilage-specific content and significantly higher mechanical strength, no significant joint effusion or bone marrow edema signal. WJ-MSCs possessed low immunogenicity and escaped destruction by the immune system | Zhang et al., 2020 [161] | |
| Human UC-MSCs-Exosomes | Rabbit | Intra-articular injection of 1 × 1010 mL−1 of 2D or 3D culture in hollow-fiber bioreactor of UC-MSCs exosomes | Enhanced gross appearance and attenuated cartilage defect; 3D-cultured exosomes showed a superior therapeutic effect | Yan et al., 2020 [162] | |
| Human UC-MSCs | Rat | WJ/CS composite scaffold loaded with UC-MSCs implanted into the articular cartilage defect | The composite scaffold loaded with UC-MSCs repaired cartilage defects better than did the WJ scaffold loaded with UC-MSCs. Both the scaffold and UC-MSCs showed low immunogenicity | Li et al., 2021 [163] | |
| Osteochondral defects | Rabbit UC-MSCs | Rabbit | PLGA scaffold with a continuous gradient transition between TGF-β1 and BMP-2 seeded with 3 × 105 UC-MSCs implanted into articular osteochondral defect | Beneficial effect for bone and cartilage regeneration | Domer et al., 2012 [164] |
| Human WJ-MSCs | Rabbit | 3 × 107 undifferentiated or chondrogenically induced WJ-MSCs seeded in ECM of swine cartilage-derived scaffolds | Tissues repair observed over 16 months, with a hyaline-like neocartilage layer and regenerated subchondral bone. No immune rejection. WJ-MSCs were superior to those differentiated |
Liu et al., 2017 [165] | |
| Human WJ-MSCs exosomes | Rat and Rabbit | Rat: 25 μg/mL of WJ-MSC exosomes injected in joint cavity (5 times, every 7 days) Rabbit: ACECM scaffold implanted into osteochondral defect with 25 μg/mL of WJ-MSCs exosomes injected in joint cavity, 5 times every 7 days |
WJ-MSC exosomes enhance the effect of the ACECM scaffold and promote osteochondral regeneration, regulate the microenvironment of the articular cavity promoting the polarization of macrophages toward the M2 phenotype and inhibiting the inflammatory response. WJ-MSC exosomes contain many miRNAs that can promote the regeneration of hyaline cartilage | Jiang et al., 2021 [166] |
ACECM: acellular cartilage extracellular matrix; AM/UC: amniotic membrane/ umbilical cord; CPCs: chondroprogenitor cells; GMs: gelatin microcryogels; GO: graphene oxide; HA: hyaluronic acid; IVD: intervertebral disc; NP: nucleus pulposus; NPCs: NP-like cells; OA: osteoarthritis; pAC: primary cartilage cells; PLGA: poly(D,L-lactic-co-glycolic acid); RA: rheumatoid arthritis; sEVs: small extracellular vesicles; SFC: cartilage superficial; SHED: stem cells derived from human exfoliated deciduous teeth layer cells; WJ/CS: Wharton's jelly and chondroitin sulfate.