Osteoarthritis (OA) has traditionally been known as a “wear and tear” disease, which is mainly characterized by the degradation of articular cartilage and changes in the subchondral bone. Despite the fact that OA is often thought of as a degenerative disease, the catabolic products of the cartilage matrix often promote inflammation by activating immune cells. Current OA treatment focuses on symptomatic treatment, with a primary focus on pain management, which does not promote cartilage regeneration or attenuate joint inflammation. Since articular cartilage have no ability to regenerate, thus regeneration of the tissue is one of the key targets of modern treatments for OA. Cell-based therapies are among the new therapeutic strategies for OA. Mesenchymal stem cells (MSCs) have been extensively researched as potential therapeutic agents in cell-based therapy of OA due to their ability to differentiate into chondrocytes and their immunomodulatory properties that can facilitate cartilage repair and regeneration. In this review, we emphasized current knowledge and future perspectives on the use of MSCs by targeting their regeneration potential and immunomodulatory effects in the treatment of OA.

• cartilage regeneration
• extracellular vesicles
• inflammation
• mesenchymal stem cell
• osteoarthritis

• cartilage repair
• micronized cartilage matrix
• osteochondral defect

• Adipose tissue-derived stem cell
• Articular cartilage defect
• Low-intensity focused ultrasound
• Regeneration

• Adipose Tissue/radiation effects
• Aggrecans
• Animals
• Cartilage, Articular/cytology
• Cartilage, Articular/physiology
• Cartilage, Articular/radiation effects
• Chondrogenesis
• Collagen Type II
• Rats
• Regeneration/radiation effects
• Stem Cell Transplantation/methods
• Stem Cells
• Tissue Engineering/methods
• Wound Healing

• NRF-2017R1C1B5017159 the National Research Foundation of Korea
• HI18C0661 Ministry of Health & Welfare

The treatment of articular cartilage damage is a major clinical problem. More often, this clinical issue affects children, which forces doctors to find the best treatment method.

The aim of this experimental study on 2-month-old Landrace pigs was to compare the results of two cartilage defect treatments: (1) filling the cartilage defect with a scaffold incubated with bone marrow aspirate supplemented with growth plate chondrocytes (the CELLS group) and (2) filling the cartilage defect with an empty scaffold implanted after drilling the subchondral bone (the CTRL group). The treatment outcomes were assessed macroscopically and microscopically.

Based on the macroscopic evaluation, all animals showed a nearly normal morphology, with an average of 9.66/12 points (CTRL) and 10.44/12 points (CELLS). Based on the microscopic evaluation, 1 very good result and 8 good results were obtained in the CTRL group, with an average of 70.44%, while 5 very good results and 4 good results were obtained in the CELLS group, with an average of 79.61%.

(1) Growth plate chondrocytes have high chondrogenic potential and thus offer new possibilities for cartilage cell therapy. (2) The implantation of a scaffold loaded with bone marrow-derived MSCs (mesenchymal stem cells) and growth plate chondrocytes into a cartilage defect is a good therapeutic method in immature patients. (3) Cartilage repair based on a scaffold with bone marrow aspirate-derived cells supplemented with autologous growth plate chondrocytes achieves better results than repair with marrow stimulation and a hyaluronic acid-based scaffold (overall microscopic rating). (4) Chondrocyte clustering is a manifestation of the cartilage repair process but requires further observation.

The online version of this article (10.1186/s13018-019-1302-y) contains supplementary material, which is available to authorized users.

• Articular cartilage
• Chondrocyte
• Histological scoring system
• Trauma

Systematic studies indicate a growing number of clinical studies that use mesenchymal stem cells (MSCs) for the treatment of cartilage lesions. The current experimental and preclinical study aims to comparatively evaluate the potential of MSCs from a variety of tissues for the treatment of cartilage defect in rabbit’s knee which has not previously been reported.

In this experimental study, MSCs isolated from bone marrow (BMMSCs), adipose (AMSCs), and ears (EMSCs) of rabbits and expanded under in vitro culture. The growth rate and differentiation ability of MSCs into chondrocyte and the formation of cartilage pellet were investigated by drawing the growth curve and real-time polymerase chain reaction (RT-PCR), respectively. Then, the critical cartilage defect was created on the articular cartilage (AC) of the rabbit distal femur, and MSCs in collagen carrier were transplanted. The studied groups were as the control (only defect), sham (defect with scaffold), BMMSCs in the scaffold, EMSCs in the scaffold, and EMSCs in the scaffold with cartilage pellets. Histological and the gene expression analysis were performed following the transplantation.

Based on our comparative in vitro investigation, AMSCs possessed the highest growth rate, as well as the lowest chondrogenic differentiation potential. In this context, MSCs of the ear showed a significantly higher growth rate and cartilage differentiation potential than those of bone marrow tissue (P<0.05). According to our in vivo assessments, BMMSC- and EMSC-seeded scaffolds efficiently improved the cartilage defect 4 weeks post-transplantation, while no improvement was observed in the group contained the cartilage pellets.

It seems that the ear contains MSCs that promote cartilage regeneration as much as the conventional MSCs from the bone marrow. Considering a high proliferation rate and easy harvesting of MSCs of the ear, this finding could be of value for the regenerative medicine.

• Articular Cartilage
• Mesenchymal Stem Cells
• Rabbit
• Transplantation

• MSC concentration
• clinical application
• osteochondral repair
• rabbit model

• Ankle
• Arthritis
• Osteoarthritis
• Posttraumatic
• Treatment

• Animals
• Cell Count
• Cell Shape/drug effects
• Cell Survival/drug effects
• Chondrocytes/drug effects
• Chondrocytes/metabolism
• Chondrocytes/pathology
• Coculture Techniques
• Culture Media, Conditioned/pharmacology
• Gene Expression Regulation/drug effects
• Inflammation/genetics
• Inflammation/pathology
• Lipopolysaccharides
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/drug effects
• Mesenchymal Stem Cells/metabolism
• Sus scrofa

Horses are widely used as large animal preclinical models for cartilage repair studies, and hence, there is an interest in using equine synovial fluid-derived mesenchymal stem cells (SFMSCs) in research and clinical applications. Since, we have previously reported that similar to bone marrow-derived MSCs (BMMSCs), SFMSCs may also exhibit donor-to-donor variations in their stem cell properties; the current study was carried out as a proof-of-concept study, to compare the in vivo potential of equine BMMSCs and SFMSCs in articular cartilage repair. MSCs from these two sources were isolated from the same equine donor. In vitro analyses confirmed a significant increase in COMP expression in SFMSCs at day 14. The cells were then encapsulated in neutral agarose scaffold constructs and were implanted into two mm diameter full-thickness articular cartilage defect in trochlear grooves of the rat femur. MSCs were fluorescently labeled, and one week after treatment, the knee joints were evaluated for the presence of MSCs to the injured site and at 12 weeks were evaluated macroscopically, histologically, and then by immunofluorescence for healing of the defect. The macroscopic and histological evaluations showed better healing of the articular cartilage in the MSCs' treated knee than in the control. Interestingly, SFMSC-treated knees showed a significantly higher Col II expression, suggesting the presence of hyaline cartilage in the healed defect. Data suggests that equine SFMSCs may be a viable option for treating osteochondral defects; however, their stem cell properties require prior testing before application.

• Joint destruction
• Rheumatoid arthritis
• SSEA-3
• Synovial tissue

Degenerative skeletal disorders including osteoarthritis (OA) and osteoporosis (OP) are the result of attenuation of tissue regeneration and lead to painful conditions with limited treatment options. Preventative measures to limit the onset of OA and OP remain a significant unmet clinical need. MicroRNAs (miRNAs) are known to be involved in the differentiation of stem cells, and in combination with stem cell therapy could induce skeletal regeneration and potentially prevent OA and OP onset.

The combination of stem cells and miRNA has been successful at regenerating the bone and cartilage in vivo. MiRNAs, including miR-146b known to be involved in chondrogenic differentiation, could provide innovative targets for stem cell-based therapy, for the repair of articular cartilage defects forestalling the onset of OA or in the generation of a stem cell-based therapy for OP.

This review discusses the combination of skeletal stem cells (SSCs) and candidate miRNAs for application in a cell-based therapy approach for skeletal regenerative medicine.

• Bone
• Cartilage
• Osteoarthritis
• Osteoporosis
• Skeletal stem cell
• miRNA

A prospective analysis of the effect of autologous adipose derived mesenchymal stem cell (MSC) therapy in the treatment of an osteochondral defect of the knee with early progressive osteoarthritis following unsuccessful surgical intervention of osteochondritis dissecans (OCD).

After failed conventional management of OCD a patient undergoes intra-articular MSC therapy. Patient outcome measures included the Numeric Pain Rating Scale (NPRS), the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the Knee Injury and Osteoarthritis Outcome Score (KOOS). Structural outcome was assessed using MRI with the novel technique of T2 mapping used to indicate cartilage quality. Following MSC therapy the patient reported improvement in pain and function as measured by NPRS, WOMAC and KOOS. Repeat MRI analysis showed regeneration of cartilage. MRI T2 mapping indicated hyaline like cartilage regrowth.

In this report, the use of MSCs, after unsuccessful conventional OCD management, resulted in structural, functional and pain improvement. These results highlight the need to further study the regenerative potential of MSC therapy.

Australian and New Zealand Clinical Trial Registry Number - ACTRN12615000258550 (Date registered 19/03/2015 – retrospectively registered).

• Arthritis
• Case study
• Mesenchymal stem cells
• Osteoarthritis
• Osteochondral defect
• Osteochondritis dissecans

Cell-based tissue engineering has the potential to restore cartilage defects. Induced pluripotent stem cells (iPSCs) are regarded as an alternative cell source in regenerative medicine. The purpose of the present study was to evaluate the use of mesenchymal stem cells (MSCs) derived from human iPSCs (hiPSCs) for the regeneration of cartilage defects in a rabbit model. Cartilage defects were made in the patellar grooves of New Zealand white rabbits. The rabbits were then divided into three groups according to implantation: Control group, scaffold implantation group and scaffold/hiPSCs-MSCs (experimental) group. MSCs were generated from hiPSCs via a step of embryoid body formation. Following flow cytological analysis, the hiPSCs-MSCs were plated onto poly(lactic-co-glycolide) and then transplanted into the cartilage defects in the experimental group. Six rabbits from each group were sacrificed at each time point. The outcome was assessed macroscopically and histologically at 3 and 6 weeks post-surgery. At 3 and 6 weeks, the experimental group showed more cartilage defect filling compared with the control and scaffold implantation groups. At 3 weeks, the experimental group showed much more repair tissue in the cartilage defect, although no cartilage-like tissue was observed. At 6 weeks, cartilage-like tissue was observed in the experimental group but not in the control or scaffold implantation groups. No teratoma formation was observed in any of the groups. The results indicate that iPSCs have the potential to repair cartilage defects in vivo. Therefore, iPSCs could be a new cell source for cartilage defect repair.

• cartilage defect
• cell source
• induced pluripotent stem cells
• regeneration
• tissue engineering

• Autologous chondrocyte implantation
• Matrix-induced autologous chondrocyte implantation
• Mesenchymal stem cells

• Animals
• Cartilage, Articular/injuries
• Cartilage, Articular/physiology
• Chondrocytes/transplantation
• Humans
• Mesenchymal Stem Cell Transplantation/methods
• Regeneration
• Regenerative Medicine/methods
• Tissue Engineering/methods
• Tissue Scaffolds
• Translational Research, Biomedical/methods
• Wound Healing

• Bone
• aspirate
• cartilage
• concentrate
• marrow

• aspirate
• bone
• cartilage
• concentrate
• marrow

• Knee
• Mesenchymal Stem Cells
• Osteoarthritis

• Arthroplasty, Subchondral
• Cartilage, Articular/cytology
• Cartilage, Articular/pathology
• Cartilage, Articular/physiology
• Chondrocytes/transplantation
• Chronic Pain/etiology
• Chronic Pain/therapy
• Clinical Trials as Topic
• Health Care Costs
• Homeostasis
• Humans
• Mesenchymal Stem Cell Transplantation/adverse effects
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cell Transplantation/trends
• Mesenchymal Stem Cells
• Osteoarthritis/complications
• Osteoarthritis/economics
• Osteoarthritis/etiology
• Osteoarthritis/therapy
• Regeneration
• Tissue Engineering/instrumentation
• Tissue Engineering/methods
• Tissue Scaffolds
• Transplantation, Autologous
• Treatment Outcome

• CARTILAGE
• MESENCHYMAL STEM CELL
• SCAFFOLD
• TISSUE ENGINEERING

• Animal model
• Articular cartilage
• Histology
• Osteochondral unit
• Subchondral bone

• Human mesenchymal stem cells (h-MSCs)
• TREM-2 (triggering receptor expressed on myeloid cells 2)
• Toll-like receptors (TLRs)

• Adipocytes/cytology
• Adolescent
• Animals
• Cells, Cultured
• Child
• Chondrocytes/cytology
• Chondrogenesis/physiology
• Coculture Techniques
• Congenital Microtia/surgery
• Ear Auricle/cytology
• Humans
• Mice
• Mice, Nude
• Models, Animal
• Sampling Studies
• Tissue Engineering/methods
• Tissue Transplantation/methods

• biomaterials
• cartilage
• chondrocytes
• stem cells
• tissue engineering

• Chondrogenic
• Hydrogel
• Mesenchymal stem cell
• Osteochondral repair
• Osteogenic
• Pre-differentiation

Since articular cartilage possesses only a weak capacity for repair, its regeneration potential is considered one of the most important challenges for orthopedic surgeons. The treatment options, such as marrow stimulation techniques, fail to induce a repair tissue with the same functional and mechanical properties of native hyaline cartilage. Osteochondral transplantation is considered an effective treatment option but is associated with some disadvantages, including donor-site morbidity, tissue supply limitation, unsuitable mechanical properties and thickness of the obtained tissue. Although autologous chondrocyte implantation results in reasonable repair, it requires a two-step surgical procedure. Moreover, chondrocytes expanded in culture gradually undergo dedifferentiation, so lose morphological features and specialized functions. In the search for alternative cells, scientists have found mesenchymal stem cells (MSCs) to be an appropriate cellular material for articular cartilage repair. These cells were originally isolated from bone marrow samples and further investigations have revealed the presence of the cells in many other tissues. Furthermore, chondrogenic differentiation is an inherent property of MSCs noticed at the time of the cell discovery. MSCs are known to exhibit homing potential to the damaged site at which they differentiate into the tissue cells or secrete a wide spectrum of bioactive factors with regenerative properties. Moreover, these cells possess a considerable immunomodulatory potential that make them the general donor for therapeutic applications. All of these topics will be discussed in this review.

• Mesenchymal stem cells
• Regeneration
• Articular cartilage
• Cell therapy

• Canine
• Gene expression
• Immunophenotype
• Mesenchymal stem cells
• PCR array

The present work was designed to explore the feasibility and efficacy of articular cartilage repair using composites of human umbilical cord blood derived mesenchymal stem cells (hUCB-MSCs) and four different hydrogels in a rat model.

Full-thickness articular cartilage defects were created at the trochlear groove of femur in both knees of rats. Composites of hUCB-MSCs and four different hydrogels (group A, 4% hyaluronic acid; group B, 3% alginate:30% pluronic (1:1, v/v); group C, 4% hyaluronic acid: 3% alginate: 20% pluronic (2:1:1, v/v}; and group D, 4% hyaluronic acid:3% alginate:20% pluronic;chitosan (4:1:1:2, v/v).) were then transplanted into right knee defect in each study group (five rats/group). Left knees were transplanted with corresponding hydrogels without hUCB-MSCs as controls. At 16 weeks post-transplantation, degrees of cartilage repair were evaluated macroscopically and histologically using Masson’s Trichrome, safranin-O, Sirius red staining, and type-II collagen immunostaining.

Overall, group A with 4% hyaluronic acid hydrogel resulted in superior cartilage repair grossly and histologically and achieved a cellular arrangement and collagen organization pattern mimicking adjacent uninjured articular cartilage. Immunostaining and safranin-O staining also revealed that group A displayed the largest areas of type II collagen staining. Sirius red staining revealed that the organization pattern of collagen bundles was more similar to normal cartilage in group A. No evidence of rejection was found.

The results of this study suggest that hUCB-MSCs could be used to repair articular cartilage defects in vivo and that hyaluronic acid is an attractive hydrogel candidate for use in combination with hUCB-MSCs.

• Cartilage repair
• Chondrogenic differentiation
• Human iPS cells
• Human mesenchymal stem cells

Protocols based on the delivery of stem cells are currently applied in patients, showing encouraging results for the treatment of articular cartilage lesions (focal defects, osteoarthritis). Yet, restoration of a fully functional cartilage surface (native structural organization and mechanical functions) especially in the knee joint has not been reported to date, showing the need for improved designs of clinical trials. Various sources of progenitor cells are now available, originating from adult tissues but also from embryonic or reprogrammed tissues, most of which have already been evaluated for their chondrogenic potential in culture and for their reparative properties in vivo upon implantation in relevant animal models of cartilage lesions. Nevertheless, particular attention will be needed regarding their safe clinical use and their potential to form a cartilaginous repair tissue of proper quality and functionality in the patient. Possible improvements may reside in the use of biological supplements in accordance with regulations, while some challenges remain in establishing standardized, effective procedures in the clinics.

• cartilage repair
• clinical trials
• focal defects
• knee
• osteoarthritis
• stem cells

• Adipogenesis
• Chondrogenesis
• Colony-forming units assay
• Hypoxia
• Mesenchymal stem cells
• Osteogenesis

• Adipocytes/cytology
• Cell Death/physiology
• Cell Differentiation/physiology
• Cell Proliferation
• Cells, Cultured
• Chondrocytes/cytology
• Clone Cells/cytology
• Cytokines/metabolism
• Fibroblasts/cytology
• Humans
• Hypoxia/pathology
• Hypoxia/physiopathology
• Immunophenotyping
• Ischemic Preconditioning/methods
• Matrix Metalloproteinases/metabolism
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Osteocytes/cytology
• Oxygen/pharmacology

• T32 AI074490 NIAID NIH HHS
• Z01AR41131 NIAMS NIH HHS

• MSC characterization
• mesenchymal stromal cells
• unconventional model organisms

• Animals
• Base Sequence
• Bone Marrow
• Cartilage, Articular/cytology
• Cartilage, Articular/growth & development
• Cells, Cultured
• DNA Primers
• Feasibility Studies
• Mesenchymal Stem Cells/cytology
• Polyglycolic Acid
• Rabbits
• Real-Time Polymerase Chain Reaction
• Tissue Scaffolds

• Cell Transdifferentiation/genetics
• Cell Transdifferentiation/physiology
• Chondrocytes/metabolism
• Chondrogenesis/genetics
• Chondrogenesis/physiology
• Collagen Type II/metabolism
• Extracellular Matrix/metabolism
• Flow Cytometry
• Humans
• Mesenchymal Stem Cells/metabolism
• Osteoarthritis, Knee/metabolism
• Patella/metabolism
• Proteoglycans/metabolism
• Tissue Scaffolds

The relationship between biological tissue healing following knee injury or surgery and long-term clinical outcome has come to the forefront of sports medicine practice. This has led many knee surgeons to incorporate biologically mediated healing factors into the management of knee injuries. In particular, the clinical use of mesenchymal stem cells has opened new horizons.

Relevant studies were identified through a search of PubMed from January 2000 to April 2011, combining the term mesenchymal stem cells with articular cartilage, anterior cruciate ligament, and meniscus. Relevant citations from the reference lists of selected studies were also reviewed.

Knee injury treatment with mesenchymal stem cells shows potential. Most reports represent animal model studies; few advances have been translated to human clinical applications.

Mesenchymal stem cell use to promote healing following knee injury is likely to increase. There are scientific methodological concerns and ethical and legal issues regarding mesenchymal stem cell use for treating knee injuries.

• biological tissue healing
• cartilage repair
• cell-based therapy

Stem cell therapy hold the potential to meet the demand for transplant cells/tissues needed for treating damages resulting from both natural and man-made disasters. Pluripotency makes embryonic stem cells and induced pluripotent stem cells ideal for use, but their teratogenic character is a major hindrance. Therapeutic benefits of bone marrow transplantation are well known but characterizing the potentialities of haematopoietic and mesenchymal cells is essential. Haematopoietic stem cells (HSCs) have been used for treating both haematopoietic and non-haematopoietic disorders. Ease of isolation, in vitro expansion, and hypoimmunogenecity have brought mesenchymal stem cells (MSCs) into limelight. Though differentiation of MSCs into tissue-specific cells has been reported, differentiation-independent mechanisms seem to play a more significant role in tissue repair which need to be addressed further. The safety and feasibility of MSCs have been demonstrated in clinical trials, and their use in combination with HSC for radiation injury treatment seems to have extended benefit. Therefore, using stem cells for treatment of disaster injuries along with the conventional medical practice would likely accelerate the repair process and improve the quality of life of the victim.