Next Article in Journal
Preventive Effects of Dairy Products on Dementia and the Underlying Mechanisms
Next Article in Special Issue
Isolation of Adipose-Derived Stem/Stromal Cells from Cryopreserved Fat Tissue and Transplantation into Rats with Spinal Cord Injury
Previous Article in Journal
Catalpol Inhibits Ischemia-Induced Premyelinating Oligodendrocyte Damage through Regulation of Intercellular Calcium Homeostasis via Na+/Ca2+ Exchanger 3
Previous Article in Special Issue
Methods of Isolation, Characterization and Expansion of Human Adipose-Derived Stem Cells (ASCs): An Overview
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 19
Issue 7
10.3390/ijms19071926
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

Adipose-Derived Mesenchymal Stem Cells: Are They a Good Therapeutic Strategy for Osteoarthritis?

by
Elena Damia
1,2,
Deborah Chicharro
1,2,
Sergio Lopez
3,
Belen Cuervo
1,2,
Monica Rubio
1,2,
Joaquin J. Sopena
1,2,
Jose Manuel Vilar
2,3,* and
Jose Maria Carrillo
1,2
1
Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
2
Garcia Cugat Foundation CEU UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
3
Department of Animal Pathology. Instituto Universitario de Investigaciones Biomédicas y Sanitarias. University of Las Palmas de Gran Canaria, 35416 Las Palmas de Gran Canaria, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(7), 1926; https://doi.org/10.3390/ijms19071926
Submission received: 28 May 2018 / Revised: 21 June 2018 / Accepted: 28 June 2018 / Published: 30 June 2018
(This article belongs to the Special Issue Adipose Stem Cells)
Versions Notes

Abstract

:
Osteoarthritis (OA) is a major cause of disability in elderly population around the world. More than one-third of people over 65 years old shows either clinical or radiological evidence of OA. There is no effective treatment for this degenerative disease, due to the limited capacity for spontaneous cartilage regeneration. Regarding the use of regenerative therapies, it has been reported that one option to restore degenerated cartilage are adipose-derived mesenchymal stem cells (ASCs). The purpose of this review is to describe and compare the efficacy of ASCs versus other therapies in OA. Methods: Recent studies have shown that ASCs exert paracrine effects protecting against degenerative changes in chondrocytes. According to the above, we have carried out a review of the literature using a combination of osteoarthritis, stem cells, and regenerative therapies as keywords. Results: Conventional pharmacological therapies for OA treatment are considered before the surgical option, however, they do not stop the progression of the disease. Moreover, total joint replacement is not recommended for patients under 55 years, and high tibia osteotomy (HTO) is a viable solution to address lower limb malalignment with concomitant OA, but some complications have been described. In recent years, the use of mesenchymal stem cells (MSCs) as a treatment strategy for OA is increasing considerably, thanks to their capacity to improve symptoms together with joint functionality and, therefore, the patients’ quality of life. Conclusions: ASC therapy has a positive effect on patients with OA, although there is limited evidence and little long-term follow-up.

1. Introduction

Osteoarthritis (OA) is a progressive degenerative disease of the joint characterized by gradual degradation of hyaline articular cartilage and sclerosis of bone. This cartilage is composed by type II collagen and proteoglycans. An alteration in the replacement of the proteoglycan and type II collagen network leads to the loss of function of the cartilage [1]. This disease, worldwide, is considered to be the fourth leading cause of disability [2] and the second cause of inability to work in men [3]. OA is the most common articular disease in adults, and knee OA is the most common location. Although, OA also affects other large-weight-bearing joints, such as hip, hands, feet, and spine [4]. Hip and knee OA are leading causes of disability worldwide [5]. The disease is characterized, at first, by a molecular derangement (alteration of joint tissue metabolism) followed by physiologic/anatomic damages (cartilage degradation, bone remodeling, osteophyte formation, joint inflammation), culminating in a loss of normal joint function [6].
In the United States, 27 millions of people suffer from clinical OA, and the treatment costs 185.5 billion dollars per year [7]. On the other hand, this pathology is the fourth leading cause of disability in Asia [2]. In addition, this chronic degenerative disease of articular cartilage has a current prevalence of 12% in the population over 60 years old, which will increase in the next 20 years [8,9]. It has also been reported that its incidence has doubled in women, and tripled in men, in recent years [10].
Several agents have been associated with a higher risk of suffering OA, such as genetic predisposition, obesity, previous trauma, and age. It has been demonstrated that the risk of developing post-traumatic OA increases by up to four times in people over the age of 50 [11]. As one ages, the chondrocytes, that contribute to 5% of the volume of the articular cartilage, decrease their regenerative response, leading to progressive loss of the articular surface resulting in cartilage degeneration with loss of matrix (which confers the biomechanical properties to the articular cartilage and constitutes the 95% of the tissue), which can result in a complete loss of joint surface. Moreover, chondrocytes produce mediators of inflammation (cytokines, chemokines, and proteolytic enzymes) that induce serious damage [12].
Pain is one of the first symptoms, leading to movement disability and impaired quality of life [9,13]. Synovial inflammation, cartilage breakdown, and bone remodeling are associated with OA chronic pain, and the mechanism responsible for pain involves structural changes and alterations in peripheral transduction and central processing of painful sensory inputs [14]. Consequently, ideal treatment should obtain analgesia, stopping progression of chondral degeneration; modify cartilage structure and revert damage; and finally, improve joint function [15].
While conventional therapies, such as physical therapy, glucosamine and chondroitin sulfate supplementation, arthroscopic surgery, or biological therapies, such as chondrocyte implantation, have little significant results, regenerative medicine (RM), has been demonstrated to be a great option in articular cartilage regeneration [16]. On the other hand, various surgical procedures have been performed to regenerate articular cartilage but have achieved limited success, including abrasion arthroplasty, subchondral drilling, and microfracture [17]. Mesenchymal stem cells (MSCs) are considered to be a promising candidate for cartilage regeneration, due to their ability to differentiate towards cartilage and bone cells and secrete trophic factors with regenerative functions [18]. The paracrine effect and anti-apoptotic, anti-inflammatory and anti-aging functions of these stem cells, is fundamental for the regeneration process. Recently, an anti-aging effect of the conditioned medium of adipose-derived mesenchymal stem cells (ASCs) on OA chondrocytes has been reported, featured by downregulation of senescence markers induced by inflammatory stress [19]. Stem cells promote biological processes, such as vascularization, cell proliferation, differentiation, and modulation of the inflammatory process [20], and can be isolated, among others, from bone marrow, adipose tissue, umbilical cord blood, and placenta [21,22]. It is currently admitted that there are MSCs within the connective tissue of virtually all organs [20]. In humans, ASCs showed a greater capacity for proliferation than the rest of the human MSCs [23], moreover, these cells maintain the differentiation potential after a longer time of culture [24], and the age of donors has less effect on the proliferation of them; this is important in elderly patients with osteoporosis [25].
ASCs were first identified in the early 2000s, and demonstrated to have self-renewal ability and multilineage differentiation potential [26]. These cells have a several benefits: faster and easier expansion in culture, more passage cells that retain stem cell phenotypes, pluripotency [27], less susceptibility to age, and less morbidity of patients [28], furthermore, compared with bone marrow-derived mesenchymal stem cells (BMMSCs), ASCs do have an equal potential to differentiate into cells and tissues of mesodermal origin, such as adipocytes, cartilage, bone, and skeletal muscle. On the other hand, the easy and repeatable access to subcutaneous adipose tissue and the simple isolation procedures provide a clear advantage [29].
To establish the efficacy of treatment with this regenerative therapy and assess, in the case of OA, the quality and thickness of the cartilage, long-term patient controls are needed [30]. Different studies have shown that the application of MSCs as therapy in the treatment of OA has improved the symptoms suffered by patients, particularly after more than 6 months of follow-up [10,30,31].
Recent studies have focused on BMMSCs for chondrogenesis, but the clinical use of these cells has presented disadvantages, such as, donor site morbidity, pain and low cell number upon harvest [32]. On the other hand, ASCs are a positive alternative treatment for OA treatment as in vitro studies have proven they contain CD73, CD90, CD105, and CD106 markers, which are necessary for cell differentiation into cartilage, and moreover, in vivo studies have also reported good results [33]. For all of the abovementioned reasons, the aim of the present study is to review the application of MSCs in OA, with particular emphasis on the use of ASCs versus other therapies.

2. Results

The prevalence and incidence of OA have increased globally, but pharmaceutical or surgical therapies have limited efficacy in halting OA progression. Among conservative therapies, nonpharmacological treatment (physiotherapy, weight management), systemic pharmacological treatment (analgesics, nonsteroidal anti-inflammatory drugs, glucosamine, and chondroitin sulfate) and injections of intra-articular (IA) therapies are described. Local delivery of corticoids and hyaluronic acid (HA) are approved treatments by United States Food and Drug Administration (US FDA)/European Medicines Agency (EMA), however, some adverse effects have been described, such as inflammation or pain and septic arthritis at the site of injection [34].
When OA advances, some surgical treatments can rebuild the degenerated cartilage, but they do not stop the articular inflammatory process established. These treatments are arthroscopic debridement, microfracture/osteoplasty, and chondrocyte implantation techniques, such as autologous chondrocyte implantation and matrix-induced autologous chondrocyte implantation [35]. The latter is the only cell therapy approved by the FDA [36].The application of such interventions remains limited, due to the necessity of additional surgery for harvesting the donor autograft cartilage, and the poor integration of the grafted defect with the surrounded cartilage [37].
Due to the limitations regarding OA conventional therapies, for example, the pharmacological therapy could produce serious gastrointestinal, renal, and cardiac adverse effects, and some of them can be a threat to life or they can leave a permanent disability. On the other hand, the surgical option, such as microfracture, has been used for the last 20 years, but hyaline cartilage has a limited capacity for regeneration. In recent years, the interest for new therapies, such as IA injection, autologous blood therapies, and MSCs is increasing considerably. Autologous conditioned serum (ACS) is a cell-free treatment obtained by incubating venous blood in a specialized syringe, where blood cells release anti-inflammatory cytokines and growth factors (GFs), such as transforming growth factor-β (TGF-β) [38]. It has been demonstrate that ACS therapy is more effective than HA injection [39] and the treatment with ACS and physiotherapy reduce chronic pain in knee OA [40]. Plasma rich in growth factors (PRGFs), is a type of platelet rich plasma (PRP) preparation. It is an autologous product with a moderate concentration of platelets, multitude of GFs, and absence of leukocytes. It provides an anabolic effect on the resident cells, and due to its potential to inhibit inflammation, relieves OA symptoms [41]. When PRGF is injected IA, it provides a three-dimensional network in the joint composed of fibrin that contains binding sites for cell adhesion, as well as proteins that form the microenvironment leading to different adhesion molecules and cells that help biological cartilage repair [42]. Recently, it has been reported that PRGF injection is an effective option to decrease pain and improve function in patients with symptomatic mild to moderate knee OA, in the 6 month follow-up [43]. In recent years, the release of ASCs with PRP has been reported to improve the proliferation and chondrogenesis of this type of stem cells [44,45], suggesting new applications in RM for the management of osteochondral defects.
Currently, RM, that aims to promote regenerative or reparative phenomena over the degenerative processes, is in full swing. Among these therapies are the already mentioned PRGF and the MSCs.

2.1. Mesenchymal Stem Cells

MSCs are defined as those cells that meet the criteria established by the International Society of Cellular Therapy. These criteria include an ability to adhere to plastic, the expression of a number of cell markers, including CD105, CD73, and CD90 while undergoing multilineage differentiation, and the ability to self-renew [46]. Those multipotent adult stem cells synthesize mediators (cytokines, neuroregulatory peptides, trophic factors) which participate in tissue repair and regulate inflammatory and immune responses [47]. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. It has been identified that individual stem cells, when expanded to colonies, retained their multilineage potential [48].
MSCs can be obtained from various adult tissues, for example, bone marrow, umbilical cord, skeletal muscle, synovial capsule, and adipose tissue. This last origin, has a number of advantages over the others, because adipose tissue is abundant and easy to obtain, and can be obtained in large amounts, using local anesthesia and causing minimal discomfort [49]. Subcutaneous fat tissue is the most accessible source, but in recent studies, other sources for obtaining autologous ASCs as the supra- and infrapatellar fat pads have been described [50]. Bone marrow aspirate has a paucity of MSCs, comprising 0.001–0.02% of the mononucleated cell population, in comparison to ~1–7% of the mononucleated cell population within adipose tissue [51,52]. Moreover, adipose tissue is considered a primary source, because it contains 500 times more MSCs than the same volume of bone marrow [53]. Furthermore, bone marrow harvested from the iliac crest is painful, and increases the risk of infection [54]. Recently, some reports demonstrate that IA injection of allogenic ASCs combined with HA could stop OA progression and promote cartilage regeneration [55]. Additionally, a successful management of a post-traumatic chondral defect using IA autologous ASC therapy has been suggested [35].
The FDA regulates the use of adult stem cells. This agency adopted 21 CFR 1271, which modified its jurisdiction over human cells and tissues to include any “transfer into a human recipient”. Previously, the code was specified transfer “into another human,” excluding autologous cells. Since then, cells that are more than “minimally manipulated,” even if they are intended for autologous use, and are subject to similar regulations as manufactured drugs [56]. More research studies on the use of MSCs in OA treatment would allow the FDA and physicians to provide patients with a more confidently alternative, minimally invasive treatment options that may significantly slow disease progression.

2.1.2. The Role of Mesenchymal Stem Cells in Osteoarthritis

The mechanism by which MSCs cause cartilage regeneration is not clear. It has been postulated that these cells may act on subchondral bone, forming the primary repair cartilage [57]. The injection of MSCs in joint cavity is a novel therapy that improves OA symptoms due to their ability to stimulate local repair and regeneration of damaged joint tissues, and to reduce inflammation and associated pain [16]. MSCs modulate the inflammatory response by causing the suppression of inflammatory T-cell proliferation and inhibition of monocyte and myeloid dendritic cell maturation [58]. Moreover, the anti-inflammatory capacity can be stimulated by various pro-inflammatory cytokines (IL-6, tumor necrosis factor and interferon gamma) [59]. Furthermore, these stem cells secrete reparative cytokines, including TGF-β, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF), which are responsible for a trophic effect that produces the local tissue repair [60]. Additional in vitro studies have demonstrated that GFs, such as TGF-β and insulin-like growth factor 1 (IGF-1), can stimulate MSCs towards chondrocytes. These chondrocytes, derived from MSCs, have the same expression of type II collagen that mature adult chondrocytes, moreover, this type II collagen provides tensile strength in the joint [61].
It has been demonstrated that after IA injection of MSCs (Table 1), these cells were found in the synovial membrane and they expressed molecules with anti-inflammatory and chondrogenic properties. MSCs could help to establish a regenerative microenvironment at the site of release, which would improve the recruitment, activation, and differentiation of endogenous stem cells with the potential to repair the articular cartilage [62].
With the aim of achieving a prolonged regenerative activity in the OA joint, several studies propose using MSCs activated with biomolecules to potentially improve chondral and osteochondral lesion repair. The need to use bioactive scaffolds was proven by the fact that in the knee joint of experimental mice, only 15% of ASCs injected were detectable at 1 month post-injection, and this number decreased to 1.5% in 6 months [63]. This type of MSC co-delivery with scaffolds could have better retention, aggregation, and viability of these cells; moreover, the proliferation, migration, and chondrogenic differentiation improve in scaffolds with large pore size [64].
Some in vitro studies have demonstrated the beneficial effects of scaffolds (CDM, poly l-glutamic acid/chitosan, TGF-β1-conjugated chitosan hydrogel), such as regeneration of hyaline cartilage, enhancing ASC chondrogenesis and reparation of full-thickness cartilage defects [65,66,67]. More scaffolds include fibrin, gelatin and collagen (protein-based scaffolds), and alginate or agarose, among others (carbohydrate-based scaffolds). Other scaffolds that maintain a three-dimensional structure include the hydrogel family and hydrophilic polymer [36].

2.1.3. Mesenchymal Stem Cells Exosomes in Osteoarthritis

Exosomes are a type of secreted membrane vesicles produced by different cells. Some types of exosomes have been shown to confer immunosuppressive effects in different disease models, among others, rheumatoid arthritis [77]. MSC exosomes are accepted as the principal therapeutic agents present in MSC secretion, and are adequate to mediate the many reported therapeutic options of MSCs [78]. Zhang et al., (2016) have reported that human MSC exosomes promote cartilage regeneration in an immunocompetent rat osteochondral defect model, so MSC exosomes help to regenerate the damaged articular cartilage in OA. The mechanism of action of MSC exosomes in that study were accelerated neotissue filling and enhanced matrix synthesis of type II collagen and sulphated glycosaminoglycan [79].
Another study demonstrates that weekly IA injections of human embryonic MSC exosomes induced a regeneration cartilage and subchondral bone over a period of 12 weeks in an adult immunocompetent rat model [79]. Definitely, the efficacy of MSC-based therapies has been assigned to the paracrine secretion of trophic factors, and exosomes have a fundamental role in mediating tissue repair, thus, exosomes represent a novel therapeutic option for OA.

3. Discussion

ASCs have a series of advantages over other types of cells, because adipose tissue is abundant and easy to obtain. On the other hand, these cells have a high in vitro proliferation capacity and fibroblastic morphology, and they can adhere well to the culture plate. Furthermore, they have a low risk of rejection [80]. ASCs can be isolated from the stromal vascular fraction (SVF) of adipose tissue. The cells are obtained by liposuction, followed by collagenase digestion, centrifugation, and dilution. SVF includes ASCs, as well as other cells, including pericytes, vascular adventitia cells, fibroblasts, preadipocytes, monocytes, macrophages, and red blood cells. The SVF product has 500,000 to 2,000,000 cells per gram, of which 1 to 10% are considered ASCs [81].
It has been calculated that there are approximately 1 × 105−6 ASCs in 1 ml of lipoaspirate, while there are 50–675 BMMSCs in 1 mL of bone marrow aspirate [82]. Another alternative for OA treatment with MSCs are human umbilical cord-derived MSCs (hUC-MSCs). These cells enhance the proliferation of OA chondrocytes and downregulate the expression of inflammatory cytokines, moreover, the co-culture of hUC-MSCs and OA chondrocytes may to be a therapeutic option for OA [22]. hUC-MSCs could be an alternative to BMMSCs for clinical applications, due to their easy preparation and low risk of viral contamination. They can differentiate into the three germ layers that promote tissue and organ repair and modulate immune responses [83]. In this review, we have reported the different types of treatment that are used conventionally in joint degenerative disease. Our discussion focuses on comparing ASCs with others stem cells most commonly used in the OA treatment in recent years.

3.1. Adipose-Derived Mesenchymal Stem Cells

In human medicine, it has been shown that MSCs are a clinical promise for articular cartilage regeneration. Several authors reported studies that demonstrate the effectiveness of MSCs in OA treatment. In relation to ASCs, the first case report was published in 2001 [21]. During the last decade, these cells have attracted great interest because they have been demonstrated to be safe and efficient for articular cartilage regeneration in several trials. In recent years, IA injection of ASCs in knee OA showed clinical, radiological, arthroscopic, and histological evidence at 6-month follow-up [74]. Among other studies, the IA injection of these stem cells (isolated from abdominal subcutaneous fat tissue) in severe knee OA, reported that clinical outcomes (pain, function knee, return to sport) of the low- and medium-dose groups tended to deteriorate after 1 year, while those of the high-dose group tended to plateau after 1 year, until 2 years [10]. Recently, Spasovski et al. (2018) have demonstrated that the use of ASCs from subcutaneous fat in knee OA improves clinical symptoms and reduces pain at 3 months, obtaining the best results at 6 months [30]. ASC therapy in OA has shown chondrogenesis potential, both for the infrapatellar- and suprapatellar-derived ASCs [50,84]. A greater chondrogenesis potential has been reported by infrapatellar ASCs compared to suprapatellar in vitro and in vivo [84,85]. In addition, the suprapatellar-derived ASCs transplantation in a severe knee OA mouse model diminished inflammation and cartilage degenerative grade, increasing the synthesis of glycosaminoglycan and inducing endogenous chondrogenesis [50]. These effects may be due to ASCs-mediated reduction of pro-inflammatory cytokines and chemokines, apoptosis of chondrocytes, hypertrophic and fibrotic chondrocyte phenotypes, and collagenases [86].
One of the limitations of the studies that describe the use of ASCs in OA is the short follow-up period, Joe at al. (2014) and Pers et al. (2016) reported the efficacy of IA injections of these cells for the treatment of knee OA, but their follow-up period was only 24 weeks [72,74]. However, Song et al. (2018) have reported the first study that has demonstrated the efficacy of ASCs therapy in knee OA with long-term follow-up of 96 weeks with repeated injections. These patients showed improvement in pain, function, and cartilage volume of the knee joint with repeated IA injections of these cells [87].

3.2. Bone Marrow Mesenchymal Stem Cells

Pittenger et al. (1999) isolated MSCs from bone marrow adult cells and since then they have been used to treat chondral defects [48]. Some studies in patients with OA treated with BMMSCs obtained good results, reducing the symptoms and, therefore, increasing patient satisfaction. In a study carried out in 24 patients with knee OA infiltrated with BMMSCs, histological and arthroscopic improvement was observed [88]. Another report by Kuroda et al. (2002) concluded that the transplantation of autologous BMMSCs promotes the repair of large defects of focal articular cartilage in young and active patients [89]. Recently, safety of IA injection of BMMSCs was confirmed in 12 OA patients. They showed pain relief and improvement of cartilage quality at 2 years post-treatment [90]. Regarding the regulation of the inflammatory process in OA, Zhang et al. (2016) reported that the co-cultivation of BMMSCs with chondrocytes from patients with OA increases cell proliferation of chondrocytes and inhibits inflammatory activity in OA [91]. In a study of knee OA treatment in 13 patients with in vitro expanded BMMSCs at 12 months, a significant improvement in the thickness of knee cartilage in the femoral and tibial plates was shown [73]. Good results have also been reported with the application of BMMSCs in large [92] and small joints [71] with microfracture.

3.3. Human Umbilical Cord-Derived Mesenchymal Stem Cells

Some studies have demonstrated that chondrocytes secrete the same cytokines and induce human stem cells to differentiate into chondrocytes [93,94]. It has been reported that the hUC-MSCs improve the viability of OA-degenerated chondrocytes. A study carried out in Shangai suggested that the secretion of hUC-MSCs enhanced chondrocyte proliferation and showed that these stem cells increased expression of chondrogenic genes (aggrecan, sox-9, collagen II), indicating chondrocytes promoted chondrogenic differentiation of hUC-MSCs, compared to the control group. They also postulated that hUC-MSCs inhibited inflammatory activity in OA chondrocytes [22]. In the same line, Zheng et al. (2013) reported the chondrogenic differentiation of hUC-MSCs by co-culture with rabbit chondrocytes [95]. In other studies, hUC-MSCs were reported to inhibit the expression of some inflammatory factors [96,97]. Definitely, hUC-MSCs could regulate inflammatory activity and the proliferation of chondrocytes in OA.
Therapeutic options of OA depend on each individual case and multiple factors, such as the disease progression, degeneration degree of articular cartilage, affected joint, and patient’s expectations. The gold standard in the treatment of OA is total joint replacement, but surgery is not suitable for patients under 55 years [98], however, HTO is intended to transfer the mechanical axis from medial to slightly lateral, to the midline of the knee, to decrease the load and subsequently delay OA [99] in 40–60 years old patients [100]. Some studies showed that the regenerative process began after realignment [99], but different complications have been described, such as aseptic nonunion and deep infection [101]. MSCs may be a safe and alternative treatment strategy for OA, due to that this therapy has different advantages: it is applied in all joints, the injections are repeatable, and it is minimally invasive [12].

4. Materials and Methods

The authors searched PubMed English languages articles using a combination of “osteoarthritis”, “stem cells”, “regenerative therapies”, and “adipose-derived mesenchymal stem cells” as keywords. After the first selection of the main articles based on OA and conventional treatments, studies of OA and stem cells were selected, and there were a total of about 900 articles in the last decade. Special attention has been drawn to original analyses and studies, around 300 studies, of which we chose about 80 articles dedicated to ASCs and were published in the last 10 years. Other searches were executed using bibliographies of articles found in the primary and secondary search. One limitation in this review, is the fact that our methods, while rigorous, did not follow any formal guidelines for a systematic review (e.g., the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines).

5. Conclusions

OA is a major health problem, especially in the elderly population. Cellular therapy is an emerging modality for the treatment of OA, even the combination of conventional treatments with the application of MSCs is a therapeutic option to improve the quality of life of patients with OA. In recent years, the interest in MSCs as a therapeutic option in OA is due to the facility of harvesting, preparation, and implantation without surgery, the capacity to stimulate local repair and regeneration of damaged joint tissues, and the ability to reduce inflammation and associated pain. ASCs have different advantages, including easy cryopreservation, faster expansion in culture, more passage cells that retain stem cell phenotypes and pluripotency, and less susceptibility to aging together with lower morbidity of patients. Moreover, the obtention of adipose tissue is much less expensive than bone marrow, with less invasive intervention and available in greater quantities.
ASCs in OA may offer an exciting possibility to improve function, pain, and cartilage volume of the joint, suggestive of a good therapeutic strategy for OA. Despite this, further long-term studies are needed to prove and evaluate the effectiveness of ASCs in OA treatment and their safety capacity. However, it is important to establish a standardized therapeutic protocol for this biological therapy, and assess each patient and each pathology individually.

Author Contributions

All authors contributed equally. All authors read and approved the final manuscript.

Funding

This work was funded by García Cugat foundation CEU-UCH chair and CEU Cardenal Herrera University, CEU Universities.

Acknowledgments

The authors are grateful to the Fundación Garcia Cugat, CEU Cardenal Herrera University and CEU Universities for their technical support.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

ACSAutologous conditioned serum
ASCsAdipose-derived mesenchymal stem cells
EGFEpidermal growth factor
EMAEuropean Medicines Agency
FDAFood and Drug Administration
GFsGrowth factors
HAHyaluronic acid
hUC-MSCsHuman umbilical cord mesenchymal stem cells
IAIntra-articular
IGF-IInsulin-like growth factor-I
MSCsMesenchymal stem cells
OAOsteoarthritis
PRGFsPlasma rich in growth factors
PRPPlatelet rich plasma
RMRegenerative medicine
TGF-βTransforming growth factor-beta
VEGFVascular endothelial growth factor
HTOHigh tibia osteotomy

References

  1. Maldonado, M.; Nam, J. The role of changes in extracellular matrix of cartilage in the presence of inflammation on the pathology of osteoarthritis. Biomed. Res. Int. 2013, 2013, 284873. [Google Scholar] [CrossRef] [PubMed]
  2. Fransen, M.; Bridgett, L.; March, L.; Hoy, D.; Penserga, E.; Brooks, P. The epidemiology of osteoarthritis in Asia. Int. J. Rheum. Dis. 2011, 14, 113–121. [Google Scholar] [CrossRef] [PubMed]
  3. Orozco, L.; Munar, A.; Soler, R.; Alberca, M.; Soler, F.; Huguet, M.; Sentis, J.; Sanchez, A.; Garcia-Sancho, J. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: A pilot study. Transplantation 2013, 95, 1535–1541. [Google Scholar] [CrossRef] [PubMed]
  4. Van der Kraan, P.M.; van den Berg, W.B. Chondrocyte hypertrophy and osteoarthritis: Role in initiation and progression of cartilage degeneration? Osteoarthr. Cartil. 2012, 20, 223–232. [Google Scholar] [CrossRef] [PubMed]
  5. Cross, M.; Smith, E.; Hoy, D.; Nolte, S.; Ackerman, I.; Fransen, M.; Bridgett, L.; Williams, S.; Guillemin, F.; Hill, C.L.; et al. The global burden of hip and knee osteoarthritis: Estimates from the global burden of disease 2010 study. Ann. Rheum. Dis. 2014, 73, 1323–1330. [Google Scholar] [CrossRef] [PubMed]
  6. Goldring, S.R.; Goldring, M.B. Changes in the osteochondral unit during osteoarthritis: Structure, function and cartilage-bone crosstalk. Nat. Rev. Rheumatol. 2016, 12, 632–644. [Google Scholar] [CrossRef] [PubMed]
  7. Kotlarz, H.; Gunnarsson, C.L.; Fang, H.; Rizzo, J.A. Insurer and out-of-pocket costs of osteoarthritis in the US: Evidence from national survey data. Arthrit. Rheumatol. 2009, 60, 3546–3553. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Neogi, T.; Zhang, Y. Epidemiology of osteoarthritis. Rheum. Dis. Clin. N. Am. 2013, 39, 1–19. [Google Scholar] [CrossRef] [PubMed]
  9. Glyn-Jones, S.; Palmer, A.J.; Agricola, R.; Price, A.J.; Vincent, T.L.; Weinans, H.; Carr, A.J. Osteoarthritis. Lancet 2015, 386, 376–387. [Google Scholar] [CrossRef]
  10. Jo, C.H.; Chai, J.W.; Jeong, E.C.; Oh, S.; Shin, J.S.; Shim, H.; Yoon, K.S. Intra-articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritis of the Knee: A 2-Year Follow-up Study. Am. J. Sports Med. 2017, 45, 2774–2783. [Google Scholar] [CrossRef] [PubMed]
  11. Martin, J.A.; Brown, T.; Heiner, A.; Buckwalter, J.A. Post-traumatic osteoarthritis: The role of accelerated chondrocyte senescence. Biorheology 2004, 41, 479–491. [Google Scholar] [PubMed]
  12. Rahmati, M.; Nalesso, G.; Mobasheri, A.; Mozafari, M. Aging and osteoarthritis: Central role of the extracellular matrix. Ageing Res. Rev. 2017, 40, 20–30. [Google Scholar] [CrossRef] [PubMed]
  13. Puljak, L.; Marin, A.; Vrdoljak, D.; Markotic, F.; Utrobicic, A.; Tugwell, P. Celecoxib for osteoarthritis. Cochrane Database Syst. Rev. 2017, 5, CD009865. [Google Scholar] [CrossRef] [PubMed]
  14. De Lange-Brokaar, B.J.; Ioan-Facsinay, A.; Yusuf, E.; Visser, A.W.; Kroon, H.M.; van Osch, G.J.; Zuurmond, A.M.; Stojanovic-Susulic, V.; Bloem, J.L.; Nelissen, R.G.; et al. Association of pain in knee osteoarthritis with distinct patterns of synovitis. Arthrit. Rheumatol. 2015, 67, 733–740. [Google Scholar] [CrossRef] [PubMed]
  15. Garay-Mendoza, D.; Villarreal-Martinez, L.; Garza-Bedolla, A.; Perez-Garza, D.M.; Acosta-Olivo, C.; Vilchez-Cavazos, F.; Diaz-Hutchinson, C.; Gomez-Almaguer, D.; Jaime-Perez, J.C.; Mancias-Guerra, C. The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis. Int. J. Rheum. Dis. 2018, 21, 140–147. [Google Scholar] [CrossRef] [PubMed]
  16. Wehling, P.; Evans, C.; Wehling, J.; Maixner, W. Effectiveness of intra-articular therapies in osteoarthritis: A literature review. Ther. Adv. Musculoskelet. Dis. 2017, 9, 183–196. [Google Scholar] [CrossRef] [PubMed]
  17. Sakata, K.; Furumatsu, T.; Abe, N.; Miyazawa, S.; Sakoma, Y.; Ozaki, T. Histological analysis of failed cartilage repair after marrow stimulation for the treatment of large cartilage defect in medial compartmental osteoarthritis of the knee. Acta Med. Okayama 2013, 67, 65–74. [Google Scholar] [PubMed]
  18. Vinatier, C.; Guicheux, J. Cartilage tissue engineering: From biomaterials and stem cells to osteoarthritis treatments. Ann. Phys. Rehabil. Med. 2016, 59, 139–144. [Google Scholar] [CrossRef] [PubMed]
  19. Platas, J.; Guillen, M.I.; Perez Del Caz, M.D.; Gomar, F.; Castejon, M.A.; Mirabet, V.; Alcaraz, M.J. Paracrine effects of human adipose-derived mesenchymal stem cells in inflammatory stress-induced senescence features of osteoarthritic chondrocytes. Aging 2016, 8, 1703–1717. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. 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]
  21. Zuk, P.A.; Zhu, M.; Mizuno, H.; Huang, J.; Futrell, J.W.; Katz, A.J.; Benhaim, P.; Lorenz, H.P.; Hedrick, M.H. Multilineage cells from human adipose tissue: Implications for cell-based therapies. Tissue Eng. 2001, 7, 211–228. [Google Scholar] [CrossRef] [PubMed]
  22. 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]
  23. Kern, S.; Eichler, H.; Stoeve, J.; Kluter, H.; Bieback, K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem. Cells 2006, 24, 1294–1301. [Google Scholar] [CrossRef] [PubMed]
  24. Dmitrieva, R.I.; Minullina, I.R.; Bilibina, A.A.; Tarasova, O.V.; Anisimov, S.V.; Zaritskey, A.Y. Bone marrow- and subcutaneous adipose tissue-derived mesenchymal stem cells: Differences and similarities. Cell Cycle 2012, 11, 377–383. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Chen, H.T.; Lee, M.J.; Chen, C.H.; Chuang, S.C.; Chang, L.F.; Ho, M.L.; Hung, S.H.; Fu, Y.C.; Wang, Y.H.; Wang, H.I.; et al. Proliferation and differentiation potential of human adipose-derived mesenchymal stem cells isolated from elderly patients with osteoporotic fractures. J. Cell. Mol. Med. 2012, 16, 582–593. [Google Scholar] [CrossRef] [PubMed]
  26. Murphy, J.M.; Fink, D.J.; Hunziker, E.B.; Barry, F.P. Stem cell therapy in a caprine model of osteoarthritis. Arthrit. Rheum. 2003, 48, 3464–3474. [Google Scholar] [CrossRef] [PubMed]
  27. Zhu, Y.; Liu, T.; Song, K.; Fan, X.; Ma, X.; Cui, Z. Adipose-derived stem cell: A better stem cell than BMSC. Cell Biochem. Funct. 2008, 26, 664–675. [Google Scholar] [CrossRef] [PubMed]
  28. Mirsaidi, A.; Kleinhans, K.N.; Rimann, M.; Tiaden, A.N.; Stauber, M.; Rudolph, K.L.; Richards, P.J. Telomere length, telomerase activity and osteogenic differentiation are maintained in adipose-derived stromal cells from senile osteoporotic SAMP6 mice. J. Tissue Eng. Regen. Med. 2012, 6, 378–390. [Google Scholar] [CrossRef] [PubMed]
  29. Schaffler, A.; Buchler, C. Concise review: Adipose tissue-derived stromal cells--basic and clinical implications for novel cell-based therapies. Stem Cells 2007, 25, 818–827. [Google Scholar] [CrossRef] [PubMed]
  30. Spasovski, D.; Spasovski, V.; Bascarevic, Z.; Stojiljkovic, M.; Vreca, M.; Andelkovic, M.; Pavlovic, S. Intra-articular injection of autologous adipose-derived mesenchymal stem cells in the treatment of knee osteoarthritis. J. Gene Med. 2018, 20, e3002. [Google Scholar] [CrossRef] [PubMed]
  31. Cui, G.H.; Wang, Y.Y.; Li, C.J.; Shi, C.H.; Wang, W.S. Efficacy of mesenchymal stem cells in treating patients with osteoarthritis of the knee: A meta-analysis. Exp. Ther. Med. 2016, 12, 3390–3400. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Gupta, P.K.; Das, A.K.; Chullikana, A.; Majumdar, A.S. Mesenchymal stem cells for cartilage repair in osteoarthritis. Stem Cell. Res. Ther. 2012, 3, 25. [Google Scholar] [CrossRef] [PubMed]
  33. Hurley, E.T.; Yasui, Y.; Gianakos, A.L.; Seow, D.; Shimozono, Y.; Kerkhoffs, G.; Kennedy, J.G. Limited evidence for adipose-derived stem cell therapy on the treatment of osteoarthritis. Knee Surg. Sports Traumatol. Arthrosc. 2018. [Google Scholar] [CrossRef] [PubMed]
  34. Smith, E.; Hoy, D.G.; Cross, M.; Vos, T.; Naghavi, M.; Buchbinder, R.; Woolf, A.D.; March, L. The global burden of other musculoskeletal disorders: Estimates from the Global Burden of Disease 2010 study. Ann. Rheum. Dis. 2014, 73, 1462–1469. [Google Scholar] [CrossRef] [PubMed]
  35. Freitag, J.; Li, D.; Wickham, J.; Shah, K.; Tenen, A. Effect of autologous adipose-derived mesenchymal stem cell therapy in the treatment of a post-traumatic chondral defect of the knee. BMJ Case Rep. 2017, 2017, bcr-2017. [Google Scholar] [CrossRef] [PubMed]
  36. Mirza, Y.H.; Oussedik, S. Is there a role for stem cells in treating articular injury? Br. J. Hosp. Med. 2017, 78, 372–377. [Google Scholar] [CrossRef] [PubMed]
  37. Niemeyer, P.; Steinwachs, M.; Erggelet, C.; Kreuz, P.C.; Kraft, N.; Kostler, W.; Mehlhorn, A.; Sudkamp, N.P. Autologous chondrocyte implantation for the treatment of retropatellar cartilage defects: Clinical results referred to defect localisation. Arch. Orthop. Trauma Surg. 2008, 128, 1223–1231. [Google Scholar] [CrossRef] [PubMed]
  38. Meijer, H.; Reinecke, J.; Becker, C.; Tholen, G.; Wehling, P. The production of anti-inflammatory cytokines in whole blood by physico-chemical induction. Inflamm. Res. 2003, 52, 404–407. [Google Scholar] [CrossRef] [PubMed]
  39. Baltzer, A.W.; Moser, C.; Jansen, S.A.; Krauspe, R. Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthr. Cartil. 2009, 17, 152–160. [Google Scholar] [CrossRef] [PubMed]
  40. Baselga Garcia-Escudero, J.; Miguel Hernandez Trillos, P. Treatment of Osteoarthritis of the Knee with a Combination of Autologous Conditioned Serum and Physiotherapy: A Two-Year Observational Study. PLoS ONE 2015, 10, e0145551. [Google Scholar] [CrossRef] [PubMed]
  41. Anitua, E.; Sanchez, M.; Aguirre, J.J.; Prado, R.; Padilla, S.; Orive, G. Efficacy and safety of plasma rich in growth factors intra-articular infiltrations in the treatment of knee osteoarthritis. Arthroscopy 2014, 30, 1006–1017. [Google Scholar] [CrossRef] [PubMed]
  42. Anitua, E.; Sanchez, M.; Orive, G. Potential of endogenous regenerative technology for in situ regenerative medicine. Adv. Drug Deliv. Rev. 2010, 62, 741–752. [Google Scholar] [CrossRef] [PubMed]
  43. Raeissadat, S.A.; Rayegani, S.M.; Ahangar, A.G.; Abadi, P.H.; Mojgani, P.; Ahangar, O.G. Efficacy of Intra-articular Injection of a Newly Developed Plasma Rich in Growth Factor (PRGF) Versus Hyaluronic Acid on Pain and Function of Patients with Knee Osteoarthritis: A Single-Blinded Randomized Clinical Trial. Clin. Med. Insights Arthritis Musculoskelet. Disord. 2017, 10, 1179544117733452. [Google Scholar] [CrossRef] [PubMed]
  44. Li, G.; Fu, N.; Xie, J.; Fu, Y.; Deng, S.; Cun, X.; Wei, X.; Peng, Q.; Cai, X.; Lin, Y. Poly(3-hydroxybutyrate-co-4-hydroxybutyrate) Based Electrospun 3D Scaffolds for Delivery of Autogeneic Chondrocytes and Adipose-Derived Stem Cells: Evaluation of Cartilage Defects in Rabbit. J. Biomed. Nanotechnol. 2015, 11, 105–116. [Google Scholar] [CrossRef] [PubMed]
  45. Scioli, M.G.; Bielli, A.; Gentile, P.; Cervelli, V.; Orlandi, A. Combined treatment with platelet-rich plasma and insulin favours chondrogenic and osteogenic differentiation of human adipose-derived stem cells in three-dimensional collagen scaffolds. J. Tissue Eng. Regen. Med. 2017, 11, 2398–2410. [Google Scholar] [CrossRef] [PubMed]
  46. Ikebe, C.; Suzuki, K. Mesenchymal stem cells for regenerative therapy: Optimization of cell preparation protocols. Biomed. Res. Int. 2014, 2014, 951512. [Google Scholar] [CrossRef] [PubMed]
  47. Bashir, J.; Sherman, A.; Lee, H.; Kaplan, L.; Hare, J.M. Mesenchymal stem cell therapies in the treatment of musculoskeletal diseases. PM R 2014, 6, 61–69. [Google Scholar] [CrossRef] [PubMed]
  48. 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]
  49. Noth, U.; Steinert, A.F.; Tuan, R.S. Technology insight: Adult mesenchymal stem cells for osteoarthritis therapy. Nat. Clin. Pract. Rheumatol. 2008, 4, 371–380. [Google Scholar] [CrossRef] [PubMed]
  50. Munoz-Criado, I.; Meseguer-Ripolles, J.; Mellado-Lopez, M.; Alastrue-Agudo, A.; Griffeth, R.J.; Forteza-Vila, J.; Cugat, R.; Garcia, M.; Moreno-Manzano, V. Human Suprapatellar Fat Pad-Derived Mesenchymal Stem Cells Induce Chondrogenesis and Cartilage Repair in a Model of Severe Osteoarthritis. Stem Cells Int. 2017, 2017, 4758930. [Google Scholar] [CrossRef] [PubMed]
  51. Peng, L.; Jia, Z.; Yin, X.; Zhang, X.; Liu, Y.; Chen, P.; Ma, K.; Zhou, C. Comparative analysis of mesenchymal stem cells from bone marrow, cartilage, and adipose tissue. Stem Cells Dev. 2008, 17, 761–773. [Google Scholar] [CrossRef] [PubMed]
  52. Alvarez-Viejo, M.; Menendez-Menendez, Y.; Blanco-Gelaz, M.A.; Ferrero-Gutierrez, A.; Fernandez-Rodriguez, M.A.; Gala, J.; Otero-Hernandez, J. Quantifying mesenchymal stem cells in the mononuclear cell fraction of bone marrow samples obtained for cell therapy. Transplant Proc. 2013, 45, 434–439. [Google Scholar] [CrossRef] [PubMed]
  53. Hass, R.; Kasper, C.; Bohm, S.; Jacobs, R. Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC. Cell Commun. Signal 2011, 9, 12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Macrin, D.; Joseph, J.P.; Pillai, A.A.; Devi, A. Eminent Sources of Adult Mesenchymal Stem Cells and Their Therapeutic Imminence. Stem Cell Rev. 2017, 13, 741–756. [Google Scholar] [CrossRef] [PubMed]
  55. Feng, C.; Luo, X.; He, N.; Xia, H.; Lv, X.; Zhang, X.; Li, D.; Wang, F.; He, J.; Zhang, L.; et al. Efficacy and Persistence of Allogeneic Adipose-Derived Mesenchymal Stem Cells Combined with Hyaluronic Acid in Osteoarthritis After Intra-articular Injection in a Sheep Model. Tissue Eng. Part A 2018, 24, 219–233. [Google Scholar] [CrossRef] [PubMed]
  56. Jevotovsky, D.S.; Alfonso, A.R.; Einhorn, T.A.; Chiu, E.S. Osteoarthritis and stem cell therapy in humans: A systematic review. Osteoarthr. Cartil. 2018, 26, 711–729. [Google Scholar] [CrossRef] [PubMed]
  57. Pelttari, K.; Steck, E.; Richter, W. The use of mesenchymal stem cells for chondrogenesis. Injury 2008, 39 (Suppl. 1), S58–S65. [Google Scholar] [CrossRef] [PubMed]
  58. Caplan, A.I. Why are MSCs therapeutic? New data: New insight. J. Pathol. 2009, 217, 318–324. [Google Scholar] [CrossRef] [PubMed]
  59. Maumus, M.; Roussignol, G.; Toupet, K.; Penarier, G.; Bentz, I.; Teixeira, S.; Oustric, D.; Jung, M.; Lepage, O.; Steinberg, R.; et al. Utility of a Mouse Model of Osteoarthritis to Demonstrate Cartilage Protection by IFNgamma-Primed Equine Mesenchymal Stem Cells. Front. Immunol. 2016, 7, 392. [Google Scholar] [CrossRef] [PubMed]
  60. Caplan, A.I.; Correa, D. The MSC: An injury drugstore. Cell Stem Cell 2011, 9, 11–15. [Google Scholar] [CrossRef] [PubMed]
  61. Longobardi, L.; O’Rear, L.; Aakula, S.; Johnstone, B.; Shimer, K.; Chytil, A.; Horton, W.A.; Moses, H.L.; Spagnoli, A. Effect of IGF-I in the chondrogenesis of bone marrow mesenchymal stem cells in the presence or absence of TGF-beta signaling. J. Bone Min. Res. 2006, 21, 626–636. [Google Scholar] [CrossRef] [PubMed]
  62. Ozeki, N.; Muneta, T.; Koga, H.; Nakagawa, Y.; Mizuno, M.; Tsuji, K.; Mabuchi, Y.; Akazawa, C.; Kobayashi, E.; Matsumoto, K.; et al. Not single but periodic injections of synovial mesenchymal stem cells maintain viable cells in knees and inhibit osteoarthritis progression in rats. Osteoarthr. Cartil. 2016, 24, 1061–1070. [Google Scholar] [CrossRef] [PubMed]
  63. Maumus, M.; Manferdini, C.; Toupet, K.; Peyrafitte, J.A.; Ferreira, R.; Facchini, A.; Gabusi, E.; Bourin, P.; Jorgensen, C.; Lisignoli, G.; et al. Adipose mesenchymal stem cells protect chondrocytes from degeneration associated with osteoarthritis. Stem Cell Res. 2013, 11, 834–844. [Google Scholar] [CrossRef] [PubMed]
  64. Almeida, H.V.; Cunniffe, G.M.; Vinardell, T.; Buckley, C.T.; O’Brien, F.J.; Kelly, D.J. Coupling Freshly Isolated CD44+ Infrapatellar Fat Pad-Derived Stromal Cells with a TGF-β3 Eluting Cartilage ECM-Derived Scaffold as a Single-Stage Strategy for Promoting Chondrogenesis. Adv. Healthc. Mater. 2015, 4, 1043–1053. [Google Scholar] [CrossRef] [PubMed]
  65. Kang, H.; Peng, J.; Lu, S.; Liu, S.; Zhang, L.; Huang, J.; Sui, X.; Zhao, B.; Wang, A.; Xu, W.; et al. In vivo cartilage repair using adipose-derived stem cell-loaded decellularized cartilage ECM scaffolds. J. Tissue Eng. Regen. Med. 2014, 8, 442–453. [Google Scholar] [CrossRef] [PubMed]
  66. Choi, B.; Kim, S.; Fan, J.; Kowalski, T.; Petrigliano, F.; Evseenko, D.; Lee, M. Covalently conjugated transforming growth factor-β1 in modular chitosan hydrogels for the effective treatment of articular cartilage defects. Biomater. Sci. 2015, 3, 742–752. [Google Scholar] [CrossRef] [PubMed]
  67. Zhang, K.; Yan, S.; Li, G.; Cui, L.; Yin, J. In-situ birth of MSCs multicellular spheroids in poly(l-glutamic acid)/chitosan scaffold for hyaline-like cartilage regeneration. Biomaterials 2015, 71, 24–34. [Google Scholar] [CrossRef] [PubMed]
  68. Sun, Q.; Zhang, L.; Xu, T.; Ying, J.; Xia, B.; Jing, H.; Tong, P. Combined use of adipose derived stem cells and TGF-β3 microspheres promotes articular cartilage regeneration in vivo. Biotech. Histochem. 2018, 93, 168–176. [Google Scholar] [CrossRef] [PubMed]
  69. Desance, M.; Contentin, R.; Bertoni, L.; Gomez-Leduc, T.; Branly, T.; Jacquet, S.; Betsch, J.M.; Batho, A.; Legendre, F.; Audigie, F.; et al. Chondrogenic Differentiation of Defined Equine Mesenchymal Stem Cells Derived from Umbilical Cord Blood for Use in Cartilage Repair Therapy. Int. J. Mol. Sci. 2018, 19, 537. [Google Scholar] [CrossRef] [PubMed]
  70. Abbas, M. Combination of bone marrow mesenchymal stem cells and cartilage fragments contribute to enhanced repair of osteochondral defects. Bioinformation 2017, 13, 196–201. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  71. Murphy, M.P.; Buckley, C.; Sugrue, C.; Carr, E.; O’Reilly, A.; O’Neill, S.; Carroll, S.M. ASCOT: Autologous Bone Marrow Stem Cell Use for Osteoarthritis of the Thumb-First Carpometacarpal Joint. Plast. Reconstr. Surg. Glob. Open 2017, 5, e1486. [Google Scholar] [CrossRef] [PubMed]
  72. Pers, Y.M.; Rackwitz, L.; Ferreira, R.; Pullig, O.; Delfour, C.; Barry, F.; Sensebe, L.; Casteilla, L.; Fleury, S.; Bourin, P.; et al. Adipose Mesenchymal Stromal Cell-Based Therapy for Severe Osteoarthritis of the Knee: A Phase I Dose-Escalation Trial. Stem Cells Transl. Med. 2016, 5, 847–856. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Al-Najar, M.; Khalil, H.; Al-Ajlouni, J.; Al-Antary, E.; Hamdan, M.; Rahmeh, R.; Alhattab, D.; Samara, O.; Yasin, M.; Abdullah, A.A.; et al. Intra-articular injection of expanded autologous bone marrow mesenchymal cells in moderate and severe knee osteoarthritis is safe: A phase I/II study. J. Orthop. Surg. Res. 2017, 12, 190. [Google Scholar] [CrossRef] [PubMed]
  74. Jo, C.H.; Lee, Y.G.; Shin, W.H.; Kim, H.; Chai, J.W.; Jeong, E.C.; Kim, J.E.; Shim, H.; Shin, J.S.; Shin, I.S.; et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: A proof-of-concept clinical trial. Stem Cells 2014, 32, 1254–1266. [Google Scholar] [CrossRef] [PubMed]
  75. Wu, Y.; Gong, Z.; Li, J.; Meng, Q.; Fang, W.; Long, X. The pilot study of fibrin with temporomandibular joint derived synovial stem cells in repairing TMJ disc perforation. Biomed. Res. Int. 2014, 2014, 454021. [Google Scholar] [CrossRef] [PubMed]
  76. Cui, D.; Li, H.; Xu, X.; Ye, L.; Zhou, X.; Zheng, L.; Zhou, Y. Mesenchymal Stem Cells for Cartilage Regeneration of TMJ Osteoarthritis. Stem Cells Int. 2017, 2017, 5979741. [Google Scholar] [CrossRef] [PubMed]
  77. Yang, C.; Robbins, P.D. Immunosuppressive exosomes: A new approach for treating arthritis. Int. J. Rheumatol. 2012, 2012, 573528. [Google Scholar] [CrossRef] [PubMed]
  78. Toh, W.S.; Lai, R.C.; Hui, J.H.P.; Lim, S.K. MSC exosome as a cell-free MSC therapy for cartilage regeneration: Implications for osteoarthritis treatment. Semin. Cell Dev. Biol. 2017, 67, 56–64. [Google Scholar] [CrossRef] [PubMed]
  79. Zhang, S.; Chu, W.C.; Lai, R.C.; Lim, S.K.; Hui, J.H.; Toh, W.S. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthr. Cartil. 2016, 24, 2135–2140. [Google Scholar] [CrossRef] [PubMed]
  80. McIntosh, K.R.; Frazier, T.; Rowan, B.G.; Gimble, J.M. Evolution and future prospects of adipose-derived immunomodulatory cell therapeutics. Expert Rev. Clin. Immunol. 2013, 9, 175–184. [Google Scholar] [CrossRef] [PubMed]
  81. Baer, P.C. Adipose-derived mesenchymal stromal/stem cells: An update on their phenotype in vivo and in vitro. World J. Stem. Cells 2014, 6, 256–265. [Google Scholar] [CrossRef] [PubMed]
  82. Li, J.; Wong, W.H.; Chan, S.; Chim, J.C.; Cheung, K.M.; Lee, T.L.; Au, W.Y.; Ha, S.Y.; Lie, A.K.; Lau, Y.L.; et al. Factors affecting mesenchymal stromal cells yield from bone marrow aspiration. Chin. J. Cancer Res. 2011, 23, 43–48. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Ding, D.C.; Chang, Y.H.; Shyu, W.C.; Lin, S.Z. Human umbilical cord mesenchymal stem cells: A new era for stem cell therapy. Cell Transpl. 2015, 24, 339–347. [Google Scholar] [CrossRef] [PubMed]
  84. Tangchitphisut, P.; Srikaew, N.; Numhom, S.; Tangprasittipap, A.; Woratanarat, P.; Wongsak, S.; Kijkunasathian, C.; Hongeng, S.; Murray, I.R.; Tawonsawatruk, T. Infrapatellar Fat Pad: An Alternative Source of Adipose-Derived Mesenchymal Stem Cells. Arthritis 2016, 2016, 4019873. [Google Scholar] [CrossRef] [PubMed]
  85. Hindle, P.; Khan, N.; Biant, L.; Peault, B. The Infrapatellar Fat Pad as a Source of Perivascular Stem Cells with Increased Chondrogenic Potential for Regenerative Medicine. Stem Cells Transl. Med. 2017, 6, 77–87. [Google Scholar] [CrossRef] [PubMed]
  86. Yun, S.; Ku, S.K.; Kwon, Y.S. Adipose-derived mesenchymal stem cells and platelet-rich plasma synergistically ameliorate the surgical-induced osteoarthritis in Beagle dogs. J. Orthop. Surg. Res. 2016, 11, 9. [Google Scholar] [CrossRef] [PubMed]
  87. Song, Y.; Du, H.; Dai, C.; Zhang, L.; Li, S.; Hunter, D.J.; Lu, L.; Bao, C. Human adipose-derived mesenchymal stem cells for osteoarthritis: A pilot study with long-term follow-up and repeated injections. Regen. Med. 2018, 13, 295–307. [Google Scholar] [CrossRef] [PubMed]
  88. Wakitani, S.; Imoto, K.; Yamamoto, T.; Saito, M.; Murata, N.; Yoneda, M. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthr. Cartil. 2002, 10, 199–206. [Google Scholar] [CrossRef] [PubMed]
  89. Kuroda, R.; Ishida, K.; Matsumoto, T.; Akisue, T.; Fujioka, H.; Mizuno, K.; Ohgushi, H.; Wakitani, S.; Kurosaka, M. Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells. Osteoarthr. Cartil. 2007, 15, 226–231. [Google Scholar] [CrossRef] [PubMed]
  90. Orozco, L.; Munar, A.; Soler, R.; Alberca, M.; Soler, F.; Huguet, M.; Sentis, J.; Sanchez, A.; Garcia-Sancho, J. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: Two-year follow-up results. Transplantation 2014, 97, e66–e68. [Google Scholar] [CrossRef] [PubMed]
  91. Zhang, Q.; Chen, Y.; Wang, Q.; Fang, C.; Sun, Y.; Yuan, T.; Wang, Y.; Bao, R.; Zhao, N. Effect of bone marrow-derived stem cells on chondrocytes from patients with osteoarthritis. Mol. Med. Rep. 2016, 13, 1795–1800. [Google Scholar] [CrossRef] [PubMed]
  92. Davatchi, F.; Sadeghi Abdollahi, B.; Mohyeddin, M.; Nikbin, B. Mesenchymal stem cell therapy for knee osteoarthritis: 5 years follow-up of three patients. Int. J. Rheum. Dis. 2016, 19, 219–225. [Google Scholar] [CrossRef] [PubMed]
  93. Wu, L.; Prins, H.J.; Helder, M.N.; van Blitterswijk, C.A.; Karperien, M. Trophic effects of mesenchymal stem cells in chondrocyte co-cultures are independent of culture conditions and cell sources. Tissue Eng. Part A 2012, 18, 1542–1551. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Meretoja, V.V.; Dahlin, R.L.; Kasper, F.K.; Mikos, A.G. Enhanced chondrogenesis in co-cultures with articular chondrocytes and mesenchymal stem cells. Biomaterials 2012, 33, 6362–6369. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Zheng, P.; Ju, L.; Jiang, B.; Chen, L.; Dong, Z.; Jiang, L.; Wang, R.; Lou, Y. Chondrogenic differentiation of human umbilical cord bloodderived mesenchymal stem cells by coculture with rabbit chondrocytes. Mol. Med. Rep. 2013, 8, 1169–1182. [Google Scholar] [CrossRef] [PubMed]
  96. Zhu, Y.; Guan, Y.M.; Huang, H.L.; Wang, Q.S. Human umbilical cord blood mesenchymal stem cell transplantation suppresses inflammatory responses and neuronal apoptosis during early stage of focal cerebral ischemia in rabbits. Acta Pharmacol. Sin. 2014, 35, 585–591. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Min, F.; Gao, F.; Li, Q.; Liu, Z. Therapeutic effect of human umbilical cord mesenchymal stem cells modified by angiotensin-converting enzyme 2 gene on bleomycin-induced lung fibrosis injury. Mol. Med. Rep. 2015, 11, 2387–2396. [Google Scholar] [CrossRef] [PubMed]
  98. Chapman, V.; Markides, H.; Sagar, D.R.; Xu, L.; Burston, J.J.; Mapp, P.; Kay, A.; Morris, R.H.; Kehoe, O.; El Haj, A.J. Therapeutic Benefit for Late, but Not Early, Passage Mesenchymal Stem Cells on Pain Behaviour in an Animal Model of Osteoarthritis. Stem Cells Int. 2017, 2017, 2905104. [Google Scholar] [CrossRef] [PubMed]
  99. Akamatsu, Y.; Koshino, T.; Saito, T.; Wada, J. Changes in osteosclerosis of the osteoarthritic knee after high tibial osteotomy. Clin. Orthop. Relat. Res. 1997, 207–214. [Google Scholar] [CrossRef]
  100. Sabzevari, S.; Ebrahimpour, A.; Roudi, M.K.; Kachooei, A.R. High Tibial Osteotomy: A Systematic Review and Current Concept. Arch. Bone Jt. Surg. 2016, 4, 204–212. [Google Scholar] [PubMed]
  101. Martin, R.; Birmingham, T.B.; Willits, K.; Litchfield, R.; Lebel, M.E.; Giffin, J.R. Adverse event rates and classifications in medial opening wedge high tibial osteotomy. Am. J. Sports Med. 2014, 42, 1118–1126. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Research on osteoarthritis with MSC-based therapy.
Table 1. Research on osteoarthritis with MSC-based therapy.
StudyModelMSCs TypeOA LocationResults
Garay-Mendoza et al., 2018 [15]HumanBMMSCsKneeImprovement in knee pain and quality of life since first evaluation until the last one at 6 months
Sun et al., 2018 [68]RabbitASCs + TGF-β3 poly-lactic-co-glycolic acid MicrospheresKneePromoted cartilage regeneration and lessened the severity of OA in vivo
Desancé et al., 2018 [69]EquineUCBMSCsIn vitroHigh proliferative capacity and differentiated into osteoblasts and chondrocytes. Have a great potential for cartilage tissue engineering
Freitag et al., 2017 [35]HumanArthroscopy with removal of a chondral loose body + ASCsPost-traumatic chondral defect of the patellaComplete regeneration of hyaline-like cartilage within the defect and improvement of the pain and function
Abbas 2017 [70]HumanBMMSCs + cartilage fragmentsOsteochondral bone samples from patients with total knee arthroplasty and a central drill defect (human ex vivo osteochondral defect model)Improvement in chondrogenic differentiation and positive staining for type II collagen antibodies
Murphy et al., 2017 [71]HumanBMMSCsFirst Carpometacarpal jointFunctional and symptomatic relief for the patients
Pers et al., 2016 [72]HumanASCsKneePatients treated with ASCs experienced significant improvements in pain levels and function knee compared with baseline.
Rich et al., 2015 [73]HumanBMMSCsKneeSignificantly improved the knee injury and Osteoarthritis Outcome Score and knee cartilage thickness (measured by magnetic resonance imaging), indicating that they may enhance the functional outcome as well as the structural component
Jo et al., 2014 [74]HumanASCsKneeImprove function and pain of the knee joint without causing adverse events, and reduce cartilage defects by regeneration of hyaline-like articular cartilage
Wu et al., 2014 [75]RatSMSCs + fibrin/chitosan scaffold + TGF-β3Temporomandibular JointFibrocartilage formation with deposition of Col1 and Col2
Chen et al., 2013 [76]RabbitBMMSCsTemporomandibular JointEnhance the regenerative process of cartilage repair at the early stage of Temporomandibular joint OA
MSCs mesenchymal stem cells, BMMSCs bone marrow mesenchymal stem cells, OA osteoarthritis, TGF-β3 transforming growth factor β3, UCBMSCs umbilical cord blood mesenchymal stem cells, ASCs adipose-derived stromal cells, SMSCs synovial mesenchymal stem cells, Col1 and Col2 type 1 and type 2 collagen.

Share and Cite

MDPI and ACS Style

Damia, E.; Chicharro, D.; Lopez, S.; Cuervo, B.; Rubio, M.; Sopena, J.J.; Vilar, J.M.; Carrillo, J.M. Adipose-Derived Mesenchymal Stem Cells: Are They a Good Therapeutic Strategy for Osteoarthritis? Int. J. Mol. Sci. 2018, 19, 1926. https://doi.org/10.3390/ijms19071926

AMA Style

Damia E, Chicharro D, Lopez S, Cuervo B, Rubio M, Sopena JJ, Vilar JM, Carrillo JM. Adipose-Derived Mesenchymal Stem Cells: Are They a Good Therapeutic Strategy for Osteoarthritis? International Journal of Molecular Sciences. 2018; 19(7):1926. https://doi.org/10.3390/ijms19071926

Chicago/Turabian Style

Damia, Elena, Deborah Chicharro, Sergio Lopez, Belen Cuervo, Monica Rubio, Joaquin J. Sopena, Jose Manuel Vilar, and Jose Maria Carrillo. 2018. "Adipose-Derived Mesenchymal Stem Cells: Are They a Good Therapeutic Strategy for Osteoarthritis?" International Journal of Molecular Sciences 19, no. 7: 1926. https://doi.org/10.3390/ijms19071926

APA Style

Damia, E., Chicharro, D., Lopez, S., Cuervo, B., Rubio, M., Sopena, J. J., Vilar, J. M., & Carrillo, J. M. (2018). Adipose-Derived Mesenchymal Stem Cells: Are They a Good Therapeutic Strategy for Osteoarthritis? International Journal of Molecular Sciences, 19(7), 1926. https://doi.org/10.3390/ijms19071926

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