Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Hormone Molecular Biology and Clinical Investigation

Editor-in-Chief: Chetrite, Gérard S.

Editorial Board: Alexis, Michael N. / Baniahmad, Aria / Beato, Miguel / Bouillon, Roger / Brodie, Angela / Carruba, Giuseppe / Chen, Shiuan / Cidlowski, John A. / Clarke, Robert / Coelingh Bennink, Herjan J.T. / Darbre, Philippa D. / Drouin, Jacques / Dufau, Maria L. / Edwards, Dean P. / Falany, Charles N. / Fernandez-Perez, Leandro / Ferroud, Clotilde / Feve, Bruno / Flores-Morales, Amilcar / Foster, Michelle T. / Garcia-Segura, Luis M. / Gastaldelli, Amalia / Gee, Julia M.W. / Genazzani, Andrea R. / Greene, Geoffrey L. / Groner, Bernd / Hampl, Richard / Hilakivi-Clarke, Leena / Hubalek, Michael / Iwase, Hirotaka / Jordan, V. Craig / Klocker, Helmut / Kloet, Ronald / Labrie, Fernand / Mendelson, Carole R. / Mück, Alfred O. / Nicola, Alejandro F. / O'Malley, Bert W. / Raynaud, Jean-Pierre / Ruan, Xiangyan / Russo, Jose / Saad, Farid / Sanchez, Edwin R. / Schally, Andrew V. / Schillaci, Roxana / Schindler, Adolf E. / Söderqvist, Gunnar / Speirs, Valerie / Stanczyk, Frank Z. / Starka, Luboslav / Sutter, Thomas R. / Tresguerres, Jesús A. / Wahli, Walter / Wildt, Ludwig / Yang, Kaiping / Yu, Qi

CiteScore 2017: 2.48

SCImago Journal Rank (SJR) 2017: 1.021
Source Normalized Impact per Paper (SNIP) 2017: 0.830

See all formats and pricing
More options …
Volume 28, Issue 3


Adipose derived stem cells for regenerative therapy in osteoarticular diseases

Yves-Marie Pers
  • Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Lapeyronie University Hospital, Montpellier, France
  • INSERM, U1183, IRMB, University Hospital Saint Eloi, Montpellier, France
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Christian Jorgensen
  • Corresponding author
  • INSERM, U1183, IRMB, University Hospital Saint Eloi, Montpellier, France
  • Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, CHRU Lapeyronie, Lapeyronie University Hospital, 371, avenue du doyen Gaston Giraud, 34295 Montpellier, France, Phone: +(33) 4 67 33 72 31, Fax: +(33) 4 67 33 72 27
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2016-04-19 | DOI: https://doi.org/10.1515/hmbci-2016-0010


In the recent years, adipose derived stem cells (ASCs) led to significant findings in the field of regenerative therapy. ASCs have various biological properties and capacity as differentiation in three lineages (chondrocytes, osteocytes and adipocytes) or immunomodulation by releasing paracrine factors. Osteoarthritis (OA) is the most frequent osteoarticular disease characterized by none curative treatment. We reviewed all current data on the proof of concept of ASCs in OA pathophysiology as well as an inventory of ASC promising cell therapy in OA.

Keywords: adipose stem cells; adipose tissue; osteoarthritis; regenerative therapy


Mesenchymal stromal cells (MSCs) can be isolated from a large number of tissues, including bone marrow, adipose tissue or umbilical cord [1], [2]. Adipose tissue-derived mesenchymal stem cells (ASCs) share similar properties with bone marrow-derived MSCs but are easier to collect for clinical application with higher isolation yields. MSCs are defined by their functional abilities of differentiation and differ from hematopoietic stem cells by the expression of mesenchymal markers (CD105, CD70, CD90), while lacking expression of CD34, CD45, CD14 monocyte or markers of T or B cells, or the major histocompatibility class II (MHC II) [3]. They are able to differentiate into mesodermal lineages (osteoblasts, chondrocytes and adipocytes) [4] and to exhibit immunosuppressive as well as healing capacities, through the secretion of paracrine mediators [5]. This led to the development of innovative strategies for the treatment of inflammatory and degenerative rheumatic diseases [6].

ASC obtained from lipoaspirates as described within offer technical advantages over other MSC sources in that there is an abundance of tissue, availability, differentiation potential and minimally invasive harvest procedure compared to other sources. Currently, due to their biological capacity and pre-clinical data, many ASC therapeutic applications are on going. We choose to illustrate our purpose with osteoarthritis (OA), because OA is the most common joint disease in adults with a prevalence of 12% in the age group above 60 years. Furthermore, no therapy reducing the course of the disease is available and perspectives on cell therapy are promising. Thus, we will describe preclinical and clinical data that support ASC potential in the treatment of OA.

Characterisation of adipose stem cells

Differentiation potential

Adipose stem cells are commonly characterized by their adherence to plastic in culture, their immunophenotype in the undifferentiated state and by their differentiation potential towards the adipogenic, osteogenic, and chondrogenic lineages in the presence of specific induction factors (Figure 1). Ten years ago, the International Society for Cell Therapy (ISCT) has established a common definition of mesenchymal stromal cells based on seven cell-surface markers routinely used for MSC production. MSC should be positive for CD90, CD105 and CD73 and negative for CD45, CD34, CD14, and HLA class II [4]. However, in contrast to MSC, ASC express CD34, which is lost during the early phase of culture [7]. In the light of recent research, some other markers could be considered. For example, MSCA-1, CD271, CD146 and some others seem useful [8]. A new version of ISCT definition should be soon available to take into account these factors [8]. As well, ASCs express embryonic stem cell markers: OCT4, Nanog and Sox2 [9].

Characteristics of ASCs. ASCs are defined by their functional abilities of differentiation into different lineages such as chondrocytes, osteoblasts or adipocytes. They differ from hematopoietic stem cells by the expression of mesenchymal markers (CD90, CD105, CD73), while lacking expression of CD34, CD45, CD14 or the human major histocompatibility complex class II (MHC II). ASCs have a phenotypic heterogeneity through the releasing of trophic factors such as hepatocyte growth factor (HGF), interleukin-6 (IL-6), macrophage colony-stimulating factor (M-CSF), transforming growth factor-b 1 (TGF-β 1), tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor (VEGF).
Figure 1:

Characteristics of ASCs.

ASCs are defined by their functional abilities of differentiation into different lineages such as chondrocytes, osteoblasts or adipocytes. They differ from hematopoietic stem cells by the expression of mesenchymal markers (CD90, CD105, CD73), while lacking expression of CD34, CD45, CD14 or the human major histocompatibility complex class II (MHC II). ASCs have a phenotypic heterogeneity through the releasing of trophic factors such as hepatocyte growth factor (HGF), interleukin-6 (IL-6), macrophage colony-stimulating factor (M-CSF), transforming growth factor-b 1 (TGF-β 1), tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor (VEGF).

ASCs may induce a trophic effect trough the secretion of a large number of cytokines and growth factors that support angiogenesis, tissue remodeling, and anti-apoptotic events, such as hepatocyte growth factor (HGF), interleukin-6 (IL-6), macrophage colony-stimulating factor (M-CSF), transforming growth factor-b 1 (TGF-β 1), tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor (VEGF) [6], [10], [11]. The cytokine expression profiles of ASCs display similar properties to those reported for bone marrow-derived MSCs [10].

Immunomodulatory properties

In addition to their function of stem cells capable of regenerating supporting cells, ASCs stimulate the formation of blood vessels, produce chemokines and growth factors, and strongly inhibit the activation of T lymphocytes, cells critical to the immune system, in particular involved in the organ rejection.

MSCs are involved in both the innate and the adaptive immunity [6], [12], [13]. Whatever the T cell status (naive or activated), MSCs have a suppressor role in CD4+ and CD8+ T cells by blocking their cell cycle and inhibiting the expression of cyclin D2. Moreover, MSCs promotes the expression of a regulator phenotype (Treg) CD4+CD25+Foxp3+. Recently, our team demonstrated that systemic MSC injection was associated with a reduction in Th17 population and an increase in CD4+CD25+Foxp3+ T lymphocytes percentage in an experimental autoimmune encephalomyelitis mouse model [14].

MSCs acquire their immunosuppressive properties after exposure to an inflammatory environment. Some cytokines such as IFNγ and/or TNFα, IL-1β are able to activate MSCs [15]. The suppressive properties of MSCs is induced both by cell contact and transwell cultures conditions. Indeed, MSC secret regulatory molecules able to modulate the immune response [12]. Once induced, MSCs should be defined as coordinators of the immune system by providing a tolerogenic environment for both innate and adaptive response [16].

ASCs have been demonstrated to exhibit immunosuppressive effects both in vitro and in vivo and may contribute to a reduction in local inflammation through the secretion of soluble factors of the Interleukin 6 (IL-6) family [17], [18], [19], [20]. IL-6 may have a random role in inflammation depending of the microenvironnement. Mostly pro-inflammatory, IL-6 can lead to chemokines expression by monocytes/macrophages and can activate T/B lymphocytes. On the other hand, IL-6 may enhance production of anti-inflammatory IL-1Ra and suppresses pro-inflammatory cytokines such as IL-1, TNFα and IL-12 [21]. Through the constitutive secretion of IL-6, MSCs induce M2 monocytes characterized by an anti-inflammatory function leading to the production of IL-10. Indeed, IL-6 pathway has a central role because it is induced by PGE2, and IL-6 is able to positively regulate COX2 [13].

Inhibition of T-cell proliferation by ASC is similar with MSC from umbilical cord but more efficient compared to BM-MSC suggesting a difference on immunosuppressive function depending of the MSC source [22]. In contrast, ASCs behave differently and have less therapeutic potential to induce neovascularization in critical limb ischemia [23]. This concept has to be known for on-going and future clinical trials [24], [25] as well as the heterogeneity of the therapeutic potential of MSC between different donors [25]. Based on large donor variation on immunosuppressive effect, different teams are currently providing potency assays [25]. This work is essential to perform efficient cell therapy in the future.

Through expression of Interleukin 1 receptor antagonist (IL1-RA), a potent IL-1β antagonist, ASCs may also prevent tissue fibrosis in vivo and exhibit some anti-inflammatory effects, as IL-1β is also a major pro-inflammatory cytokine [26]. Indeed, MSCs are currently investigated in a variety of diseases, including autoimmune disorders such as diabetes mellitus, lupus erythematous, multiple sclerosis, and Crohn’s disease, as well as in cardio-vascular regeneration and prevention and treatment of graft-versus-host disease [27]. More than 1000 patients have been treated by systemic or local injections of stromal cells without any related adverse events.

ASC potential in osteoarticular disease: osteoarthritis (OA) as a “proof of concept”

OA is an incurable disease associated with chronic disability [28]. The primary symptom of OA is pain. Pain and other symptoms of OA have a profound effect on quality of life, affecting both physical function and psychological parameters [28]. Treatment normally involves palliative measures to reduce pain and swelling, sometimes surgical intervention to increase longevity of the joint and finally, total joint replacement once the inevitable joint destruction has occurred [28]. This presents with several clear clinical and financial implications. To begin with, OA is increasing in prevalence [29]. It is a disease that does not discriminate between sex, age or ethnicity. Over 40 million Europeans are presently affected by OA [30]. Two studies have identified a 45% and 25% lifetime risk of developing knee and hip OA, respectively [31], [32]. Furthermore, treatment is costly, currently estimated as representing 1:2.5% of gross national product [33].

The pathogenesis and pathophysiology of knee OA is not yet fully understood. Damage to the cartilage is a consistent feature associated with changes to the synovium and subchondral bone [28]. Recently, published data suggest that alterations of subchondral knee bone visible in magnetic resonance imaging (MRI) may precede cartilage changes [34]. Subchondral bone may therefore be the site of the causally most significant pathophysiological events occurring in cartilage. Furthermore, synovial inflammation probably is the result, not the cause, of knee OA, but may play an important role in disease chronicity and progression [35].

Insights from “in vitro” biological functions

Putative biological activity of ASCs is to help the endogenous cartilage cells to repair the defects through secretion of growth and anti-apoptotic factors (Figure 2). The proposed mode of action of autologous ASCs in the prevention of deterioration and repair of cartilage lesions in knee OA is based on various properties of this cell type [36]. ASCs have been shown to protect various types of cells against the detrimental effects of oxidative stress and apoptosis in vitro and in vivo [37].

Summary of in vitro and in vivo mechanisms related to ASCs efficiency during osteoarthritis pathophysiology. ASCs may exert different functions on cells via the release of different types of molecules depending on the microenvironment. ASCs may act to reduce cartilage degeneration, osteophyte formation and synovial inflammation in a rabbit model of OA. Moreover, ASC inhibit fibrotic remodeling and apoptosis, enhance endogenous stem cell recruitment and proliferation, and reduce immune responses.
Figure 2:

Summary of in vitro and in vivo mechanisms related to ASCs efficiency during osteoarthritis pathophysiology.

ASCs may exert different functions on cells via the release of different types of molecules depending on the microenvironment. ASCs may act to reduce cartilage degeneration, osteophyte formation and synovial inflammation in a rabbit model of OA. Moreover, ASC inhibit fibrotic remodeling and apoptosis, enhance endogenous stem cell recruitment and proliferation, and reduce immune responses.

The major effect of ASCs was to maintain the chondrocyte phenotype by reducing their dedifferentiation as observed by the decrease of fibroblast-associated markers. Recently, Maumus et al. showed that ASCs induced no changes on the proliferation of chondrocytes but decreased expression of hypertrophic and fibroblastic markers on OA chondrocytes. Hepatocyte growth factor seems a key mediator of this process [38].

Pro-inflammatory cytokines (IL-1β, IL-6), chemokines (CXCL8/IL-8), disintegrins and metalloproteinase with thrombospondin motifs (ADAMTS4, ADAMTS5), metalloproteinases (MMP-1, -3, -13) and tissue inhibitors of metalloproteinases (TIMPs) are released in the synovial fluids of OA patients and contribute to the OA progression. ASCs, even if derived from three different sources (Hoffa fat or subcutaneous hip or subcutaneous abdominal adipose tissue), induced the release of trophic factors that exerted anti-inflammatory effects (down expression of IL-1β, IL-6 and CXCL8/IL-8) on both synoviocytes and chondrocytes so corroborating their potential use in preventing OA progression [39]. The complexity of this anti-inflammatory effect may be due to a combination of different molecules, however the COX2/PGE2 pathway might be one of the modulators that plays a role in mechanism of action [39]. Furthermore, ASC in co-culture with OA chondrocytes significantly reduced the expression of TIMP-3 and MMP-13. ASC in co-culture with synoviocytes significantly increased TIMP-1 expression, decreased ADAMTS5 and did not affect ADAMTS4, TIMP-3 or MMP-13. These data provided another evidence of ASCs efficiency to reduce catabolic factors secretion by OA synoviocytes and OA chondrocytes and suggested possible beneficial effects of ASC in prevention of cartilage from degradation during OA [40].

Insights from “preclinical models”

In a goat model of knee OA, Murphy et al. injected autologous MSCs into the knee joint 6 weeks after induction of experimental OA. It could be demonstrated that formation of cartilage lesions was prevented at week 26 after injection, thereby highlighting the paracrine properties of MSCs [41]. Other MSC-induced repair has been shown in various animal models of OA [42], [43], [44], [45], [46]. Similar observations were made using ASCs in two knee OA animal models in rabbits and mice, respectively [47], [48]. Intra-articular injection of 2 or 6 million autologous ASCs has been shown to improve the cartilage degradation score and to significantly reduce knee synovitis in a biomechanical induced OA rabbit model (bilateral transection of the anterior cruciate ligament) by the inhibition of TNF-α and MMP-1 [47]. Furthermore, intra-articular injection of ASCs has been demonstrated to significantly prevent OA onset in a collagenase-induced murine knee OA model [48]. Thus, ASC injection reduced synovitis, osteophyte formation and limited cartilage degeneration (Figure 2). Alarmins S100A8/A9 seems a key mediator in their effect [49]. However, these results were discordant with other models with low synovial inflammation such as destabilization of the medialmeniscus (DMM) highlighting the importance of ASCs to be activated by inflammatory stimuli to exert their protective functions in experimental OA [49].

The potential for human ASC to traffic into various tissue compartments was initially examined by Meyerrose et al. using three murine xenotransplantation models of immune-deficient mice after intravenous (IV), intraperitoneal, or subcutaneous injection. Nearly 2 months later, they did not observe any differences in the tissue distribution after human ASC injection regardless the route of administration [50]. Another team performed a preclinical toxicity test of the systemic transplantation of ASCs in mice during 13 weeks [51]. Even at the highest cell dose (2.5×108 cells/kg body weight), no side effects occurred and the mice were viable. During the same study, a tumorigenicity test was also performed in Balb/c-nu nude mice for 26 weeks and no evidence of tumor development was found [51]. Recently, our team confirmed these data after IV administration of human ASC in SCID mice [52].

Intra-articular injection of human ASCs in SCID mice led to the detection of ASC in the joint for 60% of the mice but with a small number of persistent cells (1.3%) after 6 months [52]. Moreover, human ASCs were found more frequently in the bone marrow, adipose tissue, and muscle (10%–30%). In some rare cases, they were found in the intestine, brain, or spleen of the SCID mice. Nevertheless, the cells were still functional and able to migrate through the joint toward the niche at least 3 weeks after IA injection [53]. When the cells were injected into immunocompetent mice, they were unable to survive more than a few weeks, suggesting the involvement of the immune response in the removal cell process. Furthermore, inflammation, and the degree of inflammation, did not alter the biodistribution and the persistence of human ASCs in vivo [53].

Human regenerative therapy in OA

There are only a few clinical cell therapy case reports published on the use of ASCs (Figure 3). While the treatment modalities and conditions vary dramatically, ASC or stromal vascular fraction administration has, at least, been well tolerated, with no adverse effects reported.

Current standard treatment of OA is strictly symptomatic. No therapeutic option has been shown to influence the course of the disease. This obvious medical need would best be met by an effective, safe, well-tolerated, local treatment with disease-modifying properties. ASCs exhibit many properties that could be beneficial for the prevention of formation and repair of cartilage lesions. Through the release of trophic factors and cell contact, ASCs may act to reduce cartilage degeneration, osteophyte formation and synovial inflammation. But, despite encouraging pre-clinical data, only a few preliminary clinical studies on the use of autologous stem cells have been published in OA. Recent non-controlled clinical studies showed that local injections of ASCs improved clinical symptoms of pain and WOMAC index (i.e. a functional score), and reported that up to 100 millions of cells were well tolerated [54], [55].

Cell therapy for the treatment of osteoarthritis using adipose derived stromal cells (ASCs). A lipoaspiration is performed under local anesthesia and adipose tissue is collected. Autologous ASCs adhere to the tissue culture plastic and undergo many cell divisions. They are produced and prepared on a GMP-facility. About 14 days after isolation, ASCs are recovered and undergo a defined quality control prior to shipping. A single intra-articular dose of 2–50×106 ASCs is injected into the knee joint (volume 5 mL).
Figure 3:

Cell therapy for the treatment of osteoarthritis using adipose derived stromal cells (ASCs).

A lipoaspiration is performed under local anesthesia and adipose tissue is collected. Autologous ASCs adhere to the tissue culture plastic and undergo many cell divisions. They are produced and prepared on a GMP-facility. About 14 days after isolation, ASCs are recovered and undergo a defined quality control prior to shipping. A single intra-articular dose of 2–50×106 ASCs is injected into the knee joint (volume 5 mL).

Finally, our recent results from a phase I dose escalation study with autologous ASCs (ADIPOA 1) on 18 patients with knee OA showed safety of the procedure and improvement of pain and quality of life for patients who received the lowest dose of ASCs (2×106 cells) (Pers et al., SCTM in press 2016).

The many recent publications confirmed a good safety profile for MSC on OA. However, controlled clinical trials need to be performed to go further with this treatment option. The development of stem cell therapy seems slow mainly because cell manufacturing is very controlled by national authorities, especially in Europe. Only a few centers have quality abilities to produce cells. Moreover, due to ethical issues, autologous cells are preferred leading to a painful and costly processing to perform compared to allogeneic cells. However, the most recent publication from Vega et al. demonstrates that allogeneic bone marrow MSC therapy is also a viable interesting option for OA, according to future commercialization [56]. In the next 5 years, we should have a clear response of cell therapy efficiency and utility in OA with on-going phase II/III studies results.


For instance, this emergent field of cell therapy led to promising results but the “try needs to be conversed”. Controlled randomized phase II and III studies have to be performed in OA but also in the others encouraging applications of regenerative therapy (cardiology, inflammatory and neurology specialities).


  • 1.

    Chen Y, Shao J-Z, Xiang L-X, Dong X-J, Zhang G-R. Mesenchymal stem cells: a promising candidate in regenerative medicine. Int J Biochem Cell Biol 2008;40:815–20. Google Scholar

  • 2.

    Maumus M, Jorgensen C, Noel D. Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: role of secretome and exosomes. Biochimie 2013;95:2229–34. Google Scholar

  • 3.

    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–7. Google Scholar

  • 4.

    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006;8:315–7. Google Scholar

  • 5.

    Ghannam S, Bouffi C, Djouad F, Jorgensen C, Noel D. Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications. Stem Cell Res Ther; 2010;1:2. Google Scholar

  • 6.

    Djouad F, Bouffi C, Ghannam S, Noel D, Jorgensen C. Mesenchymal stem cells: innovative therapeutic tools for rheumatic diseases. Nat Rev Rheumatol 2009;5:392–9. Google Scholar

  • 7.

    Mitchell JB, McIntosh K, Zvonic S, Garrett S, Floyd ZE, Kloster A, Di Halvorsen Y, Storms RW, Goh B, Kilroy G, Wu X, Gimble JM. Immunophenotype of human adipose-derived cells: temporal changes in stromal-associated and stem cell-associated markers. Stem Cells 2006;24:376–85. Google Scholar

  • 8.

    Krampera M, Galipeau J, Shi Y, Tarte K, Sensebe L. Immunological characterization of multipotent mesenchymal stromal cells – The International Society for Cellular Therapy (ISCT) working proposal. Cytotherapy 2013;15:1054–61. Google Scholar

  • 9.

    Rodda DJ, Chew J-L, Lim L-H, Loh Y-H, Wang B, Ng H-H, Robson P. Transcriptional regulation of nanog by OCT4 and SOX2. J Biol Chem 2005;280:24731–7. Google Scholar

  • 10.

    Kilroy GE, Foster SJ, Wu X, Ruiz J, Sherwood S, Heifetz A, Ludlow JW, Stricker DM, Potiny S, Green P, Halvorsen YDC, Cheatham B, Storms RW, Gimble JM. Cytokine profile of human adipose-derived stem cells: expression of angiogenic, hematopoietic, and pro-inflammatory factors. J Cell Physiol 2007;212:702–9. Google Scholar

  • 11.

    Conese M, Carbone A, Castellani S, Di Gioia S. Paracrine effects and heterogeneity of marrow-derived stem/progenitor cells: relevance for the treatment of respiratory diseases. Cells Tissues Organs 2013;197:445–73. Google Scholar

  • 12.

    Marigo I, Dazzi F. The immunomodulatory properties of mesenchymal stem cells. Semin Immunopathol 2011;33:593–602. Google Scholar

  • 13.

    Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol 2012;12:383–96. Google Scholar

  • 14.

    Luz-Crawford P, Kurte M, Bravo-Alegria J, Contreras R, Nova-Lamperti E, Tejedor G, Noel D, Jorgensen C, Figueroa F, Djouad F, Carrion F. Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res Ther 2013;4:65. Google Scholar

  • 15.

    Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, Santarlasci V, Mazzinghi B, Pizzolo G, Vinante F, Romagnani P, Maggi E, Romagnani S, Annunziato F. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 2006;24:386–98. Google Scholar

  • 16.

    Najar M, Raicevic G, Fayyad-Kazan H, Bron D, Toungouz M, Lagneaux L. Mesenchymal stromal cells and immunomodulation: a gathering of regulatory immune cells. Cytotherapy 2016;18:160–71. Google Scholar

  • 17.

    Hoogduijn MJ, Crop MJ, Peeters AM, Van Osch GJ, Balk AH, Ijzermans JN, Weimar W, Baan CC. Human heart, spleen, and perirenal fat-derived mesenchymal stem cells have immunomodulatory capacities. Stem Cells Dev 2007;16: 597–604. Google Scholar

  • 18.

    Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C, Taureau C, Cousin B, Abbal M, Laharrague P, Penicaud L, Casteilla L, Blancher A. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol 2005;129: 118–29. Google Scholar

  • 19.

    Wolbank S, Peterbauer A, Fahrner M, Hennerbichler S, van Griensven M, Stadler G, Redl H, Gabriel C. Dose-dependent immunomodulatory effect of human stem cells from amniotic membrane: a comparison with human mesenchymal stem cells from adipose tissue. Tissue Eng 2007;13:1173–83. Google Scholar

  • 20.

    Yanez R, Lamana ML, Garcia-Castro J, Colmenero I, Ramirez M, Bueren JA. Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells 2006;24:2582–91. Google Scholar

  • 21.

    Brzustewicz E, Bryl E. The role of cytokines in the pathogenesis of rheumatoid arthritis--Practical and potential application of cytokines as biomarkers and targets of personalized therapy. Cytokine 2015;76:527–36. Google Scholar

  • 22.

    Mattar P, Bieback K. Comparing the immunomodulatory properties of bone marrow, adipose tissue, and birth-associated tissue mesenchymal stromal cells. Front Immunol 2015;6:560. Google Scholar

  • 23.

    Bortolotti F, Ukovich L, Razban V, Martinelli V, Ruozi G, Pelos B, Dore F, Giacca M, Zacchigna S. In vivo therapeutic potential of mesenchymal stromal cells depends on the source and the isolation procedure. Stem Cell Reports 2015;4:332–9. Google Scholar

  • 24.

    Melief SM, Zwaginga JJ, Fibbe WE, Roelofs H. Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl Med 2013;2:455–63. Google Scholar

  • 25.

    Ketterl N, Brachtl G, Schuh C, Bieback K, Schallmoser K, Reinisch A, Strunk D. A robust potency assay highlights significant donor variation of human mesenchymal stem/progenitor cell immune modulatory capacity and extended radio-resistance. Stem Cell Res Ther 2015;6:236. Google Scholar

  • 26.

    Luz-Crawford P, Djouad F, Toupet K, Bony C, Franquesa M, Hoogduijn MJ, Jorgensen C, Noel D. Mesenchymal stem cell-derived IL1RA promotes macrophage polarization and inhibits B cell differentiation. Stem Cells 2016;34:483–92. Google Scholar

  • 27.

    Figueroa FE, Carrion F, Villanueva S, Khoury M. Mesenchymal stem cell treatment for autoimmune diseases: a critical review. Biol Res 2012;45:269–77. Google Scholar

  • 28.

    Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: an update with relevance for clinical practice. Lancet 2011;377:2115–26. Google Scholar

  • 29.

    Neogi T, Zhang Y. Epidemiology of osteoarthritis. Rheum Dis Clin North Am 2013;39:1–19. Google Scholar

  • 30.

    Conaghan PG, Kloppenburg M, Schett G, Bijlsma JW. Osteoarthritis research priorities: a report from a EULAR ad hoc expert committee. Ann Rheum Dis 2014;73:1442–5. Google Scholar

  • 31.

    Murphy L, Schwartz TA, Helmick CG, Renner JB, Tudor G, Koch G, Dragomir A, Kalsbeek WD, Luta G, Jordan JM. Lifetime risk of symptomatic knee osteoarthritis. Arthritis Rheum 2008;59:1207–13. Google Scholar

  • 32.

    Murphy LB, Helmick CG, Schwartz TA, Renner JB, Tudor G, Koch GG, Dragomir AD, Kalsbeek WD, Luta G, Jordan JM. One in four people may develop symptomatic hip osteoarthritis in his or her lifetime. Osteoarthritis Cartilage 2010;18:1372–9. Google Scholar

  • 33.

    Chen A, Gupte C, Akhtar K, Smith P, Cobb J. The global economic cost of osteoarthritis: how the UK compares. Arthritis 2012;2012:698709. Google Scholar

  • 34.

    Goldring SR. Alterations in periarticular bone and cross talk between subchondral bone and articular cartilage in osteoarthritis. Ther Adv Musculoskelet Dis 2012;4:249–58. Google Scholar

  • 35.

    Findlay DM. If good things come from above, do bad things come from below? Arthritis Res Ther 2010;12:119. Google Scholar

  • 36.

    Wakitani S, Goto T, Pineda SJ, Young RG, Mansour JM, Caplan AI, Goldberg VM. Mesenchymal cell-based repair of large, full-thickness defects of articular cartilage. J Bone Joint Surg Am 1994;76:579–92. Google Scholar

  • 37.

    Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, Pell CL, Johnstone BH, Considine RV, March KL. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 2004;109:1292–8. Google Scholar

  • 38.

    Maumus M, Manferdini C, Toupet K, Peyrafitte J-A, Ferreira R, Facchini A, Gabusi E, Bourin P, Jorgensen C, Lisignoli, Noel D. Adipose mesenchymal stem cells protect chondrocytes from degeneration associated with osteoarthritis. Stem Cell Res 2013;11:834–44. Google Scholar

  • 39.

    Manferdini C, Maumus M, Gabusi E, Piacentini A, Filardo G, Peyrafitte J-A, Jorgensen C, Bourin P, Fleury-Cappellesso S, Facchini A, Noel D, Lisignoli G. Adipose-derived mesenchymal stem cells exert antiinflammatory effects on chondrocytes and synoviocytes from osteoarthritis patients through prostaglandin E2. Arthritis Rheum 2013;65:1271–81. Google Scholar

  • 40.

    Manferdini C, Maumus M, Gabusi E, Paolella F, Grassi F, Jorgensen C, Fleury-Cappelleso S, Noel D, Lisignoli G. Lack of anti-inflammatory and anti-catabolic effects on basal inflamed osteoarthritic chondrocytes or synoviocytes by adipose stem cell-conditioned medium. Osteoarthritis Cartilage 2015;23:2045–57. Google Scholar

  • 41.

    Murphy JM, Fink DJ, Hunziker EB, Barry FP. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum 2003;48: 3464–74. Google Scholar

  • 42.

    Frisbie DD, Kisiday JD, Kawcak CE, Werpy NM, McIlwraith CW. Evaluation of adipose-derived stromal vascular fraction or bone marrow-derived mesenchymal stem cells for treatment of osteoarthritis. J Orthop Res 2009;27:1675–80. Google Scholar

  • 43.

    Diekman BO, Christoforou N, Willard VP, Sun H, Sanchez-Adams J, Leong KW, Guilak F. Cartilage tissue engineering using differentiated and purified induced pluripotent stem cells. Proc Natl Acad Sci USA 2012;109:19172–7. Google Scholar

  • 44.

    Horie M, Choi H, Lee RH, Reger RL, Ylostalo J, Muneta T, Sekiya I, Prockop DJ. Intra-articular injection of human mesenchymal stem cells (MSCs) promote rat meniscal regeneration by being activated to express Indian hedgehog that enhances expression of type II collagen. Osteoarthritis Cartilage 2012;20:1197–207. Google Scholar

  • 45.

    Toghraie F, Razmkhah M, Gholipour MA, Faghih Z, Chenari N, Torabi Nezhad S, Nazhvani Dehghani S, Ghaderi A. Scaffold-free adipose-derived stem cells (ASCs) improve experimentally induced osteoarthritis in rabbits. Arch Iran Med 2012;15:495–9. Google Scholar

  • 46.

    Al Faqeh H, Nor Hamdan BM, Chen HC, Aminuddin BS, Ruszymah BH. The potential of intra-articular injection of chondrogenic-induced bone marrow stem cells to retard the progression of osteoarthritis in a sheep model. Exp Gerontol 2012;47:458–64. Google Scholar

  • 47.

    Desando G, Cavallo C, Sartoni F, Martini L, Parrilli A, Veronesi F, Fini M, Giardino R, Facchini A, Grigolo Brunella. Intra-articular delivery of adipose derived stromal cells attenuates osteoarthritis progression in an experimental rabbit model. Arthritis Res Ther 2013;15:R22. Google Scholar

  • 48.

    ter Huurne M, Schelbergen R, Blattes R, Blom A, de Munter W, Grevers LC, Jeanson J, Noel D, Casteilla L, Jorgensen C, van de Berg W, van Lent PLEM. Antiinflammatory and chondroprotective effects of intraarticular injection of adipose-derived stem cells in experimental osteoarthritis. Arthritis Rheum 2012;64:3604–13. Google Scholar

  • 49.

    Schelbergen RF, van Dalen S, ter Huurne M, Roth J, Vogl T, Noel D, Jorgensen C, van den Berg WB, van de Loo FA, Blom AB, van Lent PL. Treatment efficacy of adipose-derived stem cells in experimental osteoarthritis is driven by high synovial activation and reflected by S100A8/A9 serum levels. Osteoarthritis Cartilage 2014;22:1158–66. Google Scholar

  • 50.

    Meyerrose TE, De Ugarte DA, Hofling AA, Herrbrich PE, Cordonnier TD, Shultz LD, Eagon JC, Wirthlin L, Sands MS, Hedrick MA, Nolta JA. In vivo distribution of human adipose-derived mesenchymal stem cells in novel xenotransplantation models. Stem Cells 2007;25:220–7. Google Scholar

  • 51.

    Ra JC, Shin IS, Kim SH, Kang SK, Kang BC, Lee HY, Kim YJ, Jo JY, Yoon EJ, Choi HJ, Kwon E. Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev 2011;20:1297–308. Google Scholar

  • 52.

    Toupet K, Maumus M, Peyrafitte J-A, Bourin P, van Lent PL, Ferreira R, Orsetti B, Pirot N, Casteilla L, Jorgensen C, Noel D. Long-term detection of human adipose-derived mesenchymal stem cells after intraarticular injection in SCID mice. Arthritis Rheum 2013;65:1786–94. Google Scholar

  • 53.

    Toupet K, Maumus M, Luz-Crawford P, Lombardo E, Lopez-Belmonte J, van Lent P, Garin MJ, van den Berg; Dalemans W, Jorgensen C, Noel D. Survival and biodistribution of xenogenic adipose mesenchymal stem cells is not affected by the degree of inflammation in arthritis. PLoS One 2015;10:e0114962. Google Scholar

  • 54.

    Koh YG, Choi YJ, Kwon OR, Kim YS. second-look arthroscopic evaluation of cartilage lesions after mesenchymal stem cell implantation in osteoarthritic knees. Am J Sports Med 2014;42:1628–37. Google Scholar

  • 55.

    Jo CH, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC, Kim JE, Shim H, Shin JS, Shin IS, Ra JC, Oh S, Yoon KS. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells 2014;32:1254–66. Google Scholar

  • 56.

    Vega A, Martin-Ferrero MA, Del Canto F, Alberca M, Garcia V, Munar A, Orozco L, Soler R, Fuertes JJ, Huguet M, Sanchez A, Garcia-Sancho J. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation 2015;99:1681–90. Google Scholar

About the article

Received: 2016-02-14

Accepted: 2016-03-12

Published Online: 2016-04-19

Published in Print: 2016-12-01

Citation Information: Hormone Molecular Biology and Clinical Investigation, Volume 28, Issue 3, Pages 113–120, ISSN (Online) 1868-1891, ISSN (Print) 1868-1883, DOI: https://doi.org/10.1515/hmbci-2016-0010.

Export Citation

©2016 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Alina Mieczkowska, Adriana Schumacher, Natalia Filipowicz, Anna Wardowska, Maciej Zieliński, Piotr Madanecki, Ewa Nowicka, Paulina Langa, Milena Deptuła, Jacek Zieliński, Karolina Kondej, Alicja Renkielska, Patrick G. Buckley, David K. Crossman, Michael R. Crowley, Artur Czupryn, Piotr Mucha, Paweł Sachadyn, Łukasz Janus, Piotr Skowron, Sylwia Rodziewicz-Motowidło, Mirosława Cichorek, Michał Pikuła, and Arkadiusz Piotrowski
Scientific Reports, 2018, Volume 8, Number 1
Fazal Ur Rehman Bhatti, Song Ja Kim, Ae-Kyung Yi, Karen A. Hasty, and Hongsik Cho
Cell and Tissue Research, 2018
Javier G. Casado, Rebeca Blázquez, Francisco Javier Vela, Verónica Álvarez, Raquel Tarazona, and Francisco Miguel Sánchez-Margallo
Frontiers in Veterinary Science, 2017, Volume 4

Comments (0)

Please log in or register to comment.
Log in