Mesenchymal stromal cells (MSCs) can be isolated from a large number of tissues, including bone marrow, adipose tissue or umbilical cord , . 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) . They are able to differentiate into mesodermal lineages (osteoblasts, chondrocytes and adipocytes)  and to exhibit immunosuppressive as well as healing capacities, through the secretion of paracrine mediators . This led to the development of innovative strategies for the treatment of inflammatory and degenerative rheumatic diseases .
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
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 . However, in contrast to MSC, ASC express CD34, which is lost during the early phase of culture . In the light of recent research, some other markers could be considered. For example, MSCA-1, CD271, CD146 and some others seem useful . A new version of ISCT definition should be soon available to take into account these factors . As well, ASCs express embryonic stem cell markers: OCT4, Nanog and Sox2 .
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) , , . The cytokine expression profiles of ASCs display similar properties to those reported for bone marrow-derived MSCs .
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 , , . 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 .
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 . 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 . Once induced, MSCs should be defined as coordinators of the immune system by providing a tolerogenic environment for both innate and adaptive response .
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 , , , . 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 . 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 .
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 . In contrast, ASCs behave differently and have less therapeutic potential to induce neovascularization in critical limb ischemia . This concept has to be known for on-going and future clinical trials ,  as well as the heterogeneity of the therapeutic potential of MSC between different donors . Based on large donor variation on immunosuppressive effect, different teams are currently providing potency assays . 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 . 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 . 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 . 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 . 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 . This presents with several clear clinical and financial implications. To begin with, OA is increasing in prevalence . It is a disease that does not discriminate between sex, age or ethnicity. Over 40 million Europeans are presently affected by OA . Two studies have identified a 45% and 25% lifetime risk of developing knee and hip OA, respectively , . Furthermore, treatment is costly, currently estimated as representing 1:2.5% of gross national product .
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 . Recently, published data suggest that alterations of subchondral knee bone visible in magnetic resonance imaging (MRI) may precede cartilage changes . 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 .
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 . ASCs have been shown to protect various types of cells against the detrimental effects of oxidative stress and apoptosis in vitro and in vivo .
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 .
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 . 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 . 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 .
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 . Other MSC-induced repair has been shown in various animal models of OA , , , , . Similar observations were made using ASCs in two knee OA animal models in rabbits and mice, respectively , . 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 . Furthermore, intra-articular injection of ASCs has been demonstrated to significantly prevent OA onset in a collagenase-induced murine knee OA model . Thus, ASC injection reduced synovitis, osteophyte formation and limited cartilage degeneration (Figure 2). Alarmins S100A8/A9 seems a key mediator in their effect . 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 .
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 . Another team performed a preclinical toxicity test of the systemic transplantation of ASCs in mice during 13 weeks . 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 . Recently, our team confirmed these data after IV administration of human ASC in SCID mice .
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 . 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 . 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 .
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 , .
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 . 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).
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About the article
Published Online: 2016-04-19
Published in Print: 2016-12-01