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Immunomodulatory Effect of Adipose-Derived Stem Cells: The Cutting Edge of Clinical Application

Simona Ceccarelli, Paola Pontecorvi, Eleni Anastasiadou and 2 more

Frontiers in Cell and Developmental Biology · 2020 · Review · CC BY

doi:10.3389/fcell.2020.00236

Abstract

Adipose derived stem cells (ASCs) represent a promising tool for soft tissue engineering as well as for clinical treatment of inflammatory and autoimmune pathologies. The well-characterized multi-differentiation potential and self-renewal properties of ASCs are coupled with their immunomodulatory ability in providing therapeutic efficacy. Yet, their impact in immune or inflammatory disorders might rely both on cell contact-dependent mechanisms and paracrine effects, resulting in the release of various soluble factors that regulate immune cells functions. Despite the widespread use of ASCs in clinical trials addressing several pathologies, the pathophysiological mechanisms at the basis of their clinical use have been not yet fully investigated. In particular, a thorough analysis of ASC immunomodulatory potential is mandatory. Here we explore such molecular mechanisms involved in ASC immunomodulatory properties, emphasizing the relevance of the milieu composition. We review the potential clinical use of ASC secretome as a mediator for immunomodulation, with a focus on in vitro and in vivo environmental conditions affecting clinical outcome. We describe some potential strategies for optimization of ASCs immunomodulatory capacity in clinical settings, which act either on adult stem cells gene expression and local microenvironment. Finally, we discuss the limitations of both allogeneic and autologous ASC use, highlighting the issues to be fixed in order to significantly improve the efficacy of ASC-based cell therapy.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 22, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Adipose-derived mesenchymal stem cells (ASCs) represent a population of self-renewing multipotent adult cells in the vascular stroma of adipose tissues, playing important roles in development, post-natal growth, maintenance of tissue homeostasis and tissue repair and regeneration. Significant amount of ASCs can be readily accessible from subcutaneous liposuction and, when appropriately stimulated, they can further differentiate into several cell-like types, including adipocytes, osteocytes, neural cells, vascular endothelial cells, cardiomyocytes, pancreatic cells, and hepatocytes. To date, mechanisms responsible for ASC therapeutic efficacy have been only partially investigated. The common belief is that their action relies on three major events: (1) multi-differentiation potential, (2) self-renewal properties and (3) immunomodulatory capacity. In particular, the first could account for their impact on tissue engineering applications, due to the ability to differentiate into tissue-specific cells and into endothelial cells, thus stimulating both tissue regeneration and arteriogenesis. Indeed, several researchers have analyzed the efficacy of ASC-based therapy in restoring cardiac function in ischemic heart diseases (IHD), providing evidence of an extremely low rate of survival and cardiac retention of ASCs after transplantation. Such indications suggest that ASC therapeutic efficacy in IHD should be ascribed mainly to their paracrine effects rather than the direct differentiation into cardiovascular lineage cells. So, evaluation of ASC therapeutic potential should take into account both cell retention and survival after transplantation and production of active paracrine factors.

The proliferative potential could represent a key element to consolidate the results obtained by ASC injection, leading to the generation of a relatively stable clone of self-renewing cells within the target tissue. Regarding the immunomodulatory capacity, it has been demonstrated that ASCs, as well as BMSCs, have a hypoimmunogenic phenotype, since they lack the major MHC class II molecules and express only low levels of MHC class I, this allowing them to evade immune recognition. Furthermore, ASCs can act as modulators of the host response, showing a greater in vitro immunomodulatory ability than BMSCs derived from age-matched donors, since they are able to partially suppress lymphocytes proliferation, as well as to inhibit differentiation of monocyte-derived immature dendritic cells and NK cell cytotoxic activity. Such effects are likely to depend on both cell contact-dependent mechanisms and paracrine effects through the production of cytokines and various soluble factors that regulate immune cells functions, improve the microenvironment for tissue healing and exert strong immunosuppressive effects by decreasing inflammatory cytokine production. Indeed, higher immunomodulatory potential of ASCs is also related to higher levels of cytokine production.

These findings contributed to make ASCs a viable option in regenerative medicine and a powerful tool in cell-based therapy for restoring damaged tissues and decreasing inflammatory/immune response, opening the way to their application in the treatment of a wide panel of pathologies, including inflammatory and autoimmune diseases. In preclinical studies, ASCs have been successfully used to reduce chronic disability in ischemic stroke in rats, to delay onset and slow disease progression in murine and rat models of multiple sclerosis and to limit structural changes in the lung parenchyma by reducing inflammation and neutrophils number in the airways in chronic obstructive pulmonary disease in mice and guinea pig models. Preclinical studies on ASCs, performed in swine and rodent models, also showed promising results across a wide range of cardiovascular therapeutic applications, due to both stimulation of angiogenesis and potent anti-inflammatory paracrine effect eventually favoring the cardiac healing process. ASC-based cellular therapy has been further considered for the treatment of neurodegenerative diseases, including mouse models of Alzheimer’s disease or Parkinson’s disease and amyotrophic lateral sclerosis (ALS) patients, as well as, in humans, for immunological disorders, such as graft versus host disease (GvHD) and autoimmune pathologies, such as type I diabetes mellitus, systemic sclerosis, rheumatoid arthritis and systemic lupus erythematosus (SLE). A consistent number of clinical trials using ASCs are ongoing for the treatment of some of these disorders1, even though only some complete clinical results are now available, but the greatest number of human studies are in patients with osteoarthritis and inflammatory bowel disease (IBD). In particular, multiple Phase I clinical trials assessed the efficacy of intra articular injection of ASCs in improving pain, function and mobility of affected joints, with no major adverse effects. As for IBD, in a phase III study, ASCs have been shown to be effective and safe for the treatment of complex perianal fistulas in Crohn’s disease patients who did not respond to conventional and/or biological treatments. The most relevant studies on ASCs-based treatment in different pathologies are summarized in Table 1.

Despite the widespread use of ASCs in cell therapy trials, the pathophysiological mechanisms at the basis of their clinical use have been not yet fully investigated. Here, we focused on the immunomodulatory properties of ASCs, through a comprehensive description of the molecular mechanisms and factors involved and the importance of milieu chemical-physical characteristics. Indeed, a plethora of paracrine signals are involved in ASC-mediated immunomodulation, thus suggesting the potential clinical use of ASC secretome, and the importance of environmental stimuli (culture conditions as well as local in vivo microenvironment) in determining clinical outcome. We also shed light on the potential strategies for optimization of ASCs efficacy in clinical settings, especially those related to boosting immunomodulatory capacity, acting both on local microenvironment and directly on ASCs through genetic or epigenetic regulation of gene expression, and to improving ASC characterization in order to standardize clinical outcome.

Immunomodulatory Properties of ASCs

ASCs are considered more powerful suppressors of immune response than mesenchymal stem cells (MSCs) derived from different tissue sources, including trabecular bone, bone marrow, dental pulp, and umbilical cord. In particular, ASCs immunomodulatory effects exceeds that of bone marrow MSCs, which are currently considered the gold standard, due to a higher level of cytokines secretion. Indeed, a small number of highly metabolically active ASCs secrete higher amount of immune suppressive cytokines, such as IL-6 and transforming growth factor-β1 (TGF-β1). In the allogeneic setting, where HLA mismatch occurs, such as in mixed lymphocyte reactions (MLR), ASCs suppress T cell allo-proliferation, because they express low levels of MHC-I, are deficient in major MHC-II and in costimulatory molecules, like CD80, CD86, CD40 and its ligand, CD40L. ASCs also inhibit B lymphocyte proliferation and differentiation into plasmocytic cells, unable to produce antibodies. This characteristic could be important for their use in the treatment of B-cell mediated disorders and GvHD during organ transplantation. B-cells are antigen-presenting cells (APCs) that produce pro- and anti-inflammatory cytokines. When both ASCs and B-cells are in a co-culture setting, the former cells have an inhibitory effect on the chemotactic properties of the latter, by downregulating chemokine receptors on the B cells, such as CXCR4, CXCR5. In contrast, ASCs may induce proliferation of a subset of CD5 + regulatory B cells that secrete immunosuppressive IL-10. This cytokine inhibits the production of other inflammatory cytokines by activated T cells and could be relevant in the therapeutic treatment of autoimmune diseases. In addition, a negative feedback loop between activated T cells-producing interferon γ (IFNγ) and ASCs exists. The secretion of IFNγ primes ASCs against T cells proliferation. Consequently, ASCs are able to escape immune surveillance and simultaneously, they are endowed with ability to self-renew and differentiate into other cell-like types, hence facilitating allogeneic tissue regeneration. A relevant example of the immunomodulatory potential of allogeneic ASCs is the injection of human ASCs (hASCs) in a DBA/1 mouse model with collagen-induced arthritis. Administration of hASCs provoked a decrease of several inflammatory cytokines and chemokines, resulting in reduction of antigen-specific Th1/Th17 cell proliferation. In contrast, IL-10 production was induced in lymph nodes and joints. Yet, antigen-specific Tregs were also produced and as a consequence, self-reactive T effector responses were suppressed.

The stromal vascular fraction (SVF) of an adipose tissue contains not only ASCs but also different cell types, such as endothelial cells, pericytes, lymphocytes, monocytes macrophages, fibroblasts, and smooth muscle cells. In vitro, freshly isolated SVF containing ASCs secrete trophic and pro-regenerative factors, such as cytokines, growth factors, anti-inflammatory factors and extracellular vesicles harboring proteins or even microRNAs, collectively known as secretome. In fact, several studies have shown that the paracrine effects of ASCs and not the cells themselves, are pivotal players for tissue repair along with angiogenic and immunomodulatory properties occurring at the site of the damaged tissue. For example, high levels of two immunomodulatory mediators, indoleamine-pyrrole 2,3-dioxygenase (IDO) and Prostaglandin E2 (PGE2), were detected at 24 h in the supernatants from freshly isolated SVF. It is known that IDO is an immunomodulatory enzyme produced by macrophages with immunosuppressive functions for T-cells and natural killers (NK). Moreover, ASCs inhibit maturation of dendritic cells and induce macrophage to differentiate into anti-inflammatory regulatory cells. PGE2 is a major mediator of ASCs immunomodulation having multiple functions. One of these is the induction of IL-10 by macrophages, which in turn inhibits NK cells and T helper cells. Human leukocyte antigen-G5 (HLA-G5), galectins and programmed cell death ligand (PD-L1) are other factors involved in immunomodulation by ASCs. HLA-G5 is a non-classical MHC- class I molecule, expressed on the surface of ASCs, which exert immunogenic tolerance through inhibition of NK, allogeneic T-cell responses and dendritic cells (DC). Galectin-1 and PD-L1 are negative regulators of immune responses, known as immune checkpoints (ICs) and are expressed on the surface of ASCs. A milestone study conducted by showed that PD-L1 expression is induced on the surface of MSCs isolated from mouse bone marrow by T cell secreted IFNγ. This study provided further insights as to the role of PD-L1 and other ICs in the immunosuppressive potential of ASCs. co-cultured human ASCs that express PD-L1 and galectin 9 (Gal-9), with allogeneic peripheral blood mononuclear cells (PBMCs). The two ICs bound the corresponding ligands on the T cell, PD-L1 to PD-1 and Gal-9 to TIMP-3. In these experimental conditions, ASCs evoked T cell suppression through inhibition of the transcription factor NF-κB activation in TCR-stimulated T cells via the PD-L1/PD-1 and Gal-9/TIMP-3 pathways. However, the interaction between ICs and ASCs has not been explored fully and this could be an exciting area of further investigation.

The immunosuppressive ability of ASCs is both dose and cell passage dependent. After the isolation of ASCs from adipose tissues, these cells undergo multiple culture passages in vitro, since significant numbers are needed for autologous clinical applications. Critically, during serial passaging, ASCs become more differentiated and simultaneously they start losing their immunosuppressive properties. For instance, HLA-G expression dramatically decreases in adult ASCs. Furthermore, the expression of HLA class-II and the other co-stimulatory molecules, CD80 and CD86, increases in very late passaged ASCs differentiating in mature adipocytes then causing T-cell proliferation in a direct contact-dependent manner. Changes in cytokine milieu chemical-physical characteristics with subsequent passages of ASCs, also need to be taken into consideration. Therapeutic applications of ASCs are influenced by hypoxic conditions, 3D cell culture scaffolds and growth factors added in culture, that could modify cell proliferation and ultimately their secretome. Once the ASCs or their secretome are injected into an injured tissue, they might interact with an unfavorable microenvironment, provoking different therapeutic responses than expected. For this reason, it has been suggested to evaluate the inflammatory status and the disease stage of a patient prior to the recruitment and treatment for clinical trials. The safety and timing of ASCs administration are also important requirements for the favorable outcome of cell therapy.

Approaches for Optimization of ASCs Immunomodulatory Efficacy

Although ASCs demonstrated higher immunomodulatory potential with respect to other kind of MSCs, their use as a gold standard for cell therapy of immune-related disorders needs further elucidations. Once ASCs are isolated and expanded in 2D cultures in vitro, they lose the stem cell niche environmental protection and sustainment, which is important to maintain ASC pluripotency, but also their immunomodulatory properties. To date, different ASC enhancement strategies have been proposed, based on external stimuli changes and interventions focused on cells themselves.

An intuitive solution could be to directly recapitulate stem cell niche setting through 3D cultures. In these multicellular structures, adherent cells aggregate with each other through suspension culture system, generating spheroids. As such, paracrine signaling is promoted by the proximity of the cells and the interaction of ASCs with extra cellular matrix (ECM)-like structures or other cell types (co-cultures) increases the secretion level of anti-inflammatory and pro-angiogenic molecules. The employment of ASCs spheroids in the treatment of experimental in vivo disease models such as elastase-induced emphysema, hindlimb ischemia, acute kidney ischemia and diabetic skin wound healing demonstrated encouraging results regarding differentiation, pro-angiogenic and regenerative capacity of ASCs. Currently, chitosan-coated culture plates, concaved bottom wells, ultra-low attachment plates, the hanging drop technique and spinner flask are the most widely used methods for spheroid generation. In particular, showed that 3D-ASCs obtained through hanging drop method have enhanced immunomodulatory effects in systemic inflammatory response syndrome frequently observed in severe fulminant hepatic failure. Limitations of 3D spheroids may be related to the fact that in vitro nutrients and oxygen may be less available at the core of the 3D spheres, inducing necrosis and altering ASCs functions. An alternative strategy to obtain 3D ASCs cell cultures is simulate microgravity in a Rotary Cell Culture System (RCCS) bioreactor. The RCCS system can be useful to overcome the oxygen and nutrient gradient problems. Anyway, in these experimental conditions, some other factors involved in immunomodulation could be harder to control. An easier strategy may be to dissect these mechanisms and apply single level interventions.

As for the external stimuli, it has been demonstrated that the presence of growth factors in the culture medium could enhance ASCs differentiation. Likewise, pre-conditioning of ASCs with cytokines or other bioactive molecules represents one of the main approaches to boost ASCs immune regulatory functions before their therapeutic administration. IFN-γ and tumor necrosis factor α (TNF-α) are the major inflammatory cytokines used in MSC functional enhancement. After IFN-γ priming, ASCs showed overexpression of IDO, together with Cyclooxygenase 2 (COX2), TGF-β and Hepatocyte Growth Factor (HGF), central factors in immunological tolerance and anti-inflammatory mechanisms. TNF-α treatment, not only increased the production of IDO, PGE2, and HGF, but also of the pro-inflammatory cytokines IL-6 and IL-8, promoting endothelial progenitor cell migration and angiogenesis, a primary goal of regenerative medicine. Furthermore, ASCs primed with IL-17, TNF-α, and IFN-γ have increased T cell immunosuppressive capacity mediated by inducible nitric oxide synthase (iNOS) production and have been shown to reduce inflammation and tissue injury in murine model of hepatitis. An additional strategy is the pre-conditioning of ASCs with toll-like receptors (TLRs) agonists. ASCs express TLRs, cell membrane sensors that play a pivotal role in innate immune system mechanisms. Although TLRs agonists seem to be mainly implicated in ASCs multi-lineage differentiation capacity, studies demonstrated that TLR3 activation might induce suppressive phenotype. By mimicking an in vivo inflammatory milieu, the combination of cytokines and TLRs ligands seemed to generate addictive effects on MSCs immunomodulatory properties, enhancing their therapeutic efficacy more than the use of a single molecular category. The downside of this approach may be that cytokine priming can confer immunogenicity to the ASCs, exposing them to host immune responses.

To date, only few studies have been performed on the induction of epigenetic modification to enhance immunomodulatory capacity of ASCs. Recent findings have provided insight into the exposure to 5-Aza-2′-deoxycytidine (5-AZA-dC) during in vitro expansion of ASCs that resulted in the upregulation of HLA-G gene, whose sustained expression is crucial to maintain immunomodulatory capabilities in adult stem cells. MicroRNAs are also implicated in epigenetic regulation of ASCs immunomodulatory properties, as proven by in a mouse model of colitis. Mysm1, a histone deubiquitinase, is induced by TNF-α and IFNγ in ASCs and promotes miR-150 transcription, which enhances iNOS production. Nitric oxide is catalyzed by iNOS that is essential for the immunosuppressive capacity of ASCs. Therefore, miRNA-based strategies could be promising in enhancing therapeutic ASCs efficacy. Because both epigenetic modulators and ASCs have common aspects in immune modulation, their respective contributions should be established and it is important to pay attention to possible cross-interactions.

A straightforward approach is to modify MSCs in order to increase the expression of genes such as IL-10, HGF, IDO, and FOXP3 to obtain therapeutic anti-inflammatory effects. Genetically engineered ASCs have demonstrated efficacy in the treatment of inflammatory disease in vivo. Several studies reported the clinical success of different approaches to ASC genetic modification. The administration of human ASCs transduced with a bicistronic lentiviral vector encoding mouse IL-4 in C57Bl/6 mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, results in a reduction of antigen-specific T-cell responses, thus attenuating clinical disease. Human ASCs transduced with a lentiviral vector for CTLA-4 Ig overexpression, when transplanted into a mouse model of sustained severe collagen induced arthritis, are able to enable CTLA-4 binding to CD28, which results in the induction of T-cell clonal anergy and the amelioration of autoimmune disease. The introduction of IL-1 receptor-like-1 (sST2), a decoy receptor for IL-33, in ASCs using a bicistronic lentiviral vector encoding the sST2–C-terminal promotes inflammation suppression and alleviation of the pathological events in acute lung injury (ALI) mouse model. Furthermore, overexpression of IL-35, a recently discovered anti-inflammatory cytokine, represent a powerful tool to potentiate ASC-based cell therapy approach for auto-immune diseases. Results obtained by Zhao et al. demonstrated that murine ASCs transduced with a recombinant lentiviral vector to overexpress IL-35 are able to decrease CD4 + T-cell proliferation and IL-17 secretion in an in vitro co-culture model.

The Road Ahead in Immunomodulatory Potential of ASCs

Much effort has been done regarding the use of autologous versus allogeneic cells for in vivo applications, with the first being preferred especially for chronic pathologies since the time required for the isolation and expansion of cells is not a limit given to the non-acute nature of the diseases. However, by using autologous ASCs there were consistent variations in clinical outcome, since cell characteristics may vary between patients, not only according to biological factors as age, sex, body mass index but also depending upon the disease.

In this regard, contradictory results are available about the properties of ASCs isolated from patients affected by autoimmune and chronic inflammatory diseases. For example, some reports demonstrated that ASCs from patients affected by systemic sclerosis show the same phenotypical and functional characteristics of their healthy counterparts, while observed that ASCs from sclerodermic patients showed identical phenotype and differentiation capacity of those from healthy donors, but displayed reduced proliferation and migration capacity. Whilst, the presence of cardiovascular risk factors in cardiac patients seems to reduce ASC pluripotency and self-renewal, thus discouraging their autologous use in the clinical setting. In particular, microenvironmental factors and metabolic disorders may impact the functionality of these cells. ASCs derived from obese subjects and from patients affected by type 2 diabetes showed increased expression of inflammatory markers with respect to those derived from lean donors, as well as a remarkable reduction in their immunosuppressive activities. Moreover, ASCs from obese patients also display an impaired angiogenic potential. Other groups observed that diabetes did not alter ASC isolation efficiency, growth curves and angiogenic potential, but ASCs from diabetic patients showed a delay in the acquisition of endothelial cell markers, thus suggesting an impaired differentiation.

The use of allogeneic stem cells may overcome these limitations, but it has to be considered that adipose tissue availability is dependent on surgical procedures, thus limiting the occurrence of overall healthy donors. More attention should be also paid to the origin of allogeneic ASCs, since several studies underlined a cellular and molecular variability depending on the donor age, sex and tissue source even under similar genetic and environmental conditions. In particular, ASCs derived from different donors might have significant variations in the chemical-physical characteristics of their secretome, thus affecting their immunomodulatory capacity. In order to avoid donor-to-donor heterogeneity, a strategy with pooled ASCs of different allogeneic donors could be proposed, as previously reported for BMSCs, but immunogenic stimuli could increase. Indeed, although ASCs have been shown to possess a low immunogenic profile, the potential immunogenicity of allogeneic cells, which might determine their rejection after infusion, cannot be excluded. In fact, it has been observed that the immunogenicity of ASCs decreases with cell passaging, so that cells at low passages are more immunogenic than those at higher passages, and that ASCs are not fully immune privileged, since they elicit both humoral and cellular immune response in vivo, depending on the microenvironment. Also ASC differentiation may alter their immunogenic phenotype, increasing HLA class-I and HLA class-II expression, as well as culturing condition (e.g., use of human serum or serum-free conditions).

Conclusion

ASCs represent a valuable treatment option for a wide range of inflammatory or autoimmune diseases, which therapeutic efficacy relies primarily on immunomodulatory activities mediate by paracrine effects. An increasing number of preclinical studies and clinical trials are being developed to assess ASCs safety and efficacy. However, although there are promising results and increasing knowledge in the in vivo applications of ASCs, unfortunately, several clinical trials have failed due to differences in experimental protocols, read-out, animal models and variability in ASCs characteristics. So, the clinical translation of ASCs still requires a proper validation in large controlled trials. For a more successful outcome of ASC based therapies, thorough investigations with more standardized protocols are urgently required, as well as a better understand of ASC immunomodulatory network and the identification of key molecules and/or regulatory mechanisms responsible for ASC effects in chronic inflammatory diseases.

The in-depth analysis of the potential strategies aimed to boost ASC-mediated immunomodulation (summarized in Figure 1) will foster new targeted approaches for cell therapy applications in the field of immune diseases. Yet, such interventions need to be accurately considered, since any alteration of immune system sensitivity can be dangerous: weakening the capacity of recognize transformed cells or pathogens, or vice versa exacerbating immune response, could lead to adverse events. As for genetic modification, the engineered cells persisting in the host could generate undesirable effects, such as potential tumorigenicity related to genetic instability.

Finally, standardization of both ASC and patient’s characteristics prior to clinical use are necessary to avoid that the donor phenotype might compromise their immunomodulatory properties, thus impairing their therapeutic efficacy.

Author Contributions

SC conceived the review and wrote the manuscript. PP and EA revised the literature and helped to writing the manuscript. CN edited the manuscript. CM supervised the overall project and edited the manuscript. All authors had the opportunity to discuss and comment on the manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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    Not in our library10.1161/circresaha.108.175943

  31. 31.

    Dominici M. Le Blanc K. Mueller I. Slaper-Cortenbach I. Marini F. C. Krause D. S. (2006 ). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8 315–317.

    Not in our library10.1080/14653240600855905

  32. 32.

    Duval K. Grover H. Han L. H. Mou Y. Pegoraro A. F. Fredberg J. (2017 ). Modeling physiological events in 2D vs. 3D cell culture. Physiology 32 266–277.

    Not in our library10.1152/physiol.00036.2016

  33. 33.

    Edmondson R. Broglie J. J. Adcock A. F. Yang L. (2014 ). Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev. Technol. 12 207–218.

    Not in our library10.1089/adt.2014.573

  34. 34.
    Insights into the Secretome of Mesenchymal Stem Cells and Its Potential Applications · 2019
    No notice
  35. 35.

    El-Jawhari J. J. El-Sherbiny Y. M. Jones E. A. McGonagle D. (2014 ). Mesenchymal stem cells, autoimmunity and rheumatoid arthritis. QJM 107 505–514.

    Not in our library10.1093/qjmed/hcu033

  36. 36.

    Fang B. Song Y. Lin Q. Zhang Y. Cao Y. Zhao R. C. (2007 ). Human adipose tissue-derived mesenchymal stromal cells as salvage therapy for treatment of severe refractory acute graft-vs.-host disease in two children. Pediatr. Transplant. 11 814–817.

    Not in our library10.1111/j.1399-3046.2007.00780.x

  37. 37.

    Feisst V. Meidinger S. Locke M. B. (2015 ). From bench to bedside: use of human adipose-derived stem cells. Stem Cells Cloning 8 149–162.

    Not in our library10.2147/sccaa.s64373

  38. 38.

    Fontanilla C. V. Gu H. Liu Q. Zhu T. Z. Zhou C. Johnstone B. H. (2015 ). Adipose-derived stem cell conditioned media extends survival time of a mouse model of amyotrophic lateral sclerosis. Sci. Rep. 5:16953.

    Not in our library10.1038/srep16953

  39. 39.
    Immunomodulatory Effect of Mesenchymal Stem Cells on B Cells · 2012
    No notice
  40. 40.

    Franquesa M. Mensah F. K. Huizinga R. Strini T. Boon L. Lombardo E. (2015 ). Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells. Stem Cells 33 880–891.

    Not in our library10.1002/stem.1881

  41. 41.

    Fu Y. Karbaat L. Wu L. Leijten J. Both S. K. Karperien M. (2017 ). Trophic effects of mesenchymal stem cells in tissue regeneration. Tissue Eng. Part B Rev. 23 515–528.

    Not in our library10.1089/ten.teb.2016.0365

  42. 42.

    Galipeau J. (2017 ). Reply: “function of cryopreserved mesenchymal stromal cells with and without interferon-γ prelicensing is context dependent.”. Stem Cells 35 1440–1441.

    Not in our library10.1002/stem.2526

  43. 43.
    Mesenchymal stem cells and immunomodulation: current status and future prospects · 2016
    No notice
  44. 44.

    García-Sancho J. Sánchez A. Vega A. Noriega D. C. Nocito M. (2017 ). Influence of HLA matching on the efficacy of allogeneic mesenchymal stromal cell therapies for osteoarthritis and degenerative disc disease. Transplant. Direct 3:e205.

    Not in our library10.1097/txd.0000000000000724

  45. 45.

    Ghorbani A. Feizpour A. Hashemzahi M. Gholami L. Hosseini M. Soukhtanloo M. (2014 ). The effect of adipose derived stromal cells on oxidative stress level, lung emphysema and white blood cells of guinea pigs model of chronic obstructive pulmonary disease. DARU J. Pharm. Sci. 22:26.

    Not in our library10.1186/2008-2231-22-26

  46. 46.

    Gieseke F. Böhringer J. Bussolari R. Dominici M. Handgretinger R. Müller I. (2010 ). Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells. Blood 116 3770–3779.

    Not in our library10.1182/blood-2010-02-270777

  47. 47.

    Gnecchi M. He H. Liang O. D. Melo L. G. Morello F. Mu H. (2005 ). Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells [2]. Nat. Med. 11 367–368.

    Not in our library10.1038/nm0405-367

  48. 48.

    González M. A. Gonzalez-Rey E. Rico L. Büscher D. Delgado M. (2009a ). Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology 136 978–989.

    Not in our library10.1053/j.gastro.2008.11.041

  49. 49.

    González M. A. González-Rey E. Rico L. Büscher D. Delgado M. (2009b ). Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells. Arthritis Rheum. 60 1006–1019.

    Not in our library10.1002/art.24405

  50. 50.

    Griffin M. Ryan C. M. Pathan O. Abraham D. Denton C. P. Butler P. E. M. (2017 ). Characteristics of human adipose derived stem cells in scleroderma in comparison to sex and age matched normal controls: implications for regenerative medicine. Stem Cell Res. Ther. 8:23.

    Not in our library10.1186/s13287-016-0444-7

  51. 51.

    Grimaldi V. Mancini F. P. Casamassimi A. Al-Omran M. Zullo A. Infante T. (2013 ). Potential benefits of cell therapy in coronary heart disease. J. Cardiol. 10(Suppl. 20), S2412–S2422.

    Not in our library10.1016/j.jjcc.2013.05.017

  52. 52.
    Mesenchymal stem cells alleviate airway inflammation and emphysema in COPD through down-regulation of cyclooxygenase-2 via p38 and ERK MAPK pathways · 2015
    No notice
  53. 53.
    Effects of intravenous administration of allogenic bone marrow- and adipose tissue-derived mesenchymal stem cells on functional recovery and brain repair markers in experimental ischemic stroke · 2013
    No notice
  54. 54.

    Han X. Yang Q. Lin L. Xu C. Zheng C. Chen X. (2014 ). Interleukin-17 enhances immunosuppression by mesenchymal stem cells. Cell Death Differ. 21 1758–1768.

    Not in our library10.1038/cdd.2014.85

  55. 55.

    Hashemi S. M. Ghods S. Kolodgie F. D. Parcham-Azad K. Keane M. Hamamdzic D. (2008 ). A placebo controlled, dose-ranging, safety study of allogenic mesenchymal stem cells injected by endomyocardial delivery after an acute myocardial infarction. Eur. Heart J. 29 251–259.

    Not in our library10.1093/eurheartj/ehm559

  56. 56.

    Heslop J. A. Hammond T. G. Santeramo I. Tort Piella A. Hopp I. Zhou J. (2015 ). Concise review: workshop review: understanding and assessing the risks of stem cell-based therapies. Stem Cells Transl. Med. 4 389–400.

    Not in our library10.5966/sctm.2014-0110

  57. 57.

    Hong Y. Kim Y. S. Hong S. H. Oh Y. M. (2016 ). Therapeutic effects of adipose-derived stem cells pretreated with pioglitazone in an emphysema mouse model. Exp. Mol. Med. 48 e266.

    Not in our library10.1038/emm.2016.93

  58. 58.

    Hwa Cho H. Bae Y. C. Jung J. S. (2006 ). Role of toll-like receptors on human adipose-derived stromal cells. Stem Cells 24 2744–2752.

    Not in our library10.1634/stemcells.2006-0189

  59. 59.

    Ivanova-Todorova E. Bochev I. Mourdjeva M. Dimitrov R. Bukarev D. Kyurkchiev S. (2009 ). Adipose tissue-derived mesenchymal stem cells are more potent suppressors of dendritic cells differentiation compared to bone marrow-derived mesenchymal stem cells. Immunol. Lett. 126 37–42.

    Not in our library10.1016/j.imlet.2009.07.010

  60. 60.

    Jo C. H. Lee Y. G. Shin W. H. Kim H. Chai J. W. Jeong E. C. (2014 ). Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells 32 1254–1266.

    Not in our library10.1002/stem.1634

  61. 61.

    Jones D. L. Wagers A. J. (2008 ). No place like home: anatomy and function of the stem cell niche. Nat. Rev. Mol. Cell Biol. 9 11–21.

    Not in our library10.1038/nrm2319

  62. 62.

    Kaewsuwan S. Song S. Y. Kim J. H. Sung J. H. (2012 ). Mimicking the functional niche of adipose-derived stem cells for regenerative medicine. Expert Opin. Biol. Ther. 12 1575–1588.

    Not in our library10.1517/14712598.2012.721763

  63. 63.
    IL-10-producing regulatory B cells (B10 cells) in autoimmune disease · 2013
    No notice
  64. 64.

    Kang H. Lu S. Peng J. Yang Q. Liu S. Zhang L. (2015 ). Chondrogenic differentiation of human adiposederived stem cells using microcarrier and bioreactor combination technique. Mol. Med. Rep. 11 1195–1199.

    Not in our library10.3892/mmr.2014.2820

  65. 65.

    Kapur S. K. Wang X. Shang H. Yun S. Li X. Feng G. (2012 ). Human adipose stem cells maintain proliferative, synthetic and multipotential properties when suspension cultured as self-assembling spheroids. Biofabrication 4:025004.

    Not in our library10.1088/1758-5082/4/2/025004

  66. 66.

    Kim D. S. Jang I. K. Lee M. W. Ko Y. J. Lee D. H. Lee J. W. (2018 ). Enhanced immunosuppressive properties of human mesenchymal stem cells primed by interferon-γ. EBioMedicine 28 261–273.

    Not in our library10.1016/j.ebiom.2018.01.002

  67. 67.

    Kim J. Hematti P. (2009 ). Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. Exp. Hematol. 37 1445–1453.

    Not in our library10.1016/j.exphem.2009.09.004

  68. 68.

    Kota D. J. Prabhakara K. S. Toledano-Furman N. Bhattarai D. Chen Q. DiCarlo B. (2017 ). Prostaglandin E2 indicates therapeutic efficacy of mesenchymal stem cells in experimental traumatic brain injury. Stem Cells 35 1416–1430.

    Not in our library10.1002/stem.2603

  69. 69.

    Krampera M. (2011 ). Mesenchymal stromal cell licensing: a multistep process. Leukemia 25 1408–1414.

    Not in our library10.1038/leu.2011.108

  70. 70.

    Krawiec J. T. Weinbaum J. S. Liao H. T. Ramaswamy A. K. Pezzone D. J. Josowitz A. D. (2016 ). In vivo functional evaluation of tissue-engineered vascular grafts fabricated using human adipose-derived stem cells from high cardiovascular risk populations. Tissue Eng. Part A 22 765–775.

    Not in our library10.1089/ten.tea.2015.0379

  71. 71.

    Kronsteiner B. Wolbank S. Peterbauer A. Hackl C. Redl H. Van Griensven M. (2011 ). Human mesenchymal stem cells from adipose tissue and amnion influence T-cells depending on stimulation method and presence of other immune cells. Stem Cells Dev. 20 2115–2126.

    Not in our library10.1089/scd.2011.0031

  72. 72.

    Kuçi Z. Bönig H. Kreyenberg H. Bunos M. Jauch A. Janssen J. W. G. (2016 ). Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versus-host disease: a multicenter survey. Haematologica 101 985–994.

    Not in our library10.3324/haematol.2015.140368

  73. 73.

    Kwon Y. W. Heo S. C. Jeong G. O. Yoon J. W. Mo W. M. Lee M. J. (2013 ). Tumor necrosis factor-α-activated mesenchymal stem cells promote endothelial progenitor cell homing and angiogenesis. Biochim. Biophys. Acta 1832 2136–2144.

    Not in our library10.1016/j.bbadis.2013.08.002

  74. 74.

    Lee S. Persson P. Mathews R. D. (2015 ). an us cr ip t Ac ce pt us cr ip t Ac ce pt ed. Rev. Financ. Stud. 29 2341–2386.

    Not in our library

  75. 75.

    Leto Barone A. A. Khalifian S. Lee W. P. A. Brandacher G. (2013 ). Immunomodulatory effects of adipose-derived stem cells: Fact or fiction? Biomed Res. Int. 2103:383685.

    Not in our library10.1155/2013/383685

  76. 76.

    Li X. Ma T. Sun J. Shen M. Xue X. Chen Y. (2019 ). Harnessing the secretome of adipose-derived stem cells in the treatment of ischemic heart diseases. Stem Cell Res. Ther. 10:196.

    Not in our library10.1186/s13287-019-1289-7

  77. 77.

    Liang J. Zhang H. Hua B. Wang H. Lu L. Shi S. (2010 ). Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann. Rheum. Dis. 69 1423–1429.

    Not in our library10.1136/ard.2009.123463

  78. 78.
    Applicability of Adipose-Derived Stem Cells in Type 1 Diabetes Mellitus · 2015
    Not checked
  79. 79.

    Lombardo E. Delarosa O. Mancheño-Corvo P. Menta R. Ramírez C. Büscher D. (2009 ). Toll-like receptor-mediated signaling in human adipose-derived stem cells: implications for immunogenicity and immunosuppressive potential. Tissue Eng. Part A 15 1579–1589.

    Not in our library10.1089/ten.tea.2008.0340

  80. 80.

    Machado C. D. da Silva Telles P. D. Nascimento I. L. O. (2013 ). Immunological characteristics of mesenchymal stem cells. Rev. Bras. Hematol. Hemoter. 35 62–67.

    Not in our library10.5581/1516-8484.20130017

  81. 81.

    Madonna R. Geng Y. J. De Caterina R. (2009 ). Adipose tissue-derived stem cells: characterization and potential for cardiovascular repair. Arterioscler. Thromb. Vasc. Biol. 29 1723–1729.

    Not in our library10.1161/atvbaha.109.187179

  82. 82.
    A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods · 2014
    No notice
  83. 83.

    Martínez-González I. Roca O. Masclans J. R. Moreno R. Salcedo M. T. Baekelandt V. (2013 ). Human mesenchymal stem cells overexpressing the IL-33 antagonist soluble IL-1 receptor-like-1 attenuate endotoxin-induced acute lung injury. Am. J. Respir. Cell Mol. Biol. 49 552–562.

    Not in our library10.1165/rcmb.2012-0406oc

  84. 84.

    McCoy M. K. Martinez T. N. Ruhn K. A. Wrage P. C. Keefer E. W. Botterman B. R. (2008 ). Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson’s disease. Exp. Neurol. 210 14–29.

    Not in our library10.1016/j.expneurol.2007.10.011

  85. 85.

    McIntosh K. Zvonic S. Garrett S. Mitchell J. B. Floyd Z. E. Hammill L. (2006 ). The immunogenicity of human adipose-derived cells: temporal changes in vitro. Stem Cells 24 1246–1253.

    Not in our library10.1634/stemcells.2005-0235

  86. 86.

    Melief S. M. Zwaginga J. J. Fibbe W. E. Roelofs H. (2013 ). Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl. Med. 2 455–463.

    Not in our library10.5966/sctm.2012-0184

  87. 87.

    Min C. K. Kim B. G. Park G. Cho B. Oh I. H. (2007 ). IL-10-transduced bone marrow mesenchymal stem cells can attenuate the severity of acute graft-versus-host disease after experimental allogeneic stem cell transplantation. Bone Marrow Transplant. 39 637–645.

    Not in our library10.1038/sj.bmt.1705644

  88. 88.

    Mineda K. Feng J. Ishimine H. Takada H. Doi K. Kuno S. (2015 ). therapeutic potential of human adipose-derived stem/stromal cell microspheroids prepared by three-dimensional culture in non-cross-linked hyaluronic acid gel. Stem Cells Transl. Med. 4 1511–1522.

    Not in our library10.5966/sctm.2015-0037

  89. 89.

    Montespan F. Deschaseaux F. Sensébé L. Carosella E. D. Rouas-Freiss N. (2014 ). Osteodifferentiated mesenchymal stem cells from bone marrow and adipose tissue express HLA-G and display immunomodulatory properties in Hla-mismatched settings: implications in bone repair therapy. J. Immunol. Res. 2014:230346.

    Not in our library10.1155/2014/230346

  90. 90.

    Naaijkens B. A. van Dijk A. Kamp O. Krijnen P. A. J. Niessen H. W. M. Juffermans L. (2014 ). Therapeutic application of adipose derived stem cells in acute myocardial infarction: lessons from animal models. Stem Cell Rev. Rep. 10 389–398.

    Not in our library10.1007/s12015-014-9502-7

  91. 91.

    Najar M. Raicevic G. Boufker H. I. Kazan H. F. De Bruyn C. Meuleman N. (2010 ). Mesenchymal stromal cells use PGE2 to modulate activation and proliferation of lymphocyte subsets: combined comparison of adipose tissue. Wharton’s Jelly and bone marrow sources. Cell. Immunol. 264 171–179.

    Not in our library10.1016/j.cellimm.2010.06.006

  92. 92.

    Najar M. Raicevic G. Fayyad-Kazan H. Bron D. Toungouz M. Lagneaux L. (2016 ). Mesenchymal stromal cells and immunomodulation: a gathering of regulatory immune cells. Cytotherapy 18 160–171.

    Not in our library10.1016/j.jcyt.2015.10.011

  93. 93.

    Najar M. Raicevic G. Fayyad-Kazan H. De Bruyn C. Bron D. Toungouz M. (2013 ). Impact of different mesenchymal stromal cell types on T-cell activation, proliferation and migration. Int. Immunopharmacol. 15 693–702.

    Not in our library10.1016/j.intimp.2013.02.020

  94. 94.

    Nancarrow-Lei R. Mafi P. Mafi R. Khan W. (2017 ). A systemic review of adult mesenchymal stem cell sources and their multilineage differentiation potential relevant to musculoskeletal tissue repair and regeneration. Curr. Stem Cell Res. Ther. 12 601–610.

    Not in our library10.2174/1574888x12666170608124303

  95. 95.

    Napoli C. William-Ignarro S. Byrns R. Balestrieri M. L. Crimi E. Farzati B. (2008 ). Therapeutic targeting of the stem cell niche in experimental hindlimb ischemia. Nat. Clin. Pract. Cardiovasc. Med. 5 571–579.

    Not in our library10.1038/ncpcardio1214

  96. 96.

    Nasef A. Mathieu N. Chapel A. Frick J. François S. Mazurier C. (2007 ). Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation 84 231–237.

    Not in our library10.1097/01.tp.0000267918.07906.08

  97. 97.
    Genetic Stability of Mesenchymal Stromal Cells for Regenerative Medicine Applications: A Fundamental Biosafety Aspect · 2019
    No notice
  98. 98.

    Nürnberger S. Lindner C. Maier J. Strohmeier K. Wurzer C. Slezak P. (2019 ). Adipose-tissue-derived therapeutic cells in their natural environment as an autologous cell therapy strategy: the microtissue-stromal vascular fraction. Eur. Cell Mater. 37 113–133.

    Not in our library10.22203/ecm.v037a08

  99. 99.

    Ock S. A. Lee Y. M. Park J. S. Shivakumar S. B. Moon S. W. Sung N. J. (2016 ). Evaluation of phenotypic, functional and molecular characteristics of porcine mesenchymal stromal/stem cells depending on donor age, gender and tissue source. J. Vet. Med. Sci. 78 987–995.

    Not in our library10.1292/jvms.15-0596

  100. 100.

    Oh S. H. Choi C. Chang D. J. Shin D. A. Lee N. Jeon I. (2015 ). Early neuroprotective effect with lack of long-term cell replacement effect on experimental stroke after intra-arterial transplantation of adipose-derived mesenchymal stromal cells. Cytotherapy 17 1090–1103.

    Not in our library10.1016/j.jcyt.2015.04.007

  101. 101.
    Stem cells isolated from adipose tissue of obese patients show changes in their transcriptomic profile that indicate loss in stemcellness and increased commitment to an adipocyte-like phenotype · 2013
    No notice
  102. 102.

    Oñate B. Vilahur G. Ferrer-Lorente R. Ybarra J. Díez-Caballero A. Ballesta-López C. (2012 ). The subcutaneous adipose tissue reservoir of functionally active stem cells is reduced in obese patients. FASEB J. 26 4327–4336.

    Not in our library10.1096/fj.12-207217

  103. 103.

    Onesti M. G. Carella S. Ceccarelli S. Marchese C. Scuderi N. (2016 ). The use of human adipose-derived stem cells in the treatment of physiological and pathological vulvar dystrophies. Stem Cells Int. 2016:2561461.

    Not in our library10.1155/2016/2561461

  104. 104.

    Panés J. García-Olmo D. Van Assche G. Colombel J. F. Reinisch W. Baumgart D. C. (2016 ). Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet 388 1281–1290.

    Not in our library10.1016/s0140-6736(16)31203-x

  105. 105.

    Park I. S. Chung P. S. Ahn J. C. (2017 ). Adipose-derived stem cell spheroid treated with low-level light irradiation accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia. Cytotherapy 19 1070–1078.

    Not in our library10.1016/j.jcyt.2017.06.005

  106. 106.
    Adipose Tissue-Derived Mesenchymal Stem Cells Induce Expansion of Interleukin-10-Producing Regulatory B Cells and Ameliorate Autoimmunity in a Murine Model of Systemic Lupus Erythematosus · 2015
    Not checked
  107. 107.

    Patrikoski M. Sivula J. Huhtala H. Helminen M. Salo F. Mannerström B. (2014 ). Different culture conditions modulate the immunological properties of adipose stem cells. Stem Cells Transl. Med. 3 1220–1230.

    Not in our library10.5966/sctm.2013-0201

  108. 108.

    Payne N. L. Dantanarayana A. Sun G. Moussa L. Caine S. McDonald C. (2012 ). Early intervention with gene-modified mesenchymal stem cells overexpressing interleukin-4 enhances anti-inflammatory responses and functional recovery in experimental autoimmune demyelination. Cell Adhes. Migr. 6 179–189.

    Not in our library10.4161/cam.20341

  109. 109.

    Peng Y. Chen X. Liu Q. Zhang X. Huang K. Liu L. (2015 ). Mesenchymal stromal cells infusions improve refractory chronic graft versus host disease through an increase of CD5+ regulatory B cells producing interleukin 10. Leukemia 29 636–646.

    Not in our library10.1038/leu.2014.225

  110. 110.

    Pers Y.-M. Rackwitz L. Ferreira R. Pullig O. Delfour C. Barry F. (2016 ). Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase i dose-escalation trial. Stem Cells Transl. Med. 5 847–856.

    Not in our library10.5966/sctm.2015-0245

  111. 111.

    Planat-Bénard V. Menard C. André M. Puceat M. Perez A. Garcia-Verdugo J. M. (2004 ). Spontaneous cardiomyocyte differentiation from adipose tissue stroma cells. Circ. Res. 94 223–229.

    Not in our library10.1161/01.res.0000109792.43271.47

  112. 112.

    Policha A. Zhang P. Chang L. Lamb K. Tulenko T. DiMuzio P. (2014 ). Endothelial differentiation of diabetic adipose-derived stem cells. J. Surg. Res. 192 656–663.

    Not in our library10.1016/j.jss.2014.06.041

  113. 113.

    Poloni A. Maurizi G. Ciarlantini M. Medici M. Mattiucci D. Mancini S. (2015 ). Interaction between human mature adipocytes and lymphocytes induces T-cell proliferation. Cytotherapy 17 1292–1301.

    Not in our library10.1016/j.jcyt.2015.06.007

  114. 114.

    Puissant B. Barreau C. Bourin P. Clavel C. Corre J. Bousquet C. (2005 ). Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br. J. Haematol. 129 118–129.

    Not in our library10.1111/j.1365-2141.2005.05409.x

  115. 115.

    Qi H. Chen G. Huang Y. Si Z. Li J. (2015 ). Foxp3-modified bone marrow mesenchymal stem cells promotes liver allograft tolerance through the generation of regulatory T cells in rats. J. Transl. Med. 13:274.

    Not in our library10.1186/s12967-015-0638-2

  116. 116.

    Regmi S. Pathak S. Thanh T. P. Nguyen T. T. Sung J. H. Yook S. (2019 ). Intraportally delivered stem cell spheroids localize in the liver and protect hepatocytes against GalN/LPS-induced fulminant hepatic toxicity. Stem Cell Res. Ther. 10:230.

    Not in our library10.1186/s13287-019-1337-3

  117. 117.
    Mesenchymal stem cells from umbilical cord matrix, adipose tissue and bone marrow exhibit different capability to suppress peripheral blood B, natural killer and T cells · 2013
    No notice
  118. 118.

    Russell K. A. Chow N. H. C. Dukoff D. Gibson T. W. G. La Marre J. Betts D. H. (2016 ). Characterization and immunomodulatory effects of canine adipose tissue- and bone marrow-derived mesenchymal stromal cells. PLoS One 11:e0167442.

    Not in our library10.1371/journal.pone.0167442

  119. 119.

    Ryan J. M. Barry F. Murphy J. M. Mahon B. P. (2007 ). Interferon-γ does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin. Exp. Immunol. 149 353–363.

    Not in our library10.1111/j.1365-2249.2007.03422.x

  120. 120.

    Sabia C. Picascia A. Grimaldi V. Amarelli C. Maiello C. Napoli C. (2017 ). The epigenetic promise to improve prognosis of heart failure and heart transplantation. Transplant. Rev. 31 249–256.

    Not in our library10.1016/j.trre.2017.08.004

  121. 121.
    Human Adipose-Derived Stromal Cells for Cell-Based Therapies in the Treatment of Systemic Sclerosis · 2013
    Not checked
  122. 122.

    Semon J. A. Maness C. Zhang X. Sharkey S. A. Beuttler M. M. Shah F. S. (2014 ). Comparison of human adult stem cells from adipose tissue and bone marrow in the treatment of experimental autoimmune encephalomyelitis. Stem Cell Res. Ther. 5:2.

    Not in our library10.1186/scrt391

  123. 123.

    Seo Y. Shin T. H. Kim H. S. (2019 ). Current strategies to enhance adipose stem cell function: an update. Int. J. Mol. Sci. 20:E3827.

    Not in our library10.3390/ijms20153827

  124. 124.

    Serena C. Keiran N. Ceperuelo-Mallafre V. Ejarque M. Fradera R. Roche K. (2016 ). Obesity and type 2 diabetes alters the immune properties of human adipose derived stem cells. Stem Cells 34 2559–2573.

    Not in our library10.1002/stem.2429

  125. 125.

    Sheng H. Wang Y. Jin Y. Zhang Q. Zhang Y. Wang L. (2008 ). A critical role of IFNγ in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res. 18 846–857.

    Not in our library10.1038/cr.2008.80

  126. 126.

    Shingyochi Y. Orbay H. Mizuno H. (2015 ). Adipose-derived stem cells for wound repair and regeneration. Expert Opin. Biol. Ther. 15 1285–1292.

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    Shu W. Shu Y. T. Dai C. Y. Zhen Q. Z. (2012 ). Comparing the biological characteristics of adipose tissue-derived stem cells of different persons. J. Cell. Biochem. 113 2020–2026.

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    Soleymaninejadian E. Pramanik K. Samadian E. (2012 ). Immunomodulatory properties of mesenchymal stem cells: cytokines and factors. Am. J. Reprod. Immunol. 67 1–8.

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    Sommese L. Zullo A. Schiano C. Mancini F. P. Napoli C. (2017 ). Possible muscle repair in the human cardiovascular system. Stem Cell Rev. Rep. 13 170–191.

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    Sotiropoulou P. A. Perez S. A. Salagianni M. Baxevanis C. N. Papamichail M. (2006 ). Cell culture medium composition and translational adult bone marrow-derived stem cell research. Stem Cells 24 1409–1410.

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    Sovrea A. S. Bosca A. B. Constantin A. M. Dronca E. Ilea A. (2019 ). State of the art in human adipose stem cells and their role in therapy. Rom. J. Morphol. Embryol. 60 7–31.

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    Staff N. P. Madigan N. N. Morris J. Jentoft M. Sorenson E. J. Butler G. (2016 ). Safety of intrathecal autologous adipose-derived mesenchymal stromal cells in patients with ALS. Neurology 87 2230–2234.

    Not in our library10.1212/wnl.0000000000003359

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    Strioga M. Viswanathan S. Darinskas A. Slaby O. Michalek J. (2012 ). Same or not the same? comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev. 21 2724–2752.

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    Sun M. Sun L. Huang C. Chen B. C. Zhou Z. (2019 ). Induction of macrophage M2b/c polarization by adipose tissue-derived mesenchymal stem cells. J. Immunol. Res. 2019:7059680.

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    Teklemariam T. Purandare B. Zhao L. Hantash B. M. (2014 ). Inhibition of DNA methylation enhances HLA-G expression in human mesenchymal stem cells. Biochem. Biophys. Res. Commun. 452 753–759.

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    Tholpady S. S. Ogle R. C. Katz A. J. (2009 ). Adipose stem cells and solid organ transplantation. Curr. Opin. Organ. Transplant. 14 51–55.

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    Tögel F. Hu Z. Weiss K. Isaac J. Lange C. Westenfelder C. (2005 ). Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am. J. Physiol. Renal Physiol. 289 F31–F42.

    Not in our library10.1152/ajprenal.00007.2005

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    Ueyama H. Okano T. Orita K. Mamoto K. Sobajima S. Iwaguro H. (2020 ). Local transplantation of adipose-derived stem cells has a significant therapeutic effect in a mouse model of rheumatoid arthritis. Sci. Rep. 10:3076.

    Not in our library10.1038/s41598-020-60041-2

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    Valencia J. Blanco B. Yáñez R. Vázquez M. Herrero Sánchez C. Fernández-García M. (2016 ). Comparative analysis of the immunomodulatory capacities of human bone marrow– and adipose tissue–derived mesenchymal stromal cells from the same donor. Cytotherapy 18 1297–1311.

    Not in our library10.1016/j.jcyt.2016.07.006

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    Valina C. Pinkernell K. Song Y. H. Bai X. Sadat S. Campeau R. J. (2007 ). Intracoronary administration of autologous adipose tissue-derived stem cells improves left ventricular function, perfusion, and remodelling after acute myocardial infarction. Eur. Heart J. 28 2667–2677.

    Not in our library10.1093/eurheartj/ehm426

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    Vanikar A. V. Dave S. D. Thakkar U. G. Trivedi H. L. (2010 ). Cotransplantation of adipose tissue-derived insulin-secreting mesenchymal stem cells and hematopoietic stem cells: a novel therapy for insulin-dependent diabetes mellitus. Stem Cells Int. 2010 582382.

    Not in our library10.4061/2010/582382

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    Systematic review of patient factors affecting adipose stem cell viability and function: implications for regenerative therapy · 2017
    No notice
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    Velier M. Simoncini S. Abellan M. Francois P. Eap S. Lagrange A. (2019 ). Adipose-derived stem cells from systemic sclerosis patients maintain pro-angiogenic and antifibrotic paracrine effects in vitro. J. Clin. Med. 8:E1979.

    Not in our library10.3390/jcm8111979

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    Voog J. Jones D. L. (2010 ). Stem cells and the niche: a dynamic duo. Cell Stem Cell 6 103–115.

    Not in our library10.1016/j.stem.2010.01.011

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    Characteristics and Immunomodulating Functions of Adipose-Derived and Bone Marrow-Derived Mesenchymal Stem Cells Across Defined Human Leukocyte Antigen Barriers · 2018
    Not checked
  146. 146.

    Wang Y. H. Huang X. H. Yang Y. M. He Y. Dong X. H. Yang H. X. (2019 ). Mysm1 epigenetically regulates the immunomodulatory function of adipose-derived stem cells in part by targeting miR-150. J. Cell. Mol. Med. 23 3737–3746.

    Not in our library10.1111/jcmm.14281

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    A New Mesenchymal Stem Cell (MSC) Paradigm: Polarization into a Pro-Inflammatory MSC1 or an Immunosuppressive MSC2 Phenotype · 2010
    No notice
  148. 148.
    3D spheroid culture enhances survival and therapeutic capacities of MSC s injected into ischemic kidney · 2016
    No notice
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    Yan Y. Ma T. Gong K. Ao Q. Zhang X. Gong Y. (2014 ). Adipose-derived mesenchymal stem cell transplantation promotes adult neurogenesis in the brains of Alzheimer’s disease mice. Neural Regen. Res. 9 798–805.

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    Yañez R. Lamana M. L. García-Castro J. Colmenero I. Ramírez M. Bueren J. A. (2006 ). Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells 24 2582–2591.

    Not in our library10.1634/stemcells.2006-0228

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    The Relative Contribution of Paracine Effect versus Direct Differentiation on Adipose-Derived Stem Cell Transplantation Mediated Cardiac Repair · 2013
    No notice
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    Yang H. M. Sung J. H. Choi Y. S. Lee H. J. Roh C. R. Kim J. (2012 ). Enhancement of the immunosuppressive effect of human adipose tissue-derived mesenchymal stromal cells through HLA-G1 expression. Cytotherapy 14 70–79.

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    Yokota N. Yamakawa M. Shirata T. Kimura T. Kaneshima H. (2017 ). Clinical results following intra-articular injection of adipose-derived stromal vascular fraction cells in patients with osteoarthritis of the knee. Regen. Ther. 6 108–112.

    Not in our library10.1016/j.reth.2017.04.002

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    Yousefi F. Ebtekar M. Soleimani M. Soudi S. Hashemi S. M. (2013 ). Comparison of in vivo immunomodulatory effects of intravenous and intraperitoneal administration of adipose-tissue mesenchymal stem cells in experimental autoimmune encephalomyelitis (EAE). Int. Immunopharmacol. 17 608–616.

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    Yu B. Yu D. Cao L. Zhao X. Long T. Liu G. (2011 ). Simulated microgravity using a rotary cell culture system promotes chondrogenesis of human adipose-derived mesenchymal stem cells via the p38 MAPK pathway. Biochem. Biophys. Res. Commun. 414 412–418.

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    Zhao N. Li H. Yan Y. Jiang R. He X. (2017 ). Mesenchymal stem cells overexpressing IL-35 effectively inhibit CD4+ T cell function. Cell. Immunol. 312 61–66.

    Not in our library10.1016/j.cellimm.2016.12.001

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    Zhao S. Wehner R. Bornhäuser M. Wassmuth R. Bachmann M. Schmitz M. (2010 ). Immunomodulatory properties of mesenchymal stromal cells and their therapeutic consequences for immune-mediated disorders. Stem Cells Dev. 19 607–614.

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    Zhou K. Guo S. Tong S. Sun Q. Li F. Zhang X. (2018 ). Immunosuppression of human adipose-derived stem cells on T cell subsets via the reduction of NF-kappaB activation mediated by PD-L1/PD-1 and Gal-9/TIM-3 Pathways. Stem Cells Dev. 27 1191–1202.

    Not in our library10.1089/scd.2018.0033

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    Zuk P. A. Zhu M. Ashjian P. De Ugarte D. A. Huang J. I. Mizuno H. (2002 ). Human adipose tissue is a source of multipotent stem cells. Mol. Biol. Cell 13 4279–4295.

    Not in our library10.1091/mbc.e02-02-0105

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    Zuk P. A. Zhu M. Mizuno H. Huang J. Futrell J. W. Katz A. J. (2001 ). Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 7 211–228.

    Not in our library10.1089/107632701300062859

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