Abstract
Dedifferentiated fat cells (DFATs), which are originated by the dedifferentiation of adipocytes, display surface markers of mesenchymal stem cells and are able to differentiate into different cell types, thus, yielding a huge therapeutic potential in repairing damaged tissues and organs. The use of allogeneic stem cells from healthy donors constitutes the basis of a new strategy for cell therapy in the field of transplantation and the first requirement for allografts is determining their immunological properties. In this study, human DFATs and ADSCs were passaged as in vitro models to investigate their immunomodulatory effects. Phenotypic analysis of cell surface markers and three-line differentiation protocols were used to identify stem cells. The immunogenic phenotypes of DFATs and ADSCs were analyzed by flow cytometry and a mixed lymphocyte reaction was used to assess their immune function. The characteristics of stem cells were confirmed by phenotypic identification of cell surface markers and three-line differentiation. Flow cytometry analysis showed that P3 generation DFATs and ADSCs contained human leukocyte antigen (HLA) class I molecules, but did not express HLA class II molecules and costimulatory molecules CD40, CD80 and CD86. Moreover, allogeneic DFATs and ADSCs could not induce the proliferation of peripheral blood mononuclear cells (PBMCs). In addition, both populations were shown to inhibit the Concanavalin A-stimulated proliferation of PBMCs and act as third-party cells responsible for inhibiting the mixed lymphocyte response. DFATs have immunosuppressive properties similar to ADSCs. Based on this, allogeneic DFATs have potential applications in tissue repair or cell therapy.
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References
Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822
Akita D, Kazama T, Tsukimura N, Taniguchi Y, Takahashi R, Arai Y, Tsurumachi-Iwasaki N, Yasuda H, Okubo T, Kano K, Matsumoto T, Honda M (2022) Transplantation of mature adipocyte-derived dedifferentiated fat cells facilitates periodontal tissue regeneration of class II furcation defects in miniature pigs. Materials (basel) 4:1311
Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, Hardy W, Devine S, Ucker D, Deans R, Moseley A, Hoffman R (2002) Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 30:42–48
Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H, Galun E, Rachmilewitz J (2005) Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 105:2214–2219
Bollmann A, Sons HC, Schiefer JL, Fuchs PC, Windolf J, Suschek CV (2022) Comparative study of the osteogenic differentiation potential of adipose tissue-derived stromal cells and dedifferentiated adipose cells of the same tissue origin under pro and antioxidant conditions. Biomedicines 12:3071
Bourin P, Bunnell BA, Casteilla L, Dominici M, Katz AJ, March KL, Redl H, Rubin JP, Yoshimura K, Gimble JM (2013) Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy 15:641–648
Bunnell BA, Flaat M, Gagliardi C, Patel B, Ripoll C (2008) Adipose-derived stem cells: isolation, expansion and differentiation. Methods 45:115–120
Chen PM, Yen ML, Liu KJ, Sytwu HK, Yen BL (2011) Immunomodulatory properties of human adult and fetal multipotent mesenchymal stem cells. J Biomed Sci 18:49
Chen J, Wang Y, Hu H, Xiong Y, Wang S, Yang J (2021) Adipose-derived cellular therapies prolong graft survival in an allogenic hind limb transplantation model. Stem Cell Res Ther 12:94
Cui L, Yin S, Liu W, Li N, Zhang W, Cao Y (2007) Expanded adipose-derived stem cells suppress mixed lymphocyte reaction by secretion of prostaglandin E2. Tissue Eng 13:1185–1195
Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99:3838–3843
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317
English K, Ryan JM, Tobin L, Murphy MJ, Barry FP, Mahon BP (2009) Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells. Clin Exp Immunol 156:149–160
Fang B, Song YP, Liao LM, Han Q, Zhao RC (2006) Treatment of severe therapy-resistant acute graft-versus-host disease with human adipose tissue-derived mesenchymal stem cells. Bone Marrow Transpl 38:389–390
Fang B, Song Y, Liao L, Zhang Y, Zhao RC (2007a) Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease. Transpl Proc 39:3358–3362
Fang B, Song Y, Lin Q, Zhang Y, Cao Y, Zhao RC, Ma Y (2007b) Human adipose tissue-derived mesenchymal stromal cells as salvage therapy for treatment of severe refractory acute graft-vs.-host disease in two children. Pediatr Transpl 11:814–817
Fang B, Song Y, Zhao RC, Han Q, Lin Q (2007c) Using human adipose tissue-derived mesenchymal stem cells as salvage therapy for hepatic graft-versus-host disease resembling acute hepatitis. Transpl Proc 39:1710–1713
Fang B, Song YP, Li N, Li J, Han Q, Zhao RC (2009) Resolution of refractory chronic autoimmune thrombocytopenic purpura following mesenchymal stem cell transplantation: a case report. Transpl Proc 41:1827–1830
Fernyhough ME, Vierck JL, Hausman GJ, Mir PS, Okine EK, Dodson MV (2004) Primary adipocyte culture: adipocyte purification methods may lead to a new understanding of adipose tissue growth and development. Cytotechnology 46:163–172
Figiel-Dabrowska A, Radoszkiewicz K, Rybkowska P, Krzesniak NE, Sulejczak D, Sarnowska A (2021) Neurogenic and neuroprotective potential of stem/stromal cells derived from adipose tissue. Cells 10:1475
Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F (2005) Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105:2821–2827
Gonzalez-Rey E, Gonzalez MA, Varela N, O’Valle F, Hernandez-Cortes P, Rico L, Büscher D, Delgado M (2010) Human adipose-derived mesenchymal stem cells reduce inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid arthritis. Ann Rheum Dis 69:241–248
Huang G, Xia B, Dai Z, Yang R, Chen R, Yang H (2022) Comparative study of dedifferentiated fat cell and adipose-derived stromal cell sheets for periodontal tissue regeneration: in vivo and in vitro evidence. J Clin Periodontol. https://doi.org/10.1111/jcpe.13705
Izadpanah R, Trygg C, Patel B, Kriedt C, Dufour J, Gimble JM, Bunnell BA (2006) Biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue. J Cell Biochem 99:1285–1297
Kashimura T, Soejima K, Asami T, Kazama T, Matsumoto T, Nakazawa H (2016) The effect of mature adipocyte-derived dedifferentiated fat (DFAT) cells on a dorsal skin flap model. J Invest Surg 29:6–12
Kishimoto N, Momota Y, Hashimoto Y, Tatsumi S, Ando K, Omasa T, Kotani J (2014) The osteoblastic differentiation ability of human dedifferentiated fat cells is higher than that of adipose stem cells from the buccal fat pad. Clin Oral Investig 18:1893–1901
Kuo YR, Chen CC, Goto S, Lee IT, Huang CW, Tsai CC, Wang CT, Chen CL (2011) Modulation of immune response and T-cell regulation by donor adipose-derived stem cells in a rodent hind-limb allotransplant model. Plast Reconstr Surg 128:661e–672e
Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringdén O (2003) Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 57:11–20
Matsumine H, Takeuchi Y, Sasaki R, Kazama T, Kano K, Matsumoto T, Sakurai H, Miyata M, Yamato M (2014) Adipocyte-derived and dedifferentiated fat cells promoting facial nerve regeneration in a rat model. Plast Reconstr Surg 134:686–697
McIntosh K, Zvonic S, Garrett S, Mitchell JB, Floyd ZE, Hammill L, Kloster A, Di Halvorsen Y, Ting JP, Storms RW, Goh B, Kilroy G, Wu X, Gimble JM (2006) The immunogenicity of human adipose-derived cells: temporal changes in vitro. Stem Cells 24:1246–1253
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 (2005) Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol 129:118–129
Rasmusson I, Ringdén O, Sundberg B, Le Blanc K (2003) Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 76:1208–1213
Ryu HH, Lim JH, Byeon YE, Park JR, Seo MS, Lee YW, Kim WH, Kang KS, Kweon OK (2009) Functional recovery and neural differentiation after transplantation of allogenic adipose-derived stem cells in a canine model of acute spinal cord injury. J Vet Sci 10:273–284
Sakamoto F, Hashimoto Y, Kishimoto N, Honda Y, Matsumoto N (2015) The utility of human dedifferentiated fat cells in bone tissue engineering in vitro. Cytotechnology 67:75–84
Takabatake K, Matsubara M, Yamachika E, Fujita Y, Arimura Y, Nakatsuji K, Nakano K, Nagatsuka H, Iida S (2021) Comparing the osteogenic potential and bone regeneration capacities of dedifferentiated fat cells and adipose-derived stem cells in vitro and in vivo: application of DFAT cells isolated by a mesh method. Int J Mol Sci 22:12392
Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC (2003) Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75:389–397
Wang Y, Wang X, Zhou X, Zhu Z, Yang J, Liu F (2019) Suppressive effect mediated by human adipose-derived stem cells on T cells involves the activation of JNK. Int J Mol Med 43:177–184
Wolbank S, Peterbauer A, Fahrner M, Hennerbichler S, van Griensven M, Stadler G, Redl H, Gabriel C (2007) Dose-dependent immunomodulatory effect of human stem cells from amniotic membrane: a comparison with human mesenchymal stem cells from adipose tissue. Tissue Eng 13:1173–1183
Yagi H, Soto-Gutierrez A, Parekkadan B, Kitagawa Y, Tompkins RG, Kobayashi N, Yarmush ML (2010) Mesenchymal stem cells: mechanisms of immunomodulation and homing. Cell Transpl 19:667–679
Yanagi T, Kajiya H, Fujisaki S, Maeshiba M, Yanagi-S A, Yamamoto-M N, Kakura K, Kido H, Ohno J (2021) Three-dimensional spheroids of dedifferentiated fat cells enhance bone regeneration. Regen Ther 18:472–479
Zhang J, Bai X, Zhao B, Wang Y, Su L, Chang P, Wang X, Han S, Gao J, Hu X, Hu D, Liu X (2016) Allogeneic adipose-derived stem cells promote survival of fat grafts in immunocompetent diabetic rats. Cell Tissue Res 364:357–367
Zhang J, Wang Y, Zhao B, Fan L, Bai X, Yang L, Chang P, Hu D, Liu X (2015) Allogeneic adipose-derived stem cells protect fat grafts at the early stage and improve long-term retention in immunocompetent rats. Aesthetic Plast Surg 39:625–634
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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Yan Lin and Dali Mu. The first draft of the manuscript was written by Yan Lin and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Cells were harvested with written informed consent from the donor through the Plastic Surgery Hospital, Chinese Academy of Medical Sciences. All procedures performed involving human participants in experiments were carried out per ethical standards of the institutional and/or national research committee and the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Lin, Y., Mu, D. Immunomodulatory effect of human dedifferentiated fat cells: comparison with adipose-derived stem cells. Cytotechnology 75, 231–242 (2023). https://doi.org/10.1007/s10616-023-00572-4
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DOI: https://doi.org/10.1007/s10616-023-00572-4