In regenerative medicine, adult stem cells are the most promising cell types for cell-based therapies. As a new source for multipotent stem cells, human adipose tissue has been introduced. These so called adipose tissue-derived stem cells (ADSCs) are considered to be ideal for application in regenerative therapies. Their main advantage over mesenchymal stem cells derived from other sources, e.g. from bone marrow, is that they can be easily and repeatable harvested using minimally invasive techniques with low morbidity. ADSCs are multipotent and can differentiate into various cell types of the tri-germ lineages, including e.g. osteocytes, adipocytes, neural cells, vascular endothelial cells, cardiomyocytes, pancreatic β-cells, and hepatocytes. Interestingly, ADSCs are characterized by immunosuppressive properties and low immunogenicity. Their secretion of trophic factors enforces the therapeutic and regenerative outcome in a wide range of applications. Taken together, these particular attributes of ADSCs make them highly relevant for clinical applications. Consequently, the therapeutic potential of ADSCs is enormous. Therefore, this review will provide a brief overview of the possible therapeutic applications of ADSCs with regard to their differentiation potential into the tri-germ lineages. Moreover, the relevant advancements made in the field, regulatory aspects as well as other challenges and obstacles will be highlighted.

Keywords:
Regenerative medicine, Adipose tissue-derived stem cells, Mesenchymal stem cells, Therapeutic application, Cell therapy, Tissue engineering
1.
Hyun I: The bioethics of stem cell research and therapy. J Clin Invest 2010;120:71-75.
2.
Stoltz JF, de Isla N, Li YP, Bensoussan D, Zhang L, Huselstein C, Chen Y, Decot V, Magdalou J, Li N, Reppel L, He Y: Stem cells and regenerative medicine: myth or reality of the 21th century. Stem Cells Int 2015;2015:734731.
3.
Tavassoli M, Friedenstein A: Hemopoietic stromal microenvironment. Am J Hematol 1983;15:195-203.
4.
Koobatian MT, Liang MS, Swartz DD, Andreadis ST: Differential effects of culture senescence and mechanical stimulation on the proliferation and leiomyogenic differentiation of MSC from different sources: implications for engineering vascular grafts. Tissue Eng Part A 2015;21:1364-1375.
5.
Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH: Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002;13:4279-4295.
6.
Woo DH, Hwang HS, Shim JH: Comparison of adult stem cells derived from multiple stem cell niches. Biotechnol Lett 2016;38:751-759.
7.
Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH: Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001;7:211-228.
8.
Beane OS, Fonseca VC, Cooper LL, Koren G, Darling EM: Impact of aging on the regenerative properties of bone marrow-, muscle-, and adipose-derived mesenchymal stem/stromal cells. PLoS One 2014;9:e115963.
9.
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003;112:1821-1830.
10.
Digirolamo CM, Stokes D, Colter D, Phinney DG, Class R, Prockop DJ: Propagation and senescence of human marrow stromal cells in culture: a simple colony-forming assay identifies samples with the greatest potential to propagate and differentiate. Br J Haematol 1999;107:275-281.
11.
Sterodimas A, de Faria J, Nicaretta B, Pitanguy I: Tissue engineering with adipose-derived stem cells (ADSCs): current and future applications. J Plast Reconstr Aesthet Surg 2010;63:1886-1892.
12.
Bieback K: Platelet lysate as replacement for fetal bovine serum in mesenchymal stromal cell cultures. Transfus Med Hemother 2013;40:326-335.
13.
Bourin P, Bunnell BA, Casteilla L, Dominici M, Katz AJ, March KL, Redl H, Rubin JP, Yoshimura K, Gimble JM: 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 2013;15:641-648.
14.
Oedayrajsingh-Varma MJ, van Ham SM, Knippenberg M, Helder MN, Klein-Nulend J, Schouten TE, Ritt MJ, van Milligen FJ: Adipose tissue-derived mesenchymal stem cell yield and growth characteristics are affected by the tissue-harvesting procedure. Cytotherapy 2006;8:166-177.
15.
Smith P, Adams WP Jr, Lipschitz AH, Chau B, Sorokin E, Rohrich RJ, Brown SA: Autologous human fat grafting: effect of harvesting and preparation techniques on adipocyte graft survival. Plast Reconstr Surg 2006;117:1836-1844.
16.
Wu W, Le AV, Mendez JJ, Chang J, Niklason LE, Steinbacher DM: Osteogenic performance of donor-matched human adipose and bone marrow mesenchymal cells under dynamic culture. Tissue Eng Part A 2015;21:1621-1632.
17.
Melief SM, Zwaginga JJ, Fibbe WE, Roelofs H: Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl Med 2013;2:455-463.
18.
Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J: Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev 2012;21:2724-2752.
19.
Steingen C, Brenig F, Baumgartner L, Schmidt J, Schmidt A, Bloch W: Characterization of key mechanisms in transmigration and invasion of mesenchymal stem cells. J Mol Cell Cardiol 2008;44:1072-1084.
20.
Roh JD, Sawh-Martinez R, Brennan MP, Jay SM, Devine L, Rao DA, Yi T, Mirensky TL, Nalbandian A, Udelsman B, Hibino N, Shinoka T, Saltzman WM, Snyder E, Kyriakides TR, Pober JS, Breuer CK: Tissue-engineered vascular grafts transform into mature blood vessels via an inflammation-mediated process of vascular remodeling. Proc Natl Acad Sci U S A 2010;107:4669-4674.
21.
Bertolini F, Lohsiriwat V, Petit JY, Kolonin MG: Adipose tissue cells, lipotransfer and cancer: A challenge for scientists, oncologists and surgeons. Biochim Biophys Acta 2012;1826:209-214.
22.
http://clinicaltrials.gov, 2016.
23.
Godoy Zanicotti D, Coates DE, Duncan WJ: In vivo bone regeneration on titanium devices using serum-free grown adipose-derived stem cells, in a sheep femur model. Clin Oral Implants Res 2016; doi: 10.1111/clr.12761.
24.
Lu W, Ji K, Kirkham J, Yan Y, Boccaccini AR, Kellett M, Jin Y, Yang XB: Bone tissue engineering by using a combination of polymer/bioglass composites with human adipose-derived stem cells. Cell Tissue Res 2014;356:97-107.
25.
Abudusaimi A, Aihemaitijiang Y, Wang YH, Cui L, Maimaitiming S, Abulikemu M: Adipose-derived stem cells enhance bone regeneration in vascular necrosis of the femoral head in the rabbit. J Int Med Res 2011;39:1852-1860.
26.
Lendeckel S, Jodicke A, Christophis P, Heidinger K, Wolff J, Fraser JK, Hedrick MH, Berthold L, Howaldt HP: Autologous stem cells (adipose) and fibrin glue used to treat widespread traumatic calvarial defects: case report. J Craniomaxillofac Surg 2004;32:370-373.
27.
Missana MC, Laurent I, Barreau L, Balleyguier C: Autologous fat transfer in reconstructive breast surgery: Indications, technique and results. Eur J Surg Oncol 2007;33:685-690.
28.
Weichman KE, Broer PN, Tanna N, Wilson SC, Allan A, Levine JP, Ahn C, Choi M, Karp NS, Allen R: The role of autologous fat grafting in secondary microsurgical breast reconstruction. Ann Plast Surg 2013;71:24-30.
29.
Suga H, Eto H, Shigeura T, Inoue K, Aoi N, Kato H, Nishimura S, Manabe I, Gonda K, Yoshimura K: IFATS collection: fibroblast growth factor-2-induced hepatocyte growth factor secretion by adipose-derived stromal cells inhibits postinjury fibrogenesis through a c-Jun N-terminal kinase-dependent mechanism. Stem Cells 2009;27:238-249.
30.
Steinstraesser L, Flak E, Witte B, Ring A, Tilkorn D, Hauser J, Langer S, Steinau HU, Al-Benna S: Pressure garment therapy alone and in combination with silicone for the prevention of hypertrophic scarring: randomized controlled trial with intraindividual comparison. Plast Reconstr Surg 2011;128:306e-313e.
31.
Zhang Q, Liu LN, Yong Q, Deng JC, Cao WG: Intralesional injection of adipose-derived stem cells reduces hypertrophic scarring in a rabbit ear model. Stem Cell Res Ther 2015;6:145.
32.
Li G, Fu N, Xie J, Fu Y, Deng S, Cun X, Wei X, Peng Q, Cai X, Lin Y: Poly(3-hydroxybutyrate-co-4-hydroxybutyrate) based electrospun 3D scaffolds for delivery of autogeneic chondrocytes and adipose-derived stem cells: evaluation of cartilage defects in rabbit. J Biomed Nanotechnol 2015;11:105-116.
33.
Latief N, Raza FA, Bhatti FU, Tarar MN, Khan SN, Riazuddin S: Adipose stem cells differentiated chondrocytes regenerate damaged cartilage in rat model of osteoarthritis. Cell Biol Int 2016;40:579-588.
34.
Zhong J, Guo B, Xie J, Deng S, Fu N, Lin S, Li G, Lin Y, Cai X: Crosstalk between adipose-derived stem cells and chondrocytes: when growth factors matter. Bone Res 2016;4:15036.
35.
Schaun MI, Eibel B, Kristocheck M, Sausen G, Machado L, Koche A, Markoski MM: Cell therapy in ischemic heart disease: interventions that modulate cardiac regeneration. Stem Cells Int 2016;2016:2171035.
36.
Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS, Dzau VJ: Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 2005;11:367-368.
37.
Valina C, Pinkernell K, Song YH, Bai X, Sadat S, Campeau RJ, Le Jemtel TH, Alt E: Intracoronary administration of autologous adipose tissue-derived stem cells improves left ventricular function, perfusion, and remodelling after acute myocardial infarction. Eur Heart J 2007;28:2667-2677.
38.
Nagata H, Ii M, Kohbayashi E, Hoshiga M, Hanafusa T, Asahi M: Cardiac adipose-derived stem cells exhibit high differentiation potential to cardiovascular cells in C57BL/6 mice. Stem Cells Transl Med 2016;5:141-151.
39.
Frese L, Sanders B, Beer GM, Weber B, Driessen-Mol A, Baaijens FPT, Hoerstrup SP: Adipose derived tissue engineered heart valve. J Tissue Sci Eng 2015;6:156.
40.
Colazzo F, Chester AH, Taylor PM, Yacoub MH: Induction of mesenchymal to endothelial transformation of adipose-derived stem cells. J Heart Valve Dis 2010;19:736-744.
41.
Madhu V, Dighe AS, Cui Q, Deal DN: Dual inhibition of activin/nodal/TGF-beta and BMP signaling pathways by SB431542 and dorsomorphin induces neuronal differentiation of human adipose derived stem cells. Stem Cells Int 2016;2016:1035374.
42.
Radtke C, Schmitz B, Spies M, Kocsis JD, Vogt PM: Peripheral glial cell differentiation from neurospheres derived from adipose mesenchymal stem cells. Int J Dev Neurosci 2009;27:817-823.
43.
Gutierrez-Fernandez M, Otero-Ortega L, Ramos-Cejudo J, Rodriguez-Frutos B, Fuentes B, Diez-Tejedor E: Adipose tissue-derived mesenchymal stem cells as a strategy to improve recovery after stroke. Expert Opin Biol Ther 2015;15:873-881.
44.
Schwerk A, Altschuler J, Roch M, Gossen M, Winter C, Berg J, Kurtz A, Akyuz L, Steiner B: Adipose-derived human mesenchymal stem cells induce long-term neurogenic and anti-inflammatory effects and improve cognitive but not motor performance in a rat model of Parkinson's disease. Regen Med 2015;10:431-446.
45.
Hao L, Zou Z, Tian H, Zhang Y, Zhou H, Liu L: Stem cell-based therapies for ischemic stroke. Biomed Res Int 2014;2014:468748.
46.
Zhou F, Gao S, Wang L, Sun C, Chen L, Yuan P, Zhao H, Yi Y, Qin Y, Dong Z, Cao L, Ren H, Zhu L, Li Q, Lu B, Liang A, Xu GT, Zhu H, Gao Z, Ma J, Xu J, Chen X: Human adipose-derived stem cells partially rescue the stroke syndromes by promoting spatial learning and memory in mouse middle cerebral artery occlusion model. Stem Cell Res Ther 2015;6:92.
47.
Xu D, Nishimura T, Zheng M, Wu M, Su H, Sato N, Lee G, Michie S, Glenn J, Peltz G: Enabling autologous human liver regeneration with differentiated adipocyte stem cells. Cell Transplant 2014;23:1573-1584.
48.
Seo MJ, Suh SY, Bae YC, Jung JS: Differentiation of human adipose stromal cells into hepatic lineage in vitro and in vivo. Biochem Biophys Res Commun 2005;328:258-264.
49.
Lee J, Han DJ, Kim SC: In vitro differentiation of human adipose tissue-derived stem cells into cells with pancreatic phenotype by regenerating pancreas extract. Biochem Biophys Res Commun 2008;375:547-551.
50.
Hefei W, Yu R, Haiqing W, Xiao W, Jingyuan W, Dongjun L: Morphological characteristics and identification of islet-like cells derived from rat adipose-derived stem cells cocultured with pancreas adult stem cells. Cell Biol Int 2015;39:253-263.
51.
De Rosa A, De Francesco F, Tirino V, Ferraro GA, Desiderio V, Paino F, Pirozzi G, D'Andrea F, Papaccio G: A new method for cryopreserving adipose-derived stem cells: an attractive and suitable large-scale and long-term cell banking technology. Tissue Eng Part C Methods 2009;15:659-667.
52.
Schulz JC, Germann A, Kemp-Kamke B, Mazzotta A, von Briesen H, Zimmermann H: Towards a xeno-free and fully chemically defined cryopreservation medium for maintaining viability, recovery, and antigen-specific functionality of PBMC during long-term storage. J Immunol Methods 2012;382:24-31.
53.
Devitt SM, Carter CM, Dierov R, Weiss S, Gersch RP, Percec I: Successful isolation of viable adipose-derived stem cells from human adipose tissue subject to long-term cryopreservation: positive implications for adult stem cell-based therapeutics in patients of advanced age. Stem Cells Int 2015;2015:146421.
54.
Phillips MI, Tang YL: Genetic modification of stem cells for transplantation. Adv Drug Deliv Rev 2008;60:160-172.
55.
Lin L, Fu X, Zhang X, Chen LX, Zhang JY, Yu CL, Ma KT, Zhou CY: Rat adipose-derived stromal cells expressing BMP4 induce ectopic bone formation in vitro and in vivo. Acta Pharmacol Sin 2006;27:1608-1615.
56.
Shevchenko EK, Makarevich PI, Tsokolaeva ZI, Boldyreva MA, Sysoeva VY, Tkachuk VA, Parfyonova YV: Transplantation of modified human adipose derived stromal cells expressing VEGF165 results in more efficient angiogenic response in ischemic skeletal muscle. J Transl Med 2013;11:138.
57.
Yiou R, Mahrouf-Yorgov M, Trebeau C, Zanaty M, Lecointe C, Souktani R, Zadigue P, Figeac F, Rodriguez AM: Delivery of human mesenchymal adipose-derived stem cells restores multiple urological dysfunctions in a rat model mimicking radical prostatectomy damages through tissue-specific paracrine mechanisms. Stem Cells 2016;34:392-404.
58.
Fang B, Song Y, Liao L, Zhang Y, Zhao RC: Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease. Transplant Proc 2007;39:3358-3362.
59.
Lee WY, Park KJ, Cho YB, Yoon SN, Song KH, Kim do S, Jung SH, Kim M, Yoo HW, Kim I, Ha H, Yu CS: Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn's fistula. Stem Cells 2013;31:2575-2581.
60.
Garimella MG, Kour S, Piprode V, Mittal M, Kumar A, Rani L, Pote ST, Mishra GC, Chattopadhyay N, Wani MR: Adipose-derived mesenchymal stem cells prevent systemic bone loss in collagen-induced arthritis. J Immunol 2015;195:5136-5148.
61.
Rohringer S, Hofbauer P, Schneider KH, Husa AM, Feichtinger G, Peterbauer-Scherb A, Redl H, Holnthoner W: Mechanisms of vasculogenesis in 3D fibrin matrices mediated by the interaction of adipose-derived stem cells and endothelial cells. Angiogenesis 2014;17:921-933.
62.
Merfeld-Clauss S, Lupov IP, Lu H, March KL, Traktuev DO: Adipose stromal cell contact with endothelial cells results in loss of complementary vasculogenic activity mediated by induction of activin A. Stem Cells 2015;33:3039-3051.
63.
Jeong JO, Han JW, Kim JM, Cho HJ, Park C, Lee N, Kim DW, Yoon YS: Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy. Circ Res 2011;108:1340-1347.
64.
Ji SQ, Cao J, Zhang QY, Li YY, Yan YQ, Yu FX: Adipose tissue-derived stem cells promote pancreatic cancer cell proliferation and invasion. Braz J Med Biol Res 2013;46:758-764.
65.
Centeno CJ, Schultz JR, Cheever M, Freeman M, Faulkner S, Robinson B, Hanson R: Safety and complications reporting update on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther 2011;6:368-378.
66.
Zhao W, Ren G, Zhang L, Zhang Z, Liu J, Kuang P, Yin Z, Wang X: Efficacy of mesenchymal stem cells derived from human adipose tissue in inhibition of hepatocellular carcinoma cells in vitro. Cancer Biother Radiopharm 2012;27:606-613.
67.
Donnenberg VS, Zimmerlin L, Rubin JP, Donnenberg AD: Regenerative therapy after cancer: what are the risks? Tissue Eng Part B Rev 2010;16:567-575.
68.
Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA: Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007;449:557-563.
69.
Koellensperger E, Gramley F, Preisner F, Leimer U, Germann G, Dexheimer V: Alterations of gene expression and protein synthesis in co-cultured adipose tissue-derived stem cells and squamous cell-carcinoma cells: consequences for clinical applications. Stem Cell Res Ther 2014;5:65.
70.
Alvaro-Gracia JM, Jover JA, Garcia-Vicuna R, Carreno L, Alonso A, Marsal S, Blanco F, Martinez-Taboada VM, Taylor P, Martin-Martin C, DelaRosa O, Tagarro I, Diaz-Gonzalez F: Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib/IIa clinical trial. Ann Rheum Dis 2016; doi: 10.1136/annrheumdis-2015- 208918.
© 2016 S. Karger GmbH, Freiburg
2016
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.