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REVIEW
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Adipose-derived cells: building blocks of three-dimensional microphysiological systems

Trivia P. Frazier1* ,  Katie Hamel1 ,  Xiying Wu1 ,  Emma Rogers1 ,  Haley Lassiter1 ,  Jordan Robinson1 ,  Omair Mohiuddin2 ,  Michael Henderson1 ,  Jeffrey M. Gimble1
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1 Obatala Sciences Inc., New Orleans, LA, USA
2 Dr. Panjwani Center for Molecular Medicine and Drug Research, International Centre for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
BMT 2021 , 2(4), 301–306; https://doi.org/10.12336/biomatertransl.2021.04.005
Submitted: 5 November 2021 | Revised: 15 December 2021 | Accepted: 20 December 2021 | Published: 28 December 2021
Copyright © 2021 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution–NonCommercial–ShareAlike 4.0 License.
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Abstract

Microphysiological systems (MPS) created with human-derived cells and biomaterial scaffolds offer a potential in vitro alternative to in vivo animal models. The adoption of three-dimensional MPS models has economic, ethical, regulatory, and scientific implications for the fields of regenerative medicine, metabolism/obesity, oncology, and pharmaceutical drug discovery. Key opinion leaders acknowledge that MPS tools are uniquely positioned to aid in the objective to reduce, refine, and eventually replace animal experimentation while improving the accuracy of the finding’s clinical translation. Adipose tissue has proven to be an accessible and available source of human-derived stromal vascular fraction (SVF) cells, a heterogeneous population available at point of care, and adipose-derived stromal/stem cells, a relatively homogeneous population requiring plastic adherence and culture expansion of the SVF cells. The adipose-derived stromal/stem cells or SVF cells, in combination with human tissue or synthetic biomaterial scaffolds, can be maintained for extended culture periods as three-dimensional MPS models under angiogenic, stromal, adipogenic, or osteogenic conditions. This review highlights recent literature relating to the versatile use of adipose-derived cells as fundamental components of three-dimensional MPS models for discovery research and development. In this context, it compares the merits and limitations of the adipose-derived stromal/stem cells relative to SVF cell models and considers the likely directions that this emerging field of scientific discovery will take in the near future.

Keywords
adipose-derived stromal/stem cells ; extracellular matrix ; Food and Drug Administration ; microphysiological systems ; stromal vascular fraction cells ; three dimensional
References

Below is the content of the Citations in the paper which has been de-formatted, however, the content stays consistent with the original.

1. Langer, R.; Vacanti, J. P. Tissue engineering. Science. 1993, 260, 920-926.  
2. Prestwich, G. D. Simplifying the extracellular matrix for 3-D cell culture and tissue engineering: a pragmatic approach. J Cell Biochem. 2007, 101, 1370-1383.  
3. Prestwich, G. D. Evaluating drug efficacy and toxicology in three dimensions: using synthetic extracellular matrices in drug discovery. Acc Chem Res. 2008, 41, 139-148.  
4. Prestwich, G. D.; Liu, Y.; Yu, B.; Shu, X. Z.; Scott, A. 3-D culture in synthetic extracellular matrices: new tissue models for drug toxicology and cancer drug discovery. Adv Enzyme Regul. 2007, 47, 196-207.  
5. Sutherland, M. L.; Fabre, K. M.; Tagle, D. A. The National Institutes of Health Microphysiological Systems Program focuses on a critical challenge in the drug discovery pipeline. Stem Cell Res Ther. 2013, 4 Suppl 1, I1.  
6. Marx, U.; Akabane, T.; Andersson, T. B.; Baker, E.; Beilmann, M.; Beken, S.; Brendler-Schwaab, S.; Cirit, M.; David, R.; Dehne, E. M.; Durieux, I.; Ewart, L.; Fitzpatrick, S. C.; Frey, O.; Fuchs, F.; Griffith, L. G.; Hamilton, G. A.; Hartung, T.; Hoeng, J.; Hogberg, H.; Hughes, D. J.; Ingber, D. E.; Iskandar, A.; Kanamori, T.; Kojima, H.; Kuehnl, J.; Leist, M.; Li, B.; Loskill, P.; Mendrick, D. L.; Neumann, T.; Pallocca, G.; Rusyn, I.; Smirnova, L.; Steger-Hartmann, T.; Tagle, D. A.; Tonevitsky, A.; Tsyb, S.; Trapecar, M.; Van de Water, B.; Van den Eijnden-van Raaij, J.; Vulto, P.; Watanabe, K.; Wolf, A.; Zhou, X.; Roth, A. Biology-inspired microphysiological systems to advance patient benefit and animal welfare in drug development. Altex. 2020, 37, 365-394.  
7. Watson, D. E.; Hunziker, R.; Wikswo, J. P. Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology. Exp Biol Med (Maywood). 2017, 242, 1559-1572.  
8. Thomas, E. D., Sr. Stem cell transplantation: past, present and future. Stem Cells. 1994, 12, 539-544.  
9. Zuk, P. A.; Zhu, M.; Mizuno, H.; Huang, J.; Futrell, J. W.; Katz, A. J.; Benhaim, P.; Lorenz, H. P.; Hedrick, M. H. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001, 7, 211-228.  
10. Bourin, P.; Bunnell, B. A.; Casteilla, L.; Dominici, M.; Katz, A. J.; March, K. L.; Redl, H.; Rubin, J. P.; Yoshimura, K.; Gimble, J. M. 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.  
11. DeLany, J. P.; Floyd, Z. E.; Zvonic, S.; Smith, A.; Gravois, A.; Reiners, E.; Wu, X.; Kilroy, G.; Lefevre, M.; Gimble, J. M. Proteomic analysis of primary cultures of human adipose-derived stem cells: modulation by Adipogenesis. Mol Cell Proteomics. 2005, 4, 731-740.  
12. Zvonic, S.; Lefevre, M.; Kilroy, G.; Floyd, Z. E.; DeLany, J. P.; Kheterpal, I.; Gravois, A.; Dow, R.; White, A.; Wu, X.; Gimble, J. M. Secretome of primary cultures of human adipose-derived stem cells: modulation of serpins by adipogenesis. Mol Cell Proteomics. 2007, 6, 18-28.  
13. Kheterpal, I.; Ku, G.; Coleman, L.; Yu, G.; Ptitsyn, A. A.; Floyd, Z. E.; Gimble, J. M. Proteome of human subcutaneous adipose tissue stromal vascular fraction cells versus mature adipocytes based on DIGE. J Proteome Res. 2011, 10, 1519-1527.  
14. Martin, E. C.; Qureshi, A. T.; Dasa, V.; Freitas, M. A.; Gimble, J. M.; Davis, T. A. MicroRNA regulation of stem cell differentiation and diseases of the bone and adipose tissue: perspectives on miRNA biogenesis and cellular transcriptome. Biochimie. 2016, 124, 98-111.  
15. Hicok, K. C.; Hedrick, M. H. Automated isolation and processing of adipose-derived stem and regenerative cells. Methods Mol Biol. 2011, 702, 87-105.  
16. Williams, S. K.; Kosnik, P. E.; Kleinert, L. B.; Vossman, E. M.; Lye, K. D.; Shine, M. H. Adipose stromal vascular fraction cells isolated using an automated point of care system improve the patency of expanded polytetrafluoroethylene vascular grafts. Tissue Eng Part A. 2013, 19, 1295-1302.  
17. Williams, S. K.; Morris, M. E.; Kosnik, P. E.; Lye, K. D.; Gentzkow, G. D.; Ross, C. B.; Dwevidi, A. J.; Kleinert, L. B. Point-of-care adipose-derived stromal vascular fraction cell isolation and expanded polytetrafluoroethylene graft sodding. Tissue Eng Part C Methods. 2017, 23, 497-504.  
18. Brown, J. C.; Shang, H.; Li, Y.; Yang, N.; Patel, N.; Katz, A. J. Isolation of adipose-derived stromal vascular fraction cells using a novel point-of-care device: cell characterization and review of the literature. Tissue Eng Part C Methods. 2017, 23, 125-135.  
19. Doi, K.; Tanaka, S.; Iida, H.; Eto, H.; Kato, H.; Aoi, N.; Kuno, S.; Hirohi, T.; Yoshimura, K. Stromal vascular fraction isolated from lipo-aspirates using an automated processing system: bench and bed analysis. J Tissue Eng Regen Med. 2013, 7, 864-870.  
20. Güven, S.; Karagianni, M.; Schwalbe, M.; Schreiner, S.; Farhadi, J.; Bula, S.; Bieback, K.; Martin, I.; Scherberich, A. Validation of an automated procedure to isolate human adipose tissue-derived cells by using the Sepax® technology. Tissue Eng Part C Methods. 2012, 18, 575-582.  
21. SundarRaj, S.; Deshmukh, A.; Priya, N.; Krishnan, V. S.; Cherat, M.; Majumdar, A. S. Development of a system and method for automated isolation of stromal vascular fraction from adipose tissue lipoaspirate. Stem Cells Int. 2015, 2015, 109353.  
22. Hanke, A.; Prantl, L.; Wenzel, C.; Nerlich, M.; Brockhoff, G.; Loibl, M.; Gehmert, S. Semi-automated extraction and characterization of stromal vascular fraction using a new medical device. Clin Hemorheol Microcirc. 2016, 64, 403-412.  
23. Bender, R.; McCarthy, M.; Brown, T.; Bukowska, J.; Smith, S.; Abbott, R. D.; Kaplan, D. L.; Williams, C.; Wade, J. W.; Alarcon, A.; Wu, X.; Lau, F.; Gimble, J. M.; Frazier, T. Human adipose derived cells in two-and three-dimensional cultures: functional validation of an in vitro fat construct. Stem Cells Int. 2020, 2020, 4242130.  
24. Pope, B. D.; Warren, C. R.; Dahl, M. O.; Pizza, C. V.; Henze, D. E.; Sinatra, N. R.; Gonzalez, G. M.; Chang, H.; Liu, Q.; Glieberman, A. L.; Ferrier, J. P., Jr.; Cowan, C. A.; Parker, K. K. Fattening chips: hypertrophy, feeding, and fasting of human white adipocytes in vitro. Lab Chip. 2020, 20, 4152-4165.  
25. Abbott, R. D.; Raja, W. K.; Wang, R. Y.; Stinson, J. A.; Glettig, D. L.; Burke, K. A.; Kaplan, D. L. Long term perfusion system supporting adipogenesis. Methods. 2015, 84, 84-89.  
26. Abbott, R. D.; Borowsky, F. E.; Quinn, K. P.; Bernstein, D. L.; Georgakoudi, I.; Kaplan, D. L. Non-invasive assessments of adipose tissue metabolism in vitro. Ann Biomed Eng. 2016, 44, 725-732.  
27. Choi, J. H.; Bellas, E.; Gimble, J. M.; Vunjak-Novakovic, G.; Kaplan, D. L. Lipolytic function of adipocyte/endothelial cocultures. Tissue Eng Part A. 2011, 17, 1437-1444.  
28. Choi, J. H.; Gimble, J. M.; Lee, K.; Marra, K. G.; Rubin, J. P.; Yoo, J. J.; Vunjak-Novakovic, G.; Kaplan, D. L. Adipose tissue engineering for soft tissue regeneration. Tissue Eng Part B Rev. 2010, 16, 413-426.  
29. Wang, R. Y.; Abbott, R. D.; Zieba, A.; Borowsky, F. E.; Kaplan, D. L. Development of a three-dimensional adipose tissue model for studying embryonic exposures to obesogenic chemicals. Ann Biomed Eng. 2017, 45, 1807-1818.  
30. Ward, A.; Quinn, K. P.; Bellas, E.; Georgakoudi, I.; Kaplan, D. L. Noninvasive metabolic imaging of engineered 3D human adipose tissue in a perfusion bioreactor. PLoS One. 2013, 8, e55696.  
31. Loskill, P.; Sezhian, T.; Tharp, K. M.; Lee-Montiel, F. T.; Jeeawoody, S.; Reese, W. M.; Zushin, P. H.; Stahl, A.; Healy, K. E. WAT-on-a-chip: a physiologically relevant microfluidic system incorporating white adipose tissue. Lab Chip. 2017, 17, 1645-1654.  
32. Rogal, J.; Binder, C.; Kromidas, E.; Roosz, J.; Probst, C.; Schneider, S.; Schenke-Layland, K.; Loskill, P. WAT-on-a-chip integrating human mature white adipocytes for mechanistic research and pharmaceutical applications. Sci Rep. 2020, 10, 6666.  
33. McCarthy, M.; Brown, T.; Alarcon, A.; Williams, C.; Wu, X.; Abbott, R. D.; Gimble, J.; Frazier, T. Fat-on-a-chip models for research and discovery in obesity and its metabolic comorbidities. Tissue Eng Part B Rev. 2020, 26, 586-595.  
34. Qi, L.; Zushin, P. H.; Chang, C. F.; Lee, Y. T.; Alba, D. L.; Koliwad, S. K.; Stahl, A. Probing insulin sensitivity with metabolically competent human stem cell-derived white adipose tissue microphysiological systems. Small. 2021. doi: 10.1002/smll.202103157.  
35. Kostrzewski, T.; Snow, S.; Battle, A. L.; Peel, S.; Ahmad, Z.; Basak, J.; Surakala, M.; Bornot, A.; Lindgren, J.; Ryaboshapkina, M.; Clausen, M.; Lindén, D.; Maass, C.; Young, L. M.; Corrigan, A.; Ewart, L.; Hughes, D. Modelling human liver fibrosis in the context of non-alcoholic steatohepatitis using a microphysiological system. Commun Biol. 2021, 4, 1080.  
36. Strong, A. L.; Ohlstein, J. F.; Biagas, B. A.; Rhodes, L. V.; Pei, D. T.; Tucker, H. A.; Llamas, C.; Bowles, A. C.; Dutreil, M. F.; Zhang, S.; Gimble, J. M.; Burow, M. E.; Bunnell, B. A. Leptin produced by obese adipose stromal/stem cells enhances proliferation and metastasis of estrogen receptor positive breast cancers. Breast Cancer Res. 2015, 17, 112.  
37. Strong, A. L.; Pei, D. T.; Hurst, C. G.; Gimble, J. M.; Burow, M. E.; Bunnell, B. A. Obesity enhances the conversion of adipose-derived stromal/stem cells into carcinoma-associated fibroblast leading to cancer cell proliferation and progression to an invasive phenotype. Stem Cells Int. 2017, 2017, 9216502.  
38. Strong, A. L.; Semon, J. A.; Strong, T. A.; Santoke, T. T.; Zhang, S.; McFerrin, H. E.; Gimble, J. M.; Bunnell, B. A. Obesity-associated dysregulation of calpastatin and MMP-15 in adipose-derived stromal cells results in their enhanced invasion. Stem Cells. 2012, 30, 2774-2783.  
39. Strong, A. L.; Strong, T. A.; Rhodes, L. V.; Semon, J. A.; Zhang, X.; Shi, Z.; Zhang, S.; Gimble, J. M.; Burow, M. E.; Bunnell, B. A. Obesity associated alterations in the biology of adipose stem cells mediate enhanced tumorigenesis by estrogen dependent pathways. Breast Cancer Res. 2013, 15, R102.  
40. Mohiuddin, O. A.; Campbell, B.; Poche, J. N.; Ma, M.; Rogers, E.; Gaupp, D.; Harrison, M. A.; Bunnell, B. A.; Hayes, D. J.; Gimble, J. M. Decellularized adipose tissue hydrogel promotes bone regeneration in critical-sized mouse femoral defect model. Front Bioeng Biotechnol. 2019, 7, 211.  
41. Mohiuddin, O. A.; O’Donnell, B. T.; Poche, J. N.; Iftikhar, R.; Wise, R. M.; Motherwell, J. M.; Campbell, B.; Savkovic, S. D.; Bunnell, B. A.; Hayes, D. J.; Gimble, J. M. Human adipose-derived hydrogel characterization based on in vitro ASC biocompatibility and differentiation. Stem Cells Int. 2019, 2019, 9276398.  
42. Bicer, M.; Sheard, J.; Iandolo, D.; Boateng, S. Y.; Cottrell, G. S.; Widera, D. Electrical stimulation of adipose-derived stem cells in 3D nanofibrillar cellulose increases their osteogenic potential. Biomolecules. 2020, 10, 1696.  
43. Manikowski, D.; Andrée, B.; Samper, E.; Saint-Marc, C.; Olmer, R.; Vogt, P.; Strauß, S.; Haverich, A.; Hilfiker, A. Human adipose tissue-derived stromal cells in combination with exogenous stimuli facilitate three-dimensional network formation of human endothelial cells derived from various sources. Vascul Pharmacol. 2018, 106, 28-36.  
44. Andrée, B.; Ichanti, H.; Kalies, S.; Heisterkamp, A.; Strauß, S.; Vogt, P. M.; Haverich, A.; Hilfiker, A. Formation of three-dimensional tubular endothelial cell networks under defined serum-free cell culture conditions in human collagen hydrogels. Sci Rep. 2019, 9, 5437.  
45. Mertaniemi, H.; Escobedo-Lucea, C.; Sanz-Garcia, A.; Gandía, C.; Mäkitie, A.; Partanen, J.; Ikkala, O.; Yliperttula, M. Human stem cell decorated nanocellulose threads for biomedical applications. Biomaterials. 2016, 82, 208-220.  
46. Krontiras, P.; Gatenholm, P.; Hägg, D. A. Adipogenic differentiation of stem cells in three-dimensional porous bacterial nanocellulose scaffolds. J Biomed Mater Res B Appl Biomater. 2015, 103, 195-203.  
47. Bhumiratana, S.; Bernhard, J. C.; Alfi, D. M.; Yeager, K.; Eton, R. E.; Bova, J.; Shah, F.; Gimble, J. M.; Lopez, M. J.; Eisig, S. B.; Vunjak-Novakovic, G. Tissue-engineered autologous grafts for facial bone reconstruction. Sci Transl Med. 2016, 8, 343ra383.  
48. Chen, D.; Wu, J. Y.; Kennedy, K. M.; Yeager, K.; Bernhard, J. C.; Ng, J. J.; Zimmerman, B. K.; Robinson, S.; Durney, K. M.; Shaeffer, C.; Vila, O. F.; Takawira, C.; Gimble, J. M.; Guo, X. E.; Ateshian, G. A.; Lopez, M. J.; Eisig, S. B.; Vunjak-Novakovic, G. Tissue engineered autologous cartilage-bone grafts for temporomandibular joint regeneration. Sci Transl Med. 2020, 12, eabb6683.  

Conflict of interest
The authors declare they have no competing interests.
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