Stem Cell Reviews and Reports

, Volume 14, Issue 4, pp 546–557 | Cite as

Regenerative Potential and Inflammation-Induced Secretion Profile of Human Adipose-Derived Stromal Vascular Cells Are Influenced by Donor Variability and Prior Breast Cancer Diagnosis

  • Adrienne M. Parsons
  • Deborah M. Ciombor
  • Paul Y. Liu
  • Eric M. Darling


Adipose tissue contains a heterogeneous population of stromal vascular fraction (SVF) cells that work synergistically with resident cell types to enhance tissue healing. Ease of access and processing paired with therapeutic promise make SVF cells an attractive option for autologous applications in regenerative medicine. However, inherent variability in SVF cell therapeutic potential from one patient to another hinders prognosis determination for any one person. This study investigated the regenerative properties and inflammation responses of thirteen, medically diverse human donors. Using non-expanded primary lipoaspirate samples, SVF cells were assessed for robustness of several parameters integral to tissue regeneration, including yield, viability, self-renewal capacity, proliferation, differentiation potential, and immunomodulatory cytokine secretion. Each parameter was selected either for its role in regenerative potential, defined here as the ability to heal tissues through stem cell repopulation and subsequent multipotent differentiation, or for its potential role in wound healing through trophic immunomodulatory activity. These data were then analyzed for consistent and predictable patterns between and across measurements, while also investigating the influence of the donors’ relevant medical histories, particularly if the donor was in remission following breast cancer treatment. Analyses identified positive correlations among the expression of three cytokines: interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1. The expression of these cytokines also positively related to self-renewal capacity. These results are potentially relevant for establishing expectations in both preclinical experiments and targeted clinical treatment strategies that use stem cells from patients with diverse medical histories.


Adipose-derived stromal cell Stem cell immunomodulation Breast cancer Inflammatory cytokines Heterogeneity Regenerative medicine Autologous cell therapy 



This work was supported by the National Institutes of Health (R01 AR06304) and the National Science Foundation (EAGER CBET 1547819). The authors would like to thank Lisa White, Pa-C for aiding in the collection of donor samples and medical history data. Additionally, Christoph Schorl, PhD, of the Brown University genomics facility, provided assistance with microarray imaging and analysis software. Nicholas Labriola, PhD, produced the custom MATLAB program used to measure lineage-specific metabolite production. Vikram Mookerjee aided in proofreading and editing the manuscript.

Author Contributions

AMP conducted experiments and analyses. DMC, PL, and EMD designed study. PL provided tissue samples. AMP, DMC, PL, and EMD contributed to writing and editing the manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare no potential conflict of interest.

Supplementary material

12015_2018_9813_MOESM1_ESM.docx (47 kb)
ESM 1 (DOCX 47 kb)


  1. 1.
    Murphy, J. M., Dixon, K., Beck, S., Fabian, D., Feldman, A., & Barry, F. (2002). Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis. Arthritis and Rheumatism, 46(3), 704–713.CrossRefPubMedGoogle Scholar
  2. 2.
    Isakson, P., Hammarstedt, A., Gustafson, B., & Smith, U. (2009). Impaired preadipocyte differentiation in human abdominal obesity: Role of Wnt, tumor necrosis factor-alpha, and inflammation. Diabetes, 58(7), 1550–1557.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Roldan, M., Macias-Gonzalez, M., Garcia, R., Tinahones, F. J., & Martin, M. (2011). Obesity short-circuits stemness gene network in human adipose multipotent stem cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 25(12), 4111–4126.CrossRefGoogle Scholar
  4. 4.
    van Tienen, F. H., van der Kallen, C. J., Lindsey, P. J., Wanders, R. J., van Greevenbroek, M. M., & Smeets, H. J. (2011). Preadipocytes of type 2 diabetes subjects display an intrinsic gene expression profile of decreased differentiation capacity. International Journal of Obesity, 35(9), 1154–1164.CrossRefPubMedGoogle Scholar
  5. 5.
    Gimble, J. M., Bunnell, B. A., & Guilak, F. (2012). Human adipose-derived cells: An update on the transition to clinical translation. Regenerative Medicine, 7(2), 225–235.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Hsu, V. M., Stransky, C. A., Bucky, L. P., & Percec, I. (2012). Fat grafting's past, present, and future: Why adipose tissue is emerging as a critical link to the advancement of regenerative medicine. Aesthetic Surgery Journal, 32(7), 892–899.CrossRefPubMedGoogle Scholar
  7. 7.
    Stacey, G. N. (2014). The challenge of standardization in stem cell Research and Development. In D. Ilic (Ed.), Stem Cell Banking (pp. 11–18). New York, NY: Springer New York.CrossRefGoogle Scholar
  8. 8.
    Nguyen, A., Guo, J., Banyard, D. A., Fadavi, D., Toranto, J. D., Wirth, G. A., et al. (2016). Stromal vascular fraction: A regenerative reality? Part 1: Current concepts and review of the literature. Journal of Plastic, Reconstructive & Aesthetic Surgery, 69(2), 170–179.CrossRefGoogle Scholar
  9. 9.
    Kanthilal, M. (2014). Characterization of mechanical and regenerative properties of human, adipose stromal cells., 7(4), 585–597.Google Scholar
  10. 10.
    Riordan, N. H., Ichim, T. E., Min, W. P., Wang, H., Solano, F., Lara, F., et al. (2009). Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis. Journal of Translational Medicine, 7, 29.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Rodriguez, J. P., Murphy, M. P., Hong, S., Madrigal, M., March, K. L., Minev, B., et al. (2012). Autologous stromal vascular fraction therapy for rheumatoid arthritis: Rationale and clinical safety. International Archives of Medicine, 5, 5.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Varghese, J., Griffin, M., Mosahebi, A., & Butler, P. (2017). Systematic review of patient factors affecting adipose stem cell viability and function: implications for regenerative therapy. Stem Cell Research & Therapy, 8(1), 45.CrossRefGoogle Scholar
  13. 13.
    Choudhery, M. S., Badowski, M., Muise, A., Pierce, J., & Harris, D. T. (2014). Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation. Journal of Translational Medicine, 12, 8.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Aksu, A. E., Rubin, J. P., Dudas, J. R., & Marra, K. G. (2008). Role of gender and anatomical region on induction of osteogenic differentiation of human adipose-derived stem cells. Annals of Plastic Surgery, 60(3), 306–322.CrossRefPubMedGoogle Scholar
  15. 15.
    Estes, B. T., Diekman, B. O., Gimble, J. M., & Guilak, F. (2010). Isolation of adipose-derived stem cells and their induction to a chondrogenic phenotype. Nature Protocols, 5(7), 1294–1311.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Beane, O. S., Fonseca, V. C., Cooper, L. L., Koren, G., & Darling, E. M. (2014). Impact of aging on the regenerative properties of bone marrow-, muscle-, and adipose-derived mesenchymal stem/stromal cells. PLoS One, 9(12), e115963.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ng, L. W., Yip, S. K., Wong, H. K., Yam, G. H., Liu, Y. M., Lui, W. T., et al. (2009). Adipose-derived stem cells from pregnant women show higher proliferation rate unrelated to estrogen. Human Reproduction, 24(5), 1164–1170.CrossRefPubMedGoogle Scholar
  18. 18.
    Guilak, F., Lott, K. E., Awad, H. A., Cao, Q., Hicok, K. C., Fermor, B., et al. (2006). Clonal analysis of the differentiation potential of human adipose-derived adult stem cells. Journal of Cellular Physiology, 206(1), 229–237.CrossRefPubMedGoogle Scholar
  19. 19.
    Beane, O. S., Fonseca, V. C., & Darling, E. M. (2014). Adipose-derived stem cells retain their regenerative potential after methotrexate treatment. Experimental Cell Research, 327(2), 222–233.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Estes, B. T., Diekman, B. O., & Guilak, F. (2008). Monolayer cell expansion conditions affect the chondrogenic potential of adipose-derived stem cells. Biotechnology and Bioengineering, 99(4), 986–995.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zheng, B., Cao, B., Li, G., & Huard, J. (2006). Mouse adipose-derived stem cells undergo multilineage differentiation in vitro but primarily osteogenic and chondrogenic differentiation in vivo. Tissue Engineering, 12(7), 1891–1901.CrossRefPubMedGoogle Scholar
  22. 22.
    Labriola, N. R., & Darling, E. M. (2015). Temporal heterogeneity in single-cell gene expression and mechanical properties during adipogenic differentiation. Journal of Biomechanics, 48(6), 1058–1066.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Gonzalez-Cruz, R. D., Fonseca, V. C., & Darling, E. M. (2012). Cellular mechanical properties reflect the differentiation potential of adipose-derived mesenchymal stem cells. Proceedings of the National Academy of Sciences of the United States of America, 109(24), E1523–E1529.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Marble, H. D., Sutermaster, B. A., Kanthilal, M., Fonseca, V. C., & Darling, E. M. (2014). Gene expression-based enrichment of live cells from adipose tissue produces subpopulations with improved osteogenic potential. Stem Cell Research & Therapy, 5(5), 145.CrossRefGoogle Scholar
  25. 25.
    Zhukareva, V., Obrocka, M., Houle, J. D., Fischer, I., & Neuhuber, B. (2010). Secretion profile of human bone marrow stromal cells: Donor variability and response to inflammatory stimuli. Cytokine, 50(3), 317–321.CrossRefPubMedGoogle Scholar
  26. 26.
    Francois, M., Romieu-Mourez, R., Li, M., & Galipeau, J. (2012). Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Molecular Therapy, 20(1), 187–195.CrossRefPubMedGoogle Scholar
  27. 27.
    Bigoni, M., Sacerdote, P., Turati, M., Franchi, S., Gandolla, M., Gaddi, D., et al. (2013). Acute and late changes in intraarticular cytokine levels following anterior cruciate ligament injury. Journal of Orthopaedic Research, 31(2), 315–321.CrossRefPubMedGoogle Scholar
  28. 28.
    Sen, A., Lea-Currie, Y. R., Sujkowska, D., Franklin, D. M., Wilkison, W. O., Halvorsen, Y. D., et al. (2001). Adipogenic potential of human adipose derived stromal cells from multiple donors is heterogeneous. Journal of Cellular Biochemistry, 81(2), 312–319.CrossRefPubMedGoogle Scholar
  29. 29.
    Faustini, M., Bucco, M., Chlapanidas, T., Lucconi, G., Marazzi, M., Tosca, M. C., et al. (2010). Nonexpanded mesenchymal stem cells for regenerative medicine: Yield in stromal vascular fraction from adipose tissues. Tissue Engineering. Part C, Methods, 16(6), 1515–1521.CrossRefPubMedGoogle Scholar
  30. 30.
    Russo, V., Yu, C., Belliveau, P., Hamilton, A., & Flynn, L. E. (2014). Comparison of human adipose-derived stem cells isolated from subcutaneous, omental, and intrathoracic adipose tissue depots for regenerative applications. Stem Cells Translational Medicine, 3(2), 206–217.CrossRefPubMedGoogle Scholar
  31. 31.
    Beresford, J. N., Bennett, J. H., Devlin, C., Leboy, P. S., & Owen, M. E. (1992). Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures. Journal of Cell Science, 102(Pt 2), 341–351.PubMedGoogle Scholar
  32. 32.
    Nuttall, M. E., & Gimble, J. M. (2004). Controlling the balance between osteoblastogenesis and adipogenesis and the consequent therapeutic implications. Current Opinion in Pharmacology, 4(3), 290–294.CrossRefPubMedGoogle Scholar
  33. 33.
    Zhu, M., Kohan, E., Bradley, J., Hedrick, M., Benhaim, P., & Zuk, P. (2009). The effect of age on osteogenic, adipogenic and proliferative potential of female adipose-derived stem cells. Journal of Tissue Engineering and Regenerative Medicine, 3(4), 290–301.CrossRefPubMedGoogle Scholar
  34. 34.
    Rodriguez, J., Pratta, A. S., Abbassi, N., Fabre, H., Rodriguez, F., Debard, C., et al. (2017). Evaluation of three devices for the isolation of the stromal vascular fraction from adipose tissue and for ASC culture: A comparative study. Stem Cells International, 2017, 9289213.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Prunet-Marcassus, B., Cousin, B., Caton, D., Andre, M., Penicaud, L., & Casteilla, L. (2006). From heterogeneity to plasticity in adipose tissues: Site-specific differences. Experimental Cell Research, 312(6), 727–736.CrossRefPubMedGoogle Scholar
  36. 36.
    Leto Barone, A. A., Khalifian, S., Lee, W. P. A., & Brandacher, G. (2013). Immunomodulatory effects of adipose-derived stem cells: Fact or fiction? BioMed Research International, 2013, 1–8.CrossRefGoogle Scholar
  37. 37.
    Weitkamp, J. H., Reinsberg, J., & Bartmann, P. (2002). Interleukin-8 (IL-8) preferable to IL-6 as a marker for clinical infection. Clinical and Diagnostic Laboratory Immunology, 9(6), 1401.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Georganas, C., Liu, H., Perlman, H., Hoffmann, A., Thimmapaya, B., & Pope, R. M. (2000). Regulation of IL-6 and IL-8 expression in rheumatoid arthritis synovial fibroblasts: The dominant role for NF-kappa B but not C/EBP beta or c-Jun. Journal of Immunology, 165(12), 7199–7206.CrossRefGoogle Scholar
  39. 39.
    Bertazzolo, N., Punzi, L., Stefani, M. P., Cesaro, G., Pianon, M., Finco, B., et al. (1994). Interrelationships between interleukin (IL)-1, IL-6 and IL-8 in synovial fluid of various arthropathies. Agents and Actions, 41(1–2), 90–92.CrossRefPubMedGoogle Scholar
  40. 40.
    Gerhardt, C. C., Romero, I. A., Cancello, R., Camoin, L., & Strosberg, A. D. (2001). Chemokines control fat accumulation and leptin secretion by cultured human adipocytes. Molecular and Cellular Endocrinology, 175(1–2), 81–92.CrossRefPubMedGoogle Scholar
  41. 41.
    Dietze-Schroeder, D., Sell, H., Uhlig, M., Koenen, M., & Eckel, J. (2005). Autocrine action of adiponectin on human fat cells prevents the release of insulin resistance-inducing factors. Diabetes, 54(7), 2003–2011.CrossRefPubMedGoogle Scholar
  42. 42.
    Deshmane, S. L., Kremlev, S., Amini, S., & Sawaya, B. E. (2009). Monocyte chemoattractant protein-1 (MCP-1): An overview. Journal of Interferon & Cytokine Research, 29(6), 313–326.CrossRefGoogle Scholar
  43. 43.
    Niu, J., & Kolattukudy, P. E. (2009). Role of MCP-1 in cardiovascular disease: Molecular mechanisms and clinical implications. Clinical Science (London, England), 117(3), 95–109.CrossRefGoogle Scholar
  44. 44.
    Behm, B., Babilas, P., Landthaler, M., & Schreml, S. (2012). Cytokines, chemokines and growth factors in wound healing. Journal of the European Academy of Dermatology and Venereology, 26(7), 812–820.CrossRefPubMedGoogle Scholar
  45. 45.
    Mast, B. A., & Schultz, G. S. (1996). Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Repair and Regeneration, 4(4), 411–420.CrossRefPubMedGoogle Scholar
  46. 46.
    McFarland-Mancini, M. M., Funk, H. M., Paluch, A. M., Zhou, M., Giridhar, P. V., Mercer, C. A., et al. (2010). Differences in wound healing in mice with deficiency of IL-6 versus IL-6 receptor. Journal of Immunology, 184(12), 7219–7228.CrossRefGoogle Scholar
  47. 47.
    Lin, Z. Q., Kondo, T., Ishida, Y., Takayasu, T., & Mukaida, N. (2003). Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice. Journal of Leukocyte Biology, 73(6), 713–721.CrossRefPubMedGoogle Scholar
  48. 48.
    Scheller, J., Chalaris, A., Schmidt-Arras, D., & Rose-John, S. (2011). The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochimica et Biophysica Acta, 1813(5), 878–888.CrossRefPubMedGoogle Scholar
  49. 49.
    Djouad, F., Charbonnier, L. M., Bouffi, C., Louis-Plence, P., Bony, C., Apparailly, F., et al. (2007). Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem cells (Dayton, Ohio), 25(8), 2025–2032.CrossRefGoogle Scholar
  50. 50.
    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 and Development, 21(14), 2724–2752.CrossRefPubMedGoogle Scholar
  51. 51.
    Ivanova-Todorova, E., Bochev, I., Mourdjeva, M., Dimitrov, R., Bukarev, D., Kyurkchiev, S., et al. (2009). Adipose tissue-derived mesenchymal stem cells are more potent suppressors of dendritic cells differentiation compared to bone marrow-derived mesenchymal stem cells. Immunology Letters, 126(1–2), 37–42.CrossRefPubMedGoogle Scholar
  52. 52.
    Yanez, R., Oviedo, A., Aldea, M., Bueren, J. A., & Lamana, M. L. (2010). Prostaglandin E2 plays a key role in the immunosuppressive properties of adipose and bone marrow tissue-derived mesenchymal stromal cells. Experimental Cell Research, 316(19), 3109–3123.CrossRefPubMedGoogle Scholar
  53. 53.
    Heo, S. C., Jeon, E. S., Lee, I. H., Kim, H. S., Kim, M. B., & Kim, J. H. (2011). Tumor necrosis factor-alpha-activated human adipose tissue-derived mesenchymal stem cells accelerate cutaneous wound healing through paracrine mechanisms. The Journal of Investigative Dermatology, 131(7), 1559–1567.CrossRefPubMedGoogle Scholar
  54. 54.
    Beane, O. S., Darling, L. E., Fonseca, V. C., & Darling, E. M. (2016). Disparate response to methotrexate in stem versus non-stem cells. Stem Cell Reviews, 12(3), 340–351.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    (EBCTCG) EBCTCG. (2012). Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. Lancet (London, England), 379(9814), 432–444.CrossRefGoogle Scholar
  56. 56.
    Pike, S., Zhang, P., Wei, Z., Wu, N., Klinger, A., Chang, S., et al. (2015). In vitro effects of tamoxifen on adipose-derived stem cells. Wound Repair and Regeneration, 23(5), 728–736.CrossRefPubMedGoogle Scholar
  57. 57.
    Korkaya, H., Liu, S., & Wicha, M. S. (2011). Breast cancer stem cells, cytokine networks, and the tumor microenvironment. The Journal of Clinical Investigation, 121(10), 3804–3809.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Balkwill, F., Charles, K. A., & Mantovani, A. (2005). Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell, 7(3), 211–217.CrossRefPubMedGoogle Scholar
  59. 59.
    Kolle, S. F., Fischer-Nielsen, A., Mathiasen, A. B., Elberg, J. J., Oliveri, R. S., Glovinski, P. V., et al. (2013). Enrichment of autologous fat grafts with ex-vivo expanded adipose tissue-derived stem cells for graft survival: A randomised placebo-controlled trial. Lancet, 382(9898), 1113–1120.CrossRefPubMedGoogle Scholar
  60. 60.
    Domergue, S., Bony, C., Maumus, M., Toupet, K., Frouin, E., Rigau, V., et al. (2016). Comparison between stromal vascular fraction and adipose mesenchymal stem cells in remodeling hypertrophic scars. PLoS One, 11(5), e0156161.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Garcia-Olmo, D., Herreros, D., Pascual, M., Pascual, I., De-La-Quintana, P., Trebol, J., et al. (2009). Treatment of enterocutaneous fistula in Crohn's disease with adipose-derived stem cells: A comparison of protocols with and without cell expansion. International Journal of Colorectal Disease, 24(1), 27–30.CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Molecular Pharmacology, Physiology, and BiotechnologyBrown UniversityProvidenceUSA
  2. 2.Department of Plastic and Reconstructive SurgeryBrown UniversityProvidenceUSA
  3. 3.Center for Biomedical EngineeringBrown UniversityProvidenceUSA
  4. 4.School of EngineeringBrown UniversityProvidenceUSA
  5. 5.Department of OrthopaedicsBrown UniversityProvidenceUSA

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