Table of Contents Author Guidelines Submit a Manuscript
Stem Cells International
Volume 2016, Article ID 9176357, 11 pages
http://dx.doi.org/10.1155/2016/9176357
Review Article

Spheroid Culture of Mesenchymal Stem Cells

1Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
2McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA

Received 19 February 2015; Accepted 3 April 2015

Academic Editor: Ren-Ke Li

Copyright © 2016 Zoe Cesarz and Kenichi Tamama. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. J. Friedenstein, U. F. Gorskaja, and N. N. Kulagina, “Fibroblast precursors in normal and irradiated mouse hematopoietic organs,” Experimental Hematology, vol. 4, no. 5, pp. 267–274, 1976. View at Google Scholar · View at Scopus
  2. M. Owen and A. J. Friedenstein, “Stromal stem cells: marrow-derived osteogenic precursors,” Ciba Foundation Symposium, vol. 136, pp. 42–60, 1988. View at Google Scholar
  3. M. F. Pittenger, A. M. Mackay, S. C. Beck et al., “Multilineage potential of adult human mesenchymal stem cells,” Science, vol. 284, no. 5411, pp. 143–147, 1999. View at Publisher · View at Google Scholar · View at Scopus
  4. D. J. Prockop, “Marrow stromal cells as stem cells for nonhematopoietic tissues,” Science, vol. 276, no. 5309, pp. 71–74, 1997. View at Publisher · View at Google Scholar · View at Scopus
  5. K. Tamama, V. H. Fan, L. G. Griffith, H. C. Blair, and A. Wells, “Epidermal growth factor as a candidate for ex vivo expansion of bone marrow-derived mesenchymal stem cells,” Stem Cells, vol. 24, no. 3, pp. 686–695, 2006. View at Publisher · View at Google Scholar · View at Scopus
  6. K. Tamama, C. K. Sen, and A. Wells, “Differentiation of bone marrow mesenchymal stem cells into the smooth muscle lineage by blocking ERK/MAPK signaling pathway,” Stem Cells and Development, vol. 17, no. 5, pp. 897–908, 2008. View at Publisher · View at Google Scholar · View at Scopus
  7. K. Tamama and D. J. Barbeau, “Early growth response genes signaling supports strong paracrine capability of mesenchymal stem cells,” Stem Cells International, vol. 2012, Article ID 428403, 7 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  8. K. Tamama, H. Kawasaki, and A. Wells, “Epidermal growth factor (EGF) treatment on multipotential stromal cells (MSCs). Possible enhancement of therapeutic potential of MSC,” Journal of Biomedicine and Biotechnology, vol. 2010, Article ID 795385, 10 pages, 2010. View at Publisher · View at Google Scholar · View at Scopus
  9. W. Mueller-Klieser, “Multicellular spheroids—a review on cellular aggregates in cancer research,” Journal of Cancer Research and Clinical Oncology, vol. 113, no. 2, pp. 101–122, 1987. View at Publisher · View at Google Scholar · View at Scopus
  10. W. Mueller-Klieser, “Three-dimensional cell cultures: from molecular mechanisms to clinical applications,” American Journal of Physiology—Cell Physiology, vol. 273, no. 4, pp. C1109–Cl123, 1997. View at Google Scholar · View at Scopus
  11. Y. Sasai, “Next-generation regenerative medicine: organogenesis from stem cells in 3D culture,” Cell Stem Cell, vol. 12, no. 5, pp. 520–530, 2013. View at Publisher · View at Google Scholar · View at Scopus
  12. Y. Sasai, “Cytosystems dynamics in self-organization of tissue architecture,” Nature, vol. 493, no. 7432, pp. 318–326, 2013. View at Publisher · View at Google Scholar · View at Scopus
  13. S. Sart, A. C. Tsai, Y. Li, and T. Ma, “Three-dimensional aggregates of mesenchymal stem cells: cellular mechanisms, biological properties, and applications,” Tissue Engineering Part B: Reviews, vol. 20, no. 5, pp. 365–380, 2014. View at Publisher · View at Google Scholar
  14. L. Vallier and R. A. Pedersen, “Human embryonic stem cells: an in vitro model to study mechanisms controlling pluripotency in early mammalian development,” Stem Cell Reviews, vol. 1, no. 2, pp. 119–130, 2005. View at Publisher · View at Google Scholar · View at Scopus
  15. R. Z. Lin and H. Y. Chang, “Recent advances in three-dimensional multicellular spheroid culture for biomedical research,” Biotechnology Journal, vol. 3, no. 9-10, pp. 1172–1184, 2008. View at Publisher · View at Google Scholar · View at Scopus
  16. T.-M. Achilli, J. Meyer, and J. R. Morgan, “Advances in the formation, use and understanding of multi-cellular spheroids,” Expert Opinion on Biological Therapy, vol. 12, no. 10, pp. 1347–1360, 2012. View at Publisher · View at Google Scholar · View at Scopus
  17. F. Grinnell and M. K. Feld, “Adsorption characteristics of plasma fibronectin in relationship to biological activity,” Journal of Biomedical Materials Research, vol. 15, no. 3, pp. 363–381, 1981. View at Publisher · View at Google Scholar · View at Scopus
  18. E. Ruoslahti and M. D. Pierschbacher, “New perspectives in cell adhesion: RGD and integrins,” Science, vol. 238, no. 4826, pp. 491–497, 1987. View at Publisher · View at Google Scholar · View at Scopus
  19. J. A. Zimmermann and T. C. Mcdevitt, “Pre-conditioning mesenchymal stromal cell spheroids for immunomodulatory paracrine factor secretion,” Cytotherapy, vol. 16, no. 3, pp. 331–345, 2014. View at Publisher · View at Google Scholar · View at Scopus
  20. R. Foty, “A simple hanging drop cell culture protocol for generation of 3D spheroids,” Journal of Visualized Experiments, no. 51, Article ID e2720, 2011. View at Publisher · View at Google Scholar · View at Scopus
  21. G.-S. Huang, L.-G. Dai, B. L. Yen, and S.-H. Hsu, “Spheroid formation of mesenchymal stem cells on chitosan and chitosan-hyaluronan membranes,” Biomaterials, vol. 32, no. 29, pp. 6929–6945, 2011. View at Publisher · View at Google Scholar · View at Scopus
  22. S. Schmidt and P. Friedl, “Interstitial cell migration: integrin-dependent and alternative adhesion mechanisms,” Cell and Tissue Research, vol. 339, no. 1, pp. 83–92, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. T. J. Bartosh, J. H. Ylöstalo, N. Bazhanov, J. Kuhlman, and D. J. Prockop, “Dynamic compaction of human mesenchymal stem/precursor cells into spheres self-activates caspase-dependent il1 signaling to enhance secretion of modulators of inflammation and immunity (PGE2, TSG6, and STC1),” Stem Cells, vol. 31, no. 11, pp. 2443–2456, 2013. View at Publisher · View at Google Scholar · View at Scopus
  24. A. C. Tsai, Y. Liu, X. Yuan, and T. Ma, “Compaction, fusion, and functional activation of three-dimensional human mesenchymal stem cell aggregate,” Tissue Engineering A, 2015. View at Publisher · View at Google Scholar
  25. H. Y. Yeh, B. H. Liu, and S. H. Hsu, “The calcium-dependent regulation of spheroid formation and cardiomyogenic differentiation for MSCs on chitosan membranes,” Biomaterials, vol. 33, no. 35, pp. 8943–8954, 2012. View at Publisher · View at Google Scholar · View at Scopus
  26. E. J. Lee, S. J. Park, S. K. Kang et al., “Spherical bullet formation via E-cadherin promotes therapeutic potency of mesenchymal stem cells derived from human umbilical cord blood for myocardial infarction,” Molecular Therapy, vol. 20, no. 7, pp. 1424–1433, 2012. View at Publisher · View at Google Scholar · View at Scopus
  27. J. Kim and T. Ma, “Endogenous extracellular matrices enhance human mesenchymal stem cell aggregate formation and survival,” Biotechnology Progress, vol. 29, no. 2, pp. 441–451, 2013. View at Publisher · View at Google Scholar · View at Scopus
  28. H.-Y. Yeh, B.-H. Liu, M. Sieber, and S.-H. Hsu, “Substrate-dependent gene regulation of self-assembled human MSC spheroids on chitosan membranes,” BMC Genomics, vol. 15, no. 1, article 10, 2014. View at Publisher · View at Google Scholar · View at Scopus
  29. H. Dertinger and C. L. Huhle, “A comparative study of post-irradiation growth kinetics of spheroids and monolayers,” International Journal of Radiation Biology, vol. 28, no. 3, pp. 255–265, 1975. View at Publisher · View at Google Scholar · View at Scopus
  30. R. E. Durand, “Cell cycle kinetics in an in vitro tumor model,” Cell and Tissue Kinetics, vol. 9, no. 5, pp. 403–412, 1976. View at Google Scholar · View at Scopus
  31. M. Haji-Karim and J. Carlsson, “Proliferation and viability in cellular spheroids of human origin,” Cancer Research, vol. 38, no. 5, pp. 1457–1464, 1978. View at Google Scholar · View at Scopus
  32. J. M. Yuhas and A. P. Li, “Growth fraction as the major determinant of multicellular tumor spheroid growth rates,” Cancer Research, vol. 38, no. 6, pp. 1528–1532, 1978. View at Google Scholar · View at Scopus
  33. J. Carlsson, C.-G. Stålnacke, H. Acker, M. Haji-Karim, S. Nilsson, and B. Larsson, “The influence of oxygen on viability and proliferation in cellular spheroids,” International Journal of Radiation Oncology, Biology, Physics, vol. 5, no. 11-12, pp. 2011–2020, 1979. View at Publisher · View at Google Scholar · View at Scopus
  34. J. C. Angello and H. L. Hosick, “Glycosaminoglycan synthesis by mammary tumor spheroids,” Biochemical and Biophysical Research Communications, vol. 107, no. 3, pp. 1130–1137, 1982. View at Publisher · View at Google Scholar · View at Scopus
  35. T. Nederman, B. Norling, B. Glimelius, J. Carlsson, and U. Brunk, “Demonstration of an extracellular matrix in multicellular tumor spheroids,” Cancer Research, vol. 44, no. 7, pp. 3090–3097, 1984. View at Google Scholar · View at Scopus
  36. R. M. Sutherland, W. R. Inch, J. A. McCredie, and J. Kruuv, “A multi-component radiation survival curve using an in vitro tumour model,” International Journal of Radiation Biology and Related Studies in Physics, Chemistry, and Medicine, vol. 18, no. 5, pp. 491–495, 1970. View at Publisher · View at Google Scholar · View at Scopus
  37. R. E. Durand and R. M. Sutherland, “Effects of intercellular contact on repair of radiation damage,” Experimental Cell Research, vol. 71, no. 1, pp. 75–80, 1972. View at Publisher · View at Google Scholar · View at Scopus
  38. R. E. Durand and R. M. Sutherland, “Dependence of the radiation response of an in vitro tumor model on cell cycle effects,” Cancer Research, vol. 33, no. 2, pp. 213–219, 1973. View at Google Scholar · View at Scopus
  39. R. E. Durand and R. M. Sutherland, “Growth and radiation survival characteristics of V79-171b Chinese hamster cells: a possible influence of intercellular contact,” Radiation Research, vol. 56, no. 3, pp. 513–527, 1973. View at Publisher · View at Google Scholar · View at Scopus
  40. G. Kats-Ugurlu, I. Roodink, M. de Weijert et al., “Circulating tumour tissue fragments in patients with pulmonary metastasis of clear cell renal cell carcinoma,” Journal of Pathology, vol. 219, no. 3, pp. 287–293, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. E. H. Cho, M. Wendel, M. Luttgen et al., “Characterization of circulating tumor cell aggregates identified in patients with epithelial tumors,” Physical Biology, vol. 9, no. 1, Article ID 016001, 2012. View at Publisher · View at Google Scholar · View at Scopus
  42. V. V. Glinsky, G. V. Glinsky, O. V. Glinskii et al., “Intravascular metastatic cancer cell homotypic aggregation at the sites of primary attachment to the endothelium,” Cancer Research, vol. 63, no. 13, pp. 3805–3811, 2003. View at Google Scholar · View at Scopus
  43. M. J. Evans and M. H. Kaufman, “Establishment in culture of pluripotential cells from mouse embryos,” Nature, vol. 292, no. 5819, pp. 154–156, 1981. View at Publisher · View at Google Scholar · View at Scopus
  44. G. R. Martin, “Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 78, no. 12, pp. 7634–7638, 1981. View at Publisher · View at Google Scholar · View at Scopus
  45. A. Grover, R. G. Oshima, and E. D. Adamson, “Epithelial layer formation in differentiating aggregates of F9 embryonal carcinoma cells,” Journal of Cell Biology, vol. 96, no. 6, pp. 1690–1696, 1983. View at Publisher · View at Google Scholar · View at Scopus
  46. S. Ahmed, “The culture of neural stem cells,” Journal of Cellular Biochemistry, vol. 106, no. 1, pp. 1–6, 2009. View at Publisher · View at Google Scholar · View at Scopus
  47. J. B. Jensen and M. Parmar, “Strengths and limitations of the neurosphere culture system,” Molecular Neurobiology, vol. 34, no. 3, pp. 153–161, 2006. View at Publisher · View at Google Scholar · View at Scopus
  48. K. Okumura, K. Nakamura, Y. Hisatomi et al., “Salivary gland progenitor cells induced by duct ligation differentiate into hepatic and pancreatic lineages,” Hepatology, vol. 38, no. 1, pp. 104–113, 2003. View at Publisher · View at Google Scholar · View at Scopus
  49. K. Watanabe, D. Kamiya, A. Nishiyama et al., “Directed differentiation of telencephalic precursors from embryonic stem cells,” Nature Neuroscience, vol. 8, no. 3, pp. 288–296, 2005. View at Publisher · View at Google Scholar · View at Scopus
  50. T. J. Bartosh, J. H. Ylöstalo, A. Mohammadipoor et al., “Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 31, pp. 13724–13729, 2010. View at Publisher · View at Google Scholar · View at Scopus
  51. Q. Zhang, A. L. Nguyen, S. Shi et al., “Three-dimensional spheroid culture of human gingiva-derived mesenchymal stem cells enhances mitigation of chemotherapy-induced oral mucositis,” Stem Cells and Development, vol. 21, no. 6, pp. 937–947, 2012. View at Publisher · View at Google Scholar · View at Scopus
  52. P. R. Baraniak, M. T. Cooke, R. Saeed, M. A. Kinney, K. M. Fridley, and T. C. McDevitt, “Stiffening of human mesenchymal stem cell spheroid microenvironments induced by incorporation of gelatin microparticles,” Journal of the Mechanical Behavior of Biomedical Materials, vol. 11, pp. 63–71, 2012. View at Publisher · View at Google Scholar · View at Scopus
  53. E. Bellas and C. S. Chen, “Forms, forces, and stem cell fate,” Current Opinion in Cell Biology, vol. 31, pp. 92–97, 2014. View at Publisher · View at Google Scholar
  54. R. McBeath, D. M. Pirone, C. M. Nelson, K. Bhadriraju, and C. S. Chen, “Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment,” Developmental Cell, vol. 6, no. 4, pp. 483–495, 2004. View at Publisher · View at Google Scholar · View at Scopus
  55. S. A. Ruiz and C. S. Chen, “Emergence of patterned stem cell differentiation within multicellular structures,” Stem Cells, vol. 26, no. 11, pp. 2921–2927, 2008. View at Publisher · View at Google Scholar · View at Scopus
  56. J. H. Wen, L. G. Vincent, A. Fuhrmann et al., “Interplay of matrix stiffness and protein tethering in stem cell differentiation,” Nature Materials, vol. 13, no. 10, pp. 979–987, 2014. View at Publisher · View at Google Scholar
  57. W. L. Murphy, T. C. McDevitt, and A. J. Engler, “Materials as stem cell regulators,” Nature Materials, vol. 13, no. 6, pp. 547–557, 2014. View at Publisher · View at Google Scholar · View at Scopus
  58. I. A. Potapova, G. R. Gaudette, P. R. Brink et al., “Mesenchymal stem cells support migration, extracellular matrix invasion, proliferation, and survival of endothelial cells in vitro,” Stem Cells, vol. 25, no. 7, pp. 1761–1768, 2007. View at Publisher · View at Google Scholar · View at Scopus
  59. I. A. Potapova, P. R. Brink, I. S. Cohen, and S. V. Doronin, “Culturing of human mesenchymal stem cells as three-dimensional aggregates induces functional expression of CXCR4 that regulates adhesion to endothelial cells,” The Journal of Biological Chemistry, vol. 283, no. 19, pp. 13100–13107, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. J. E. Frith, B. Thomson, and P. G. Genever, “Dynamic three-dimensional culture methods enhance mesenchymal stem cell properties and increase therapeutic potential,” Tissue Engineering Part C: Methods, vol. 16, no. 4, pp. 735–749, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. R. H. Lee, M. J. Seo, A. A. Pulin, C. A. Gregory, J. Ylostalo, and D. J. Prockop, “The CD34-like protein PODXL and α6-integrin (CD49f) identify early progenitor MSCs with increased clonogenicity and migration to infarcted heart in mice,” Blood, vol. 113, no. 4, pp. 816–826, 2009. View at Publisher · View at Google Scholar · View at Scopus
  62. R. H. Lee, A. A. Pulin, M. J. Seo et al., “Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6,” Cell Stem Cell, vol. 5, no. 1, pp. 54–63, 2009. View at Publisher · View at Google Scholar · View at Scopus
  63. M. Crisan, S. Yap, L. Casteilla et al., “A perivascular origin for mesenchymal stem cells in multiple human organs,” Cell Stem Cell, vol. 3, no. 3, pp. 301–313, 2008. View at Publisher · View at Google Scholar · View at Scopus
  64. D. T. Covas, R. A. Panepucci, A. M. Fontes et al., “Multipotent mesenchymal stromal cells obtained from diverse human tissues share functional properties and gene-expression profile with CD146+ perivascular cells and fibroblasts,” Experimental Hematology, vol. 36, no. 5, pp. 642–654, 2008. View at Publisher · View at Google Scholar · View at Scopus
  65. D. T. Covas, C. E. Piccinato, M. D. Orellana et al., “Mesenchymal stem cells can be obtained from the human saphena vein,” Experimental Cell Research, vol. 309, no. 2, pp. 340–344, 2005. View at Publisher · View at Google Scholar · View at Scopus
  66. M. Abedin, Y. Tintut, and L. L. Demer, “Mesenchymal stem cells and the artery wall,” Circulation Research, vol. 95, no. 7, pp. 671–676, 2004. View at Publisher · View at Google Scholar · View at Scopus
  67. A. I. Caplan, “All MSCs are pericytes?” Cell Stem Cell, vol. 3, no. 3, pp. 229–230, 2008. View at Publisher · View at Google Scholar · View at Scopus
  68. C. Lamagna and G. Bergers, “The bone marrow constitutes a reservoir of pericyte progenitors,” Journal of Leukocyte Biology, vol. 80, no. 4, pp. 677–681, 2006. View at Publisher · View at Google Scholar · View at Scopus
  69. A. I. Caplan, “Why are MSCs therapeutic? New data: new insight,” Journal of Pathology, vol. 217, no. 2, pp. 318–324, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. L. Diaz-Flores Jr., R. Gutierrez, J. F. Madrid, H. Varela, F. Valladares, and L. Diaz-Flores, “Adult stem cells and repair through granulation tissue,” Frontiers in Bioscience, vol. 14, no. 4, pp. 1433–1470, 2009. View at Publisher · View at Google Scholar · View at Scopus
  71. K. English, A. French, and K. J. Wood, “Mesenchymal stromal cells: facilitators of successful transplantation?” Cell Stem Cell, vol. 7, no. 4, pp. 431–442, 2010. View at Publisher · View at Google Scholar · View at Scopus
  72. J. Galipeau, “The mesenchymal stromal cells dilemma—does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road?” Cytotherapy, vol. 15, no. 1, pp. 2–8, 2013. View at Publisher · View at Google Scholar · View at Scopus
  73. J. Tongers, D. W. Losordo, and U. Landmesser, “Stem and progenitor cell-based therapy in ischaemic heart disease: promise, uncertainties, and challenges,” European Heart Journal, vol. 32, no. 10, pp. 1197–1206, 2011. View at Publisher · View at Google Scholar · View at Scopus
  74. M. Krampera, “Mesenchymal stromal cell ‘licensing’: a multistep process,” Leukemia, vol. 25, no. 9, pp. 1408–1414, 2011. View at Publisher · View at Google Scholar · View at Scopus
  75. A. Uccelli, L. Moretta, and V. Pistoia, “Mesenchymal stem cells in health and disease,” Nature Reviews Immunology, vol. 8, no. 9, pp. 726–736, 2008. View at Publisher · View at Google Scholar · View at Scopus
  76. J. A. Ankrum, J. F. Ong, and J. M. Karp, “Mesenchymal stem cells: immune evasive, not immune privileged,” Nature Biotechnology, vol. 32, no. 3, pp. 252–260, 2014. View at Publisher · View at Google Scholar · View at Scopus
  77. D. J. Prockop, “Concise review: two negative feedback loops place mesenchymal stem/stromal cells at the center of early regulators of inflammation,” Stem Cells, vol. 31, no. 10, pp. 2042–2046, 2013. View at Publisher · View at Google Scholar · View at Scopus
  78. J. H. Ylöstalo, T. J. Bartosh, K. Coble, and D. J. Prockop, “Human mesenchymal stem/stromal cells cultured as spheroids are self-activated to produce prostaglandin E2 that directs stimulated macrophages into an anti-inflammatory phenotype,” Stem Cells, vol. 30, no. 10, pp. 2283–2296, 2012. View at Publisher · View at Google Scholar · View at Scopus
  79. C. Menard, L. Pacelli, G. Bassi et al., “Clinical-grade mesenchymal stromal cells produced under various good manufacturing practice processes differ in their immunomodulatory properties: standardization of immune quality controls,” Stem Cells and Development, vol. 22, no. 12, pp. 1789–1801, 2013. View at Publisher · View at Google Scholar · View at Scopus
  80. Y. Shi, J. Su, A. I. Roberts, P. Shou, A. B. Rabson, and G. Ren, “How mesenchymal stem cells interact with tissue immune responses,” Trends in Immunology, vol. 33, no. 3, pp. 136–143, 2012. View at Publisher · View at Google Scholar · View at Scopus
  81. Y. Zhou, A. Day, S. Haykal, A. Keating, and T. K. Waddell, “Mesenchymal stromal cells augment CD4+ and CD8+ T-cell proliferation through a CCL2 pathway,” Cytotherapy, vol. 15, no. 10, pp. 1195–1207, 2013. View at Publisher · View at Google Scholar · View at Scopus
  82. M. J. Hoogduijn, M. Roemeling-van Rhijn, A. U. Engela et al., “Mesenchymal stem cells induce an inflammatory response after intravenous infusion,” Stem Cells and Development, vol. 22, no. 21, pp. 2825–2835, 2013. View at Publisher · View at Google Scholar · View at Scopus
  83. K. Anton, D. Banerjee, and J. Glod, “Macrophage-associated mesenchymal stem cells assume an activated, migratory, pro-inflammatory phenotype with increased IL-6 and CXCL10 secretion,” PLoS ONE, vol. 7, no. 4, Article ID e35036, 2012. View at Publisher · View at Google Scholar · View at Scopus
  84. G. Ren, L. Zhang, X. Zhao et al., “Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide,” Cell Stem Cell, vol. 2, no. 2, pp. 141–150, 2008. View at Publisher · View at Google Scholar · View at Scopus
  85. G. C. Gurtner, S. Werner, Y. Barrandon, and M. T. Longaker, “Wound repair and regeneration,” Nature, vol. 453, no. 7193, pp. 314–321, 2008. View at Publisher · View at Google Scholar · View at Scopus
  86. M. W. J. Ferguson and S. O'Kane, “Scar-free healing: from embryonic mechanism to adult therapeutic intervention,” Philosophical Transactions of the Royal Society of London B: Biological Sciences, vol. 359, no. 1445, pp. 839–850, 2004. View at Publisher · View at Google Scholar · View at Scopus
  87. D. Hanahan, “Signaling vascular morphogenesis and maintenance,” Science, vol. 277, no. 5322, pp. 48–50, 1997. View at Publisher · View at Google Scholar · View at Scopus
  88. H. G. Augustin, G. Y. Koh, G. Thurston, and K. Alitalo, “Control of vascular morphogenesis and homeostasis through the angiopoietin—tie system,” Nature Reviews Molecular Cell Biology, vol. 10, no. 3, pp. 165–177, 2009. View at Publisher · View at Google Scholar · View at Scopus
  89. Y. Cao, J. Arbiser, R. J. D'Amato et al., “Forty-year journey of angiogenesis translational research,” Science Translational Medicine, vol. 3, no. 114, Article ID 114rv3, 2011. View at Google Scholar
  90. M. Nomi, H. Miyake, Y. Sugita, M. Fujisawa, and S. Soker, “Role of growth factors and endothelial cells in therapeutic angiogenesis and tissue engineering,” Current Stem Cell Research & Therapy, vol. 1, no. 3, pp. 333–343, 2006. View at Publisher · View at Google Scholar · View at Scopus
  91. E. Gherardi, W. Birchmeier, C. Birchmeier, and G. V. Woude, “Targeting MET in cancer: rationale and progress,” Nature Reviews Cancer, vol. 12, no. 2, pp. 89–103, 2012. View at Publisher · View at Google Scholar · View at Scopus
  92. M. W. Laschke, T. E. Schank, C. Scheuer et al., “Three-dimensional spheroids of adipose-derived mesenchymal stem cells are potent initiators of blood vessel formation in porous polyurethane scaffolds,” Acta Biomaterialia, vol. 9, no. 6, pp. 6876–6884, 2013. View at Publisher · View at Google Scholar · View at Scopus
  93. S. H. Bhang, S. Lee, J.-Y. Shin, T.-J. Lee, and B.-S. Kim, “Transplantation of cord blood mesenchymal stem cells as spheroids enhances vascularization,” Tissue Engineering Part A, vol. 18, no. 19-20, pp. 2138–2147, 2012. View at Publisher · View at Google Scholar · View at Scopus
  94. M. Fu, J. Zhang, Y. Lin, X. Zhu, M. U. Ehrengruber, and Y. E. Chen, “Early growth response factor-1 is a critical transcriptional mediator of peroxisome proliferator-activated receptor-γ1 gene expression in human aortic smooth muscle cells,” The Journal of Biological Chemistry, vol. 277, no. 30, pp. 26808–26814, 2002. View at Publisher · View at Google Scholar · View at Scopus
  95. N.-C. Cheng, S.-Y. Chen, J.-R. Li, and T.-H. Young, “Short-term spheroid formation enhances the regenerative capacity of adipose-derived stem cells by promoting stemness, angiogenesis, and chemotaxis,” Stem Cells Translational Medicine, vol. 2, no. 8, pp. 584–594, 2013. View at Publisher · View at Google Scholar · View at Scopus
  96. C. L. Rettinger, A. B. Fourcaudot, S. J. Hong, T. A. Mustoe, R. G. Hale, and K. P. Leung, “In vitro characterization of scaffold-free three-dimensional mesenchymal stem cell aggregates,” Cell and Tissue Research, vol. 358, no. 2, pp. 395–405, 2014. View at Publisher · View at Google Scholar
  97. W. M. Jackson, L. J. Nesti, and R. S. Tuan, “Mesenchymal stem cell therapy for attenuation of scar formation during wound healing,” Stem Cell Research & Therapy, vol. 3, no. 3, article 20, 2012. View at Publisher · View at Google Scholar · View at Scopus
  98. B. Johnstone, T. M. Hering, A. I. Caplan, V. M. Goldberg, and J. U. Yoo, “In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells,” Experimental Cell Research, vol. 238, no. 1, pp. 265–272, 1998. View at Publisher · View at Google Scholar · View at Scopus
  99. J. U. Yoo, T. S. Barthel, K. Nishimura et al., “The chondrogenic potential of human bone-marrow-derived mesenchymal progenitor cells,” The Journal of Bone & Joint Surgery—American Volume, vol. 80, no. 12, pp. 1745–1757, 1998. View at Google Scholar · View at Scopus
  100. A. M. Mackay, S. C. Beck, J. M. Murphy, F. P. Barry, C. O. Chichester, and M. F. Pittenger, “Chondrogenic differentiation of cultured human mesenchymal stem cells from marrow,” Tissue Engineering, vol. 4, no. 4, pp. 415–428, 1998. View at Publisher · View at Google Scholar · View at Scopus
  101. W. Wang, K. Itaka, S. Ohba et al., “3D spheroid culture system on micropatterned substrates for improved differentiation efficiency of multipotent mesenchymal stem cells,” Biomaterials, vol. 30, no. 14, pp. 2705–2715, 2009. View at Publisher · View at Google Scholar · View at Scopus
  102. N.-C. Cheng, S. Wang, and T.-H. Young, “The influence of spheroid formation of human adipose-derived stem cells on chitosan films on stemness and differentiation capabilities,” Biomaterials, vol. 33, no. 6, pp. 1748–1758, 2012. View at Publisher · View at Google Scholar · View at Scopus
  103. M. C. Arufe, A. de La Fuente, I. Fuentes-Boquete, F. J. de Toro, and F. J. Blanco, “Differentiation of synovial CD-105+ human mesenchymal stem cells into chondrocyte-like cells through spheroid formation,” Journal of Cellular Biochemistry, vol. 108, no. 1, pp. 145–155, 2009. View at Publisher · View at Google Scholar · View at Scopus
  104. Y. Miyagawa, H. Okita, M. Hiroyama et al., “A microfabricated scaffold induces the spheroid formation of human bone marrow-derived mesenchymal progenitor cells and promotes efficient adipogenic differentiation,” Tissue Engineering A, vol. 17, no. 3-4, pp. 513–521, 2011. View at Publisher · View at Google Scholar · View at Scopus
  105. C. J. Lengner, F. D. Camargo, K. Hochedlinger et al., “Oct4 expression is not required for mouse somatic stem cell self-renewal,” Cell Stem Cell, vol. 1, no. 4, pp. 403–415, 2007. View at Publisher · View at Google Scholar · View at Scopus
  106. J. S. Berg and M. A. Goodell, “An argument against a role for Oct4 in somatic stem cells,” Cell Stem Cell, vol. 1, no. 4, pp. 359–360, 2007. View at Publisher · View at Google Scholar · View at Scopus
  107. R. Pochampally, “Colony forming unit assays for MSCs,” Methods in Molecular Biology, vol. 449, pp. 83–91, 2008. View at Google Scholar · View at Scopus
  108. L. Guo, Y. Zhou, S. Wang, and Y. Wu, “Epigenetic changes of mesenchymal stem cells in three-dimensional (3D) spheroids,” Journal of Cellular and Molecular Medicine, vol. 18, no. 10, pp. 2009–2019, 2014. View at Publisher · View at Google Scholar
  109. I. Sekiya, B. L. Larson, J. R. Smith, R. Pochampally, J.-G. Cui, and D. J. Prockop, “Expansion of human adult stem cells from bone marrow stroma: conditions that maximize the yields of early progenitors and evaluate their quality,” Stem Cells, vol. 20, no. 6, pp. 530–541, 2002. View at Publisher · View at Google Scholar · View at Scopus
  110. J. Campisi, “Replicative senescence: an old lives' tale?” Cell, vol. 84, no. 4, pp. 497–500, 1996. View at Publisher · View at Google Scholar · View at Scopus
  111. J. Campisi, “From cells to organisms: can we learn about aging from cells in culture?” Experimental Gerontology, vol. 36, no. 4–6, pp. 607–618, 2001. View at Publisher · View at Google Scholar · View at Scopus
  112. G. Lepperdinger, R. Brunauer, A. Jamnig, G. Laschober, and M. Kassem, “Controversial issue: is it safe to employ mesenchymal stem cells in cell-based therapies?” Experimental Gerontology, vol. 43, no. 11, pp. 1018–1023, 2008. View at Publisher · View at Google Scholar · View at Scopus
  113. P. R. Crisostomo, M. Wang, G. M. Wairiuko et al., “High passage number of stem cells adversely affects stem cell activation and myocardial protection,” Shock, vol. 26, no. 6, pp. 575–580, 2006. View at Publisher · View at Google Scholar · View at Scopus
  114. S. Jiang, H. K. Haider, R. P. H. Ahmed, N. M. Idris, A. Salim, and M. Ashraf, “Transcriptional profiling of young and old mesenchymal stem cells in response to oxygen deprivation and reparability of the infarcted myocardium,” Journal of Molecular and Cellular Cardiology, vol. 44, no. 3, pp. 582–596, 2008. View at Publisher · View at Google Scholar · View at Scopus
  115. C. Fehrer and G. Lepperdinger, “Mesenchymal stem cell aging,” Experimental Gerontology, vol. 40, no. 12, pp. 926–930, 2005. View at Publisher · View at Google Scholar · View at Scopus
  116. M. E. Menezes, S. Bhatia, P. Bhoopathi et al., “MDA-7/IL-24: multifunctional cancer killing cytokine,” in Anticancer Genes, vol. 818 of Advances in Experimental Medicine and Biology, pp. 127–153, Springer, London, UK, 2014. View at Publisher · View at Google Scholar
  117. P. Dent, A. Yacoub, H. A. Hamed et al., “MDA-7/IL-24 as a cancer therapeutic: from bench to bedside,” Anti-Cancer Drugs, vol. 21, no. 8, pp. 725–731, 2010. View at Publisher · View at Google Scholar · View at Scopus
  118. M. Sauane, R. V. Gopalkrishnan, D. Sarkar et al., “MDA-7/IL-24: novel cancer growth suppressing and apoptosis inducing cytokine,” Cytokine and Growth Factor Reviews, vol. 14, no. 1, pp. 35–51, 2003. View at Publisher · View at Google Scholar · View at Scopus
  119. I. A. Droujinine, M. A. Eckert, and W. Zhao, “To grab the stroma by the horns: from biology to cancer therapy with mesenchymal stem cells,” Oncotarget, vol. 4, no. 5, pp. 651–664, 2013. View at Google Scholar · View at Scopus
  120. N. Serakinci, U. Fahrioglu, and R. Christensen, “Mesenchymal stem cells, cancer challenges and new directions,” European Journal of Cancer, vol. 50, no. 8, pp. 1522–1530, 2014. View at Google Scholar · View at Scopus
  121. M. Rodrigues, L. G. Griffith, and A. Wells, “Growth factor regulation of proliferation and survival of multipotential stromal cells,” Stem Cell Research and Therapy, vol. 1, no. 4, article 32, 2010. View at Publisher · View at Google Scholar · View at Scopus
  122. C. Toma, M. F. Pittenger, K. S. Cahill, B. J. Byrne, and P. D. Kessler, “Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart,” Circulation, vol. 105, no. 1, pp. 93–98, 2002. View at Publisher · View at Google Scholar · View at Scopus
  123. C. Toma, W. R. Wagner, S. Bowry, A. Schwartz, and F. Villanueva, “Fate of culture-expanded mesenchymal stem cells in the microvasculature: in vivo observations of cell kinetics,” Circulation Research, vol. 104, no. 3, pp. 398–402, 2009. View at Publisher · View at Google Scholar · View at Scopus
  124. L. von Bahr, I. Batsis, G. Moll et al., “Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation,” Stem Cells, vol. 30, no. 7, pp. 1575–1578, 2012. View at Publisher · View at Google Scholar · View at Scopus
  125. G. L. Semenza, “Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1,” Biochemical Journal, vol. 405, no. 1, pp. 1–9, 2007. View at Publisher · View at Google Scholar · View at Scopus
  126. W. L. Grayson, F. Zhao, B. Bunnell, and T. Ma, “Hypoxia enhances proliferation and tissue formation of human mesenchymal stem cells,” Biochemical and Biophysical Research Communications, vol. 358, no. 3, pp. 948–953, 2007. View at Publisher · View at Google Scholar · View at Scopus
  127. K. Tamama, H. Kawasaki, S. S. Kerpedjieva, J. Guan, R. K. Ganju, and C. K. Sen, “Differential roles of hypoxia inducible factor subunits in multipotential stromal cells under hypoxic condition,” Journal of Cellular Biochemistry, vol. 112, no. 3, pp. 804–817, 2011. View at Publisher · View at Google Scholar · View at Scopus
  128. L. Song, N. E. Webb, Y. Song, and R. S. Tuan, “Identification and functional analysis of candidate genes regulating mesenchymal stem cell self-renewal and multipotency,” Stem Cells, vol. 24, no. 7, pp. 1707–1718, 2006. View at Publisher · View at Google Scholar · View at Scopus
  129. D. J. Barbeau, K. T. La, D. S. Kim, S. S. Kerpedjieva, G. V. Shurin, and K. Tamama, “Early growth response-2 signaling mediates immunomodulatory effects of human multipotential stromal cells,” Stem Cells and Development, vol. 23, no. 2, pp. 155–166, 2014. View at Publisher · View at Google Scholar · View at Scopus
  130. K. A. Hogquist, M. A. Nett, E. R. Unanue, and D. D. Chaplin, “Interleukin 1 is processed and released during apoptosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 19, pp. 8485–8489, 1991. View at Publisher · View at Google Scholar · View at Scopus
  131. R. J. Kaufman and J. D. Malhotra, “Calcium trafficking integrates endoplasmic reticulum function with mitochondrial bioenergetics,” Biochimica et Biophysica Acta—Molecular Cell Research, vol. 1843, no. 10, pp. 2233–2239, 2014. View at Publisher · View at Google Scholar · View at Scopus
  132. S. Orrenius, B. Zhivotovsky, and P. Nicotera, “Regulation of cell death: the calcium-apoptosis link,” Nature Reviews Molecular Cell Biology, vol. 4, no. 7, pp. 552–565, 2003. View at Publisher · View at Google Scholar · View at Scopus
  133. P. Pinton, C. Giorgi, R. Siviero, E. Zecchini, and R. Rizzuto, “Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis,” Oncogene, vol. 27, no. 50, pp. 6407–6418, 2008. View at Publisher · View at Google Scholar · View at Scopus
  134. R. Bonasio, S. Tu, and D. Reinberg, “Molecular signals of epigenetic states,” Science, vol. 330, no. 6004, pp. 612–616, 2010. View at Publisher · View at Google Scholar · View at Scopus
  135. H. Cedar and Y. Bergman, “Linking DNA methylation and histone modification: patterns and paradigms,” Nature Reviews Genetics, vol. 10, no. 5, pp. 295–304, 2009. View at Publisher · View at Google Scholar · View at Scopus
  136. G. Egger, G. Liang, A. Aparicio, and P. A. Jones, “Epigenetics in human disease and prospects for epigenetic therapy,” Nature, vol. 429, no. 6990, pp. 457–463, 2004. View at Publisher · View at Google Scholar · View at Scopus
  137. A. Watanabe, Y. Yamada, and S. Yamanaka, “Epigenetic regulation in pluripotent stem cells: a key to breaking the epigenetic barrier,” Philosophical transactions of the Royal Society of London. Series B, Biological sciences, vol. 368, no. 1609, Article ID 20120292, 2013. View at Google Scholar · View at Scopus
  138. H. Nishida, T. Suzuki, S. Kondo, H. Miura, Y.-I. Fujimura, and Y. Hayashizaki, “Histone H3 acetylated at lysine 9 in promoter is associated with low nucleosome density in the vicinity of transcription start site in human cell,” Chromosome Research, vol. 14, no. 2, pp. 203–211, 2006. View at Publisher · View at Google Scholar · View at Scopus