Effects of Physical, Chemical, and Biological Stimulus on h-MSC Expansion and Their Functional Characteristics

  • David A. Castilla-Casadiego
  • Ana M. Reyes-Ramos
  • Maribella Domenech
  • Jorge AlmodovarEmail author


Human adult mesenchymal stem or stromal cells (h-MSC) therapy has gained considerable attention due to the potential to treat or cure diseases given their immunosuppressive properties and tissue regeneration capabilities. Researchers have explored diverse strategies to promote high h-MSC production without losing functional characteristics or properties. Physical stimulus including stiffness, geometry, and topography, chemical stimulus, like varying the surface chemistry, and biochemical stimuli such as cytokines, hormones, small molecules, and herbal extracts have been studied but have yet to be translated to industrial manufacturing practice. In this review, we describe the role of those stimuli on h-MSC manufacturing, and how these stimuli positively promote h-MSC properties, impacting the cell manufacturing field for cell-based therapies. In addition, we discuss other process considerations such as bioreactor design, good manufacturing practice, and the importance of the cell donor and ethics factors for manufacturing potent h-MSC.


Human adult mesenchymal stem or stromal cells Cell manufacturing Cell therapy 



This work was financially supported by the Engineering Research Center for Cell Manufacturing Technologies (CMaT) of the National Science Foundation under Grant No. EEC-1648035, and by the “Programa de Apoyo Institucional Para la Formación en Estudios de Posgrados en Maestrías y Doctorados de La Universidad del Atlántico, Colombia” by providing DCC a scholarship. Supported by PR-INBRE an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant Number P20 GM103475.


The authors declare that no competing financial interests exist.


  1. 1.
    Aggarwal, S., and M. F. Pittenger. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822, 2005.PubMedCrossRefGoogle Scholar
  2. 2.
    Ahn, H.-J., W.-J. Lee, K. Kwack, and Y. D. Kwon. FGF2 stimulates the proliferation of human mesenchymal stem cells through the transient activation of JNK signaling. FEBS Lett. 583:2922–2926, 2009.PubMedCrossRefGoogle Scholar
  3. 3.
    Anderson, H. J., J. K. Sahoo, R. V. Ulijn, and M. J. Dalby. Mesenchymal stem cell fate: applying biomaterials for control of stem cell behavior. Front. Bioeng. Biotechnol. 4:38, 2016.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Ankrum, J. A., R. G. Dastidar, J. F. Ong, O. Levy, and J. M. Karp. Performance-enhanced mesenchymal stem cells via intracellular delivery of steroids. Sci. Rep. 4:4645, 2014.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Badenes, S. M., T. G. Fernandes, C. A. V. Rodrigues, M. M. Diogo, and J. M. S. Cabral. Microcarrier-based platforms for in vitro expansion and differentiation of human pluripotent stem cells in bioreactor culture systems. J. Biotechnol. 234:71–82, 2016.PubMedCrossRefGoogle Scholar
  6. 6.
    Baker, B. M., B. Trappmann, W. Y. Wang, M. S. Sakar, I. L. Kim, V. B. Shenoy, J. A. Burdick, and C. S. Chen. Cell-mediated fibre recruitment drives extracellular matrix mechanosensing in engineered fibrillar microenvironments. Nat. Mater. 14:1262–1268, 2015.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Baxter, M. A., R. F. Wynn, S. N. Jowitt, J. E. Wraith, L. J. Fairbairn, and I. Bellantuono. Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion. Stem Cells 22:675–682, 2004.PubMedCrossRefGoogle Scholar
  8. 8.
    Bieback, K., A. Hecker, A. Kocaömer, H. Lannert, K. Schallmoser, D. Strunk, and H. Klüter. Human alternatives to fetal bovine serum for the expansion of mesenchymal stromal cells from bone marrow. Stem Cells 27:2331–2341, 2009.PubMedCrossRefGoogle Scholar
  9. 9.
    Bigildeev, A. E., E. A. Zezina, I. N. Shipounova, and N. J. Drize. Interleukin-1 beta enhances human multipotent mesenchymal stromal cell proliferative potential and their ability to maintain hematopoietic precursor cells. Cytokine 71:246–254, 2015.PubMedCrossRefGoogle Scholar
  10. 10.
    Borsellino, N., M. Crescimanno, C. Flandina, V. Leonardi, L. Rausa, and N. D’Alessandro. Antiproliferative and chemomodulatory effects of interferon-gamma on doxorubicin-sensitive and -resistant tumor cell lines. Anticancer Drugs 4:265–272, 1993.PubMedCrossRefGoogle Scholar
  11. 11.
    Bredenoord, A. L., H. Clevers, and J. A. Knoblich. Human tissues in a dish: the research and ethical implications of organoid technology. Science 355:eaaf9414, 2017.PubMedCrossRefGoogle Scholar
  12. 12.
    Bronner, F., and M. C. Farach-Carson. Bone Formation. Berlin: Springer, 2004.CrossRefGoogle Scholar
  13. 13.
    Bruder, S. P., N. Jaiswal, and S. E. Haynesworth. Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation. J. Cell. Biochem. 64:278–294, 1997.PubMedCrossRefGoogle Scholar
  14. 14.
    Burand, A. J., O. W. Gramlich, A. J. Brown, and J. A. Ankrum. Function of cryopreserved mesenchymal stromal cells with and without interferon-γ prelicensing is context dependent. Stem Cells 35:1437–1439, 2017.PubMedCrossRefGoogle Scholar
  15. 15.
    Castilla-Casadiego, D. A., J. R. García, A. J. García, and J. Almodovar. Heparin/collagen coatings improve human mesenchymal stromal cell response to interferon gamma. ACS Biomater. Sci. Eng. 5:2793–2803, 2019.CrossRefGoogle Scholar
  16. 16.
    Chabay, R. W., and B. A. Sherwood. Matter and Interactions (4th ed.). New York: Wiley Global Education, 2015.Google Scholar
  17. 17.
    Chase, L. G., U. Lakshmipathy, L. A. Solchaga, M. S. Rao, and M. C. Vemuri. A novel serum-free medium for the expansion of human mesenchymal stem cells. Stem Cell Res. Ther. 1:8, 2010.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Chen, A. K.-L., Y. K. Chew, H. Y. Tan, S. Reuveny, and S. K. W. Oh. Increasing efficiency of human mesenchymal stromal cell culture by optimization of microcarrier concentration and design of medium feed. Cytotherapy 17:163–173, 2015.PubMedCrossRefGoogle Scholar
  19. 19.
    Chinnadurai, R., D. Rajan, M. Qayed, D. Arafat, M. Garcia, Y. Liu, S. Kugathasan, L. J. Anderson, G. Gibson, and J. Galipeau. Potency analysis of mesenchymal stromal cells using a combinatorial assay matrix approach. Cell Rep. 22:2504–2517, 2018.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Choi, J. H., S. Y. Lyu, H. J. Lee, J. Jung, W. B. Park, and G. J. Kim. Korean mistletoe lectin regulates self-renewal of placenta-derived mesenchymal stem cells via autophagic mechanisms. Cell Prolif. 45:420–429, 2012.PubMedCrossRefGoogle Scholar
  21. 21.
    Collins, J. M., P. H. Goldspink, and B. Russell. Migration and proliferation of human mesenchymal stem cells is stimulated by different regions of the mechano-growth factor prohormone. J. Mol. Cell. Cardiol. 49:1042–1045, 2010.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Cooper, K., A. SenMajumdar, and C. Viswanathan. Derivation, expansion and characterization of clinical grade mesenchymal stem cells from umbilical cord matrix using cord blood serum. Int. J. Stem. Cells 3:119–128, 2010.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Cooper, K., and C. Viswanathan. Establishment of a mesenchymal stem cell bank. Stem Cells Int. 2011:905621, 2011.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Cote, D. J., A. L. Bredenoord, T. R. Smith, M. Ammirati, J. Brennum, I. Mendez, A. S. Ammar, N. Balak, G. Bolles, I. N. Esene, T. Mathiesen, and M. L. Broekman. Ethical clinical translation of stem cell interventions for neurologic disease. Neurology 88:322–328, 2017.PubMedCrossRefGoogle Scholar
  25. 25.
    Croitoru-Lamoury, J., F. M. J. Lamoury, M. Caristo, K. Suzuki, D. Walker, O. Takikawa, R. Taylor, and B. J. Brew. Interferon-γ regulates the proliferation and differentiation of mesenchymal stem cells via activation of indoleamine 2,3 dioxygenase (IDO). PLoS ONE 6:e14698, 2011.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Curran, J. M., R. Chen, and J. A. Hunt. Controlling the phenotype and function of mesenchymal stem cells in vitro by adhesion to silane-modified clean glass surfaces. Biomaterials 26:7057–7067, 2005.PubMedCrossRefGoogle Scholar
  27. 27.
    Curran, J. M., R. Chen, and J. A. Hunt. The guidance of human mesenchymal stem cell differentiation in vitro by controlled modifications to the cell substrate. Biomaterials 27:4783–4793, 2006.PubMedCrossRefGoogle Scholar
  28. 28.
    Curran, J. M., R. Stokes, E. Irvine, D. Graham, N. A. Amro, R. G. Sanedrin, H. Jamil, and J. A. Hunt. Introducing dip pen nanolithography as a tool for controlling stem cell behaviour: unlocking the potential of the next generation of smart materials in regenerative medicine. Lab Chip 10:1662–1670, 2010.PubMedCrossRefGoogle Scholar
  29. 29.
    D’Ippolito, G., P. C. Schiller, C. Ricordi, B. A. Roos, and G. A. Howard. Age-related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow. J. Bone Miner. Res. 14:1115–1122, 1999.PubMedCrossRefGoogle Scholar
  30. 30.
    Discher, D. E., D. J. Mooney, and P. W. Zandstra. Growth factors, matrices, and forces combine and control stem cells. Science 324:1673–1677, 2009.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Dolley-Sonneville, P. J., L. E. Romeo, and Z. K. Melkoumian. Synthetic surface for expansion of human mesenchymal stem cells in xeno-free, chemically defined culture conditions. PLoS ONE 8:e70263, 2013.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Dombrowski, C., T. Helledie, L. Ling, M. Grünert, C. A. Canning, C. Michael Jones, J. H. Hui, V. Nurcombe, A. J. van Wijnen, and S. M. Cool. FGFR1 signaling stimulates proliferation of human mesenchymal stem cells by inhibiting the cyclin-dependent kinase inhibitors p21Waf1and p27Kip1. Stem Cells 31:2724–2736, 2013.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Dufey, V., A. Tacheny, M. Art, U. Becken, and F. De Longueville. Expansion of human bone marrow-derived mesenchymal stem cells in BioBLU 0.3 c single-use bioreactors. Appl. Note 305:1–8, 2016.Google Scholar
  34. 34.
    Egea, V., L. von Baumgarten, C. Schichor, B. Berninger, T. Popp, P. Neth, R. Goldbrunner, Y. Kienast, F. Winkler, M. Jochum, and C. Ries. TNF-α respecifies human mesenchymal stem cells to a neural fate and promotes migration toward experimental glioma. Cell Death Differ. 18:853–863, 2011.PubMedCrossRefGoogle Scholar
  35. 35.
    Eibes, G., F. dos Santos, P. Z. Andrade, J. S. Boura, M. M. A. Abecasis, C. L. da Silva, and J. M. S. Cabral. Maximizing the ex vivo expansion of human mesenchymal stem cells using a microcarrier-based stirred culture system. J. Biotechnol. 146:194–197, 2010.PubMedCrossRefGoogle Scholar
  36. 36.
    Engler, A. J., S. Sen, H. L. Sweeney, and D. E. Discher. Matrix elasticity directs stem cell lineage specification. Cell 126:677–689, 2006.PubMedCrossRefGoogle Scholar
  37. 37.
    Fan, W., R. Crawford, and Y. Xiao. The ratio of VEGF/PEDF expression in bone marrow mesenchymal stem cells regulates neovascularization. Differentiation 81:181–191, 2011.PubMedCrossRefGoogle Scholar
  38. 38.
    Fiedler, J., F. Leucht, J. Waltenberger, C. Dehio, and R. E. Brenner. VEGF-A and PlGF-1 stimulate chemotactic migration of human mesenchymal progenitor cells. Biochem. Biophys. Res. Commun. 334:561–568, 2005.PubMedCrossRefGoogle Scholar
  39. 39.
    Frank, N. D., M. E. Jones, B. Vang, and C. Coeshott. Evaluation of reagents used to coat the hollow-fiber bioreactor membrane of the Quantum® Cell Expansion System for the culture of human mesenchymal stem cells. Mater. Sci. Eng. C Mater. Biol. Appl. 96:77–85, 2019.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Gilbert, P. M., K. L. Havenstrite, K. E. G. Magnusson, A. Sacco, N. A. Leonardi, P. Kraft, N. K. Nguyen, S. Thrun, M. P. Lutolf, and H. M. Blau. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 329:1078–1081, 2010.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Goedhart, M., A. S. Cornelissen, C. Kuijk, S. Geerman, M. Kleijer, J. D. van Buul, S. Huveneers, M. H. G. P. Raaijmakers, H. A. Young, M. C. Wolkers, C. Voermans, and M. A. Nolte. Interferon-gamma impairs maintenance and alters hematopoietic support of bone marrow mesenchymal stromal cells. Stem Cells Dev. 27:579–589, 2018.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Guilak, F., D. M. Cohen, B. T. Estes, J. M. Gimble, W. Liedtke, and C. S. Chen. Control of stem cell fate by physical interactions with the extracellular matrix. Cell Stem Cell 5:17–26, 2009.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Hanley, P. J., Z. Mei, A. G. Durett, M. da Graca Cabreira-Hansen, M. Klis, W. Li, Y. Zhao, B. Yang, K. Parsha, O. Mir, F. Vahidy, D. Bloom, R. B. Rice, P. Hematti, S. I. Savitz, and A. P. Gee. Efficient manufacturing of therapeutic mesenchymal stromal cells with the use of the Quantum Cell Expansion System. Cytotherapy 16:1048–1058, 2014.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Heathman, T. R. J., A. W. Nienow, M. J. McCall, K. Coopman, B. Kara, and C. J. Hewitt. The translation of cell-based therapies: clinical landscape and manufacturing challenges. Regener. Med. 10:49–64, 2015.CrossRefGoogle Scholar
  45. 45.
    Heathman, T. R. J., A. Stolzing, C. Fabian, Q. A. Rafiq, K. Coopman, A. W. Nienow, B. Kara, and C. J. Hewitt. Scalability and process transfer of mesenchymal stromal cell production from monolayer to microcarrier culture using human platelet lysate. Cytotherapy 18:523–535, 2016.PubMedCrossRefGoogle Scholar
  46. 46.
    Heo, S.-J., N. L. Nerurkar, B. M. Baker, J.-W. Shin, D. M. Elliott, and R. L. Mauck. Fiber stretch and reorientation modulates mesenchymal stem cell morphology and fibrous gene expression on oriented nanofibrous microenvironments. Ann. Biomed. Eng. 39:2780–2790, 2011.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Heo, S.-J., S. E. Szczesny, D. H. Kim, K. S. Saleh, and R. L. Mauck. Expansion of mesenchymal stem cells on electrospun scaffolds maintains stemness, mechano-responsivity, and differentiation potential. J. Orthop. Res. 36:808–815, 2018.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Ho, S. S., N. L. Vollmer, M. I. Refaat, O. Jeon, E. Alsberg, M. A. Lee, and J. Kent Leach. Bone morphogenetic protein-2 promotes human mesenchymal stem cell survival and resultant bone formation when entrapped in photocrosslinked alginate hydrogels. Adv. Healthc. Mater. 5:2501–2509, 2016.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Hoffman, M. D., M. Takahata, and D. S. M. Benoit. 6-Bromoindirubin-3′-oxime (BIO) induces proliferation of human mesenchymal stem cells (hMSCs). In: 2011 IEEE 37th Annual Northeast Bioengineering Conference (NEBEC), 2011.Google Scholar
  50. 50.
    Huang, H., H. J. Kim, E.-J. Chang, Z. H. Lee, S. J. Hwang, H.-M. Kim, Y. Lee, and H.-H. Kim. IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling. Cell Death Differ. 16:1332–1343, 2009.PubMedCrossRefGoogle Scholar
  51. 51.
    Ijzermans, J. N. M., and R. L. Marquet. Interferon-gamma: a Review. Immunobiology 179:456–473, 1989.PubMedCrossRefGoogle Scholar
  52. 52.
    Ingber, D. E. Mechanical control of tissue growth: function follows form. Proc Natl Acad Sci USA 102:11571–11572, 2005.PubMedCrossRefGoogle Scholar
  53. 53.
    Ito, T., R. Sawada, Y. Fujiwara, Y. Seyama, and T. Tsuchiya. FGF-2 suppresses cellular senescence of human mesenchymal stem cells by down-regulation of TGF-β2. Biochem. Biophys. Res. Commun 359:108–114, 2007.PubMedCrossRefGoogle Scholar
  54. 54.
    Ito, T., R. Sawada, Y. Fujiwara, and T. Tsuchiya. FGF-2 increases osteogenic and chondrogenic differentiation potentials of human mesenchymal stem cells by inactivation of TGF-beta signaling. Cytotechnology 56:1–7, 2008.PubMedCrossRefGoogle Scholar
  55. 55.
    Jiang, C. M., J. Liu, J. Y. Zhao, L. Xiao, S. An, Y. C. Gou, H. X. Quan, Q. Cheng, Y. L. Zhang, W. He, Y. T. Wang, W. J. Yu, Y. F. Huang, Y. T. Yi, Y. Chen, and J. Wang. Effects of hypoxia on the immunomodulatory properties of human gingiva-derived mesenchymal stem cells. J. Dent. Res. 94:69–77, 2015.PubMedCrossRefGoogle Scholar
  56. 56.
    Jing, D., N. Sunil, S. Punreddy, M. Aysola, D. Kehoe, J. Murrel, M. Rook, and K. Niss. Growth kinetics of human mesenchymal stem cells in a 3-L single-use, stirred-tank bioreactor. BioPharm Int. 26:28–38, 2013.Google Scholar
  57. 57.
    Jones, M., M. Varella-Garcia, M. Skokan, S. Bryce, J. Schowinsky, R. Peters, B. Vang, M. Brecheisen, T. Startz, N. Frank, and B. Nankervis. Genetic stability of bone marrow-derived human mesenchymal stromal cells in the Quantum System. Cytotherapy 15:1323–1339, 2013.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Jossen, V., R. Pörtner, S. C. Kaiser, M. Kraume, D. Eibl, and R. Eibl. Mass production of mesenchymal stem cells—impact of bioreactor design and flow conditions on proliferation and differentiation. Cells Biomater. Regener. Med. 2014. Scholar
  59. 59.
    Jossen, V., C. van den Bos, R. Eibl, and D. Eibl. Manufacturing human mesenchymal stem cells at clinical scale: process and regulatory challenges. Appl. Microbiol. Biotechnol. 102:3981–3994, 2018.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Jung, S., A. Sen, L. Rosenberg, and L. A. Behie. Identification of growth and attachment factors for the serum-free isolation and expansion of human mesenchymal stromal cells. Cytotherapy 12:637–657, 2010.PubMedCrossRefGoogle Scholar
  61. 61.
    Kehoe, D., A. Schnitzler, J. Simler, A. DiLeo, and A. Ball. Scale-up of human mesenchymal stem cells on microcarriers in suspension in a single-use bioreactor. BioPharm Int. 25:28–38, 2012.Google Scholar
  62. 62.
    Kim, D. S., I. K. Jang, M. W. Lee, Y. J. Ko, D.-H. Lee, J. W. Lee, K. W. Sung, H. H. Koo, and K. H. Yoo. Enhanced immunosuppressive properties of human mesenchymal stem cells primed by interferon-γ. EBioMedicine 28:261–273, 2018.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Klinker, M. W., R. A. Marklein, J. L. Lo Surdo, C.-H. Wei, and S. R. Bauer. Morphological features of IFN-γ–stimulated mesenchymal stromal cells predict overall immunosuppressive capacity. Proc Natl Acad Sci 114:E2598–E2607, 2017.PubMedCrossRefGoogle Scholar
  64. 64.
    Kocaoemer, A., S. Kern, H. Klüter, and K. Bieback. Human AB serum and thrombin-activated platelet-rich plasma are suitable alternatives to fetal calf serum for the expansion of mesenchymal stem cells from adipose tissue. Stem Cells 25:1270–1278, 2007.PubMedCrossRefGoogle Scholar
  65. 65.
    Kureel, S. K., P. Mogha, A. Khadpekar, V. Kumar, R. Joshi, S. Das, J. Bellare, and A. Majumder. Soft substrate maintains proliferative and adipogenic differentiation potential of human mesenchymal stem cells on long-term expansion by delaying senescence. Biology Open 8:bio039453, 2019.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Lawson, T., D. E. Kehoe, A. C. Schnitzler, P. J. Rapiejko, K. A. Der, K. Philbrick, S. Punreddy, S. Rigby, R. Smith, Q. Feng, J. R. Murrell, and M. S. Rook. Process development for expansion of human mesenchymal stromal cells in a 50 L single-use stirred tank bioreactor. Biochem. Eng. J. 120:49–62, 2017.CrossRefGoogle Scholar
  67. 67.
    Lechanteur, C. Large-scale clinical expansion of mesenchymal stem cells in the GMP-compliant, closed automated quantum® cell expansion system: comparison with expansion in traditional T-flasks. Int. J. Stem Cell Res. Ther. 4:1000222, 2014.Google Scholar
  68. 68.
    Lechanteur, C., A. Briquet, O. Giet, O. Delloye, E. Baudoux, and Y. Beguin. Clinical-scale expansion of mesenchymal stromal cells: a large banking experience. J. Transl. Med. 14:145, 2016.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Lee, J., A. A. Abdeen, A. S. Kim, and K. A. Kilian. Influence of biophysical parameters on maintaining the mesenchymal stem cell phenotype. ACS Biomater. Sci. Eng. 1:218–226, 2015.CrossRefGoogle Scholar
  70. 70.
    Li, W.-J., C. T. Laurencin, E. J. Caterson, R. S. Tuan, and F. K. Ko. Electrospun nanofibrous structure: a novel scaffold for tissue engineering. J. Biomed. Mater. Res. 60:613–621, 2002.PubMedCrossRefGoogle Scholar
  71. 71.
    Li, C. X., N. P. Talele, S. Boo, A. Koehler, E. Knee-Walden, J. L. Balestrini, P. Speight, A. Kapus, and B. Hinz. MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells. Nat. Mater. 16:379–389, 2017.PubMedCrossRefGoogle Scholar
  72. 72.
    Litwack, G. Stem Cell Regulators. New York: Academic Press, 2011.Google Scholar
  73. 73.
    Maher, S., A. Romero-Weaver, A. Scarzello, and A. Gamero. Interferon: cellular executioner or white knight? Curr. Med. Chem. 14:1279–1289, 2007.PubMedCrossRefGoogle Scholar
  74. 74.
    Malik, N. N., and M. B. Durdy. Cell therapy landscape. Transl. Regener. Med. 2015:87–106, 2015.CrossRefGoogle Scholar
  75. 75.
    Mao, A. S., J.-W. Shin, and D. J. Mooney. Effects of substrate stiffness and cell-cell contact on mesenchymal stem cell differentiation. Biomaterials 98:184–191, 2016.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Mareschi, K., I. Ferrero, D. Rustichelli, S. Aschero, L. Gammaitoni, M. Aglietta, E. Madon, and F. Fagioli. Expansion of mesenchymal stem cells isolated from pediatric and adult donor bone marrow. J. Cell. Biochem. 97:744–754, 2006.PubMedCrossRefGoogle Scholar
  77. 77.
    Marks, P., and S. Gottlieb. Balancing safety and innovation for cell-based regenerative medicine. N. Engl. J. Med. 378:954–959, 2018.PubMedCrossRefGoogle Scholar
  78. 78.
    Martin-Manso, G., and P. J. Hanley. Using the quantum cell expansion system for the automated expansion of clinical-grade bone marrow-derived human mesenchymal stromal cells. Methods Mol. Biol. 1283:53–63, 2015.PubMedCrossRefGoogle Scholar
  79. 79.
    McBeath, R., D. M. Pirone, C. M. Nelson, K. Bhadriraju, and C. S. Chen. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell 6:483–495, 2004.CrossRefGoogle Scholar
  80. 80.
    McLeod, C. M., and R. L. Mauck. On the origin and impact of mesenchymal stem cell heterogeneity: new insights and emerging tools for single cell analysis. Eur. Cell. Mater. 34:217–231, 2017.PubMedCrossRefGoogle Scholar
  81. 81.
    McMurray, R. J., N. Gadegaard, P. M. Tsimbouri, K. V. Burgess, L. E. McNamara, R. Tare, K. Murawski, E. Kingham, R. O. C. Oreffo, and M. J. Dalby. Nanoscale surfaces for the long-term maintenance of mesenchymal stem cell phenotype and multipotency. Nat. Mater. 10:637–644, 2011.PubMedCrossRefGoogle Scholar
  82. 82.
    Mindaye, S. T., J. Lo Surdo, S. R. Bauer, and M. A. Alterman. The proteomic dataset for bone marrow derived human mesenchymal stromal cells: effect of in vitro passaging. Data Brief 5:864–870, 2015.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Mindaye, S. T., M. Ra, J. L. Lo Surdo, S. R. Bauer, and M. A. Alterman. Global proteomic signature of undifferentiated human bone marrow stromal cells: evidence for donor-to-donor proteome heterogeneity. Stem Cell Res. 11:793–805, 2013.PubMedCrossRefGoogle Scholar
  84. 84.
    Mizukami, A., M. S. de Abreu Neto, F. Moreira, A. Fernandes-Platzgummer, Y.-F. Huang, W. Milligan, J. M. S. Cabral, C. L. da Silva, D. T. Covas, and K. Swiech. A fully-closed and automated hollow fiber bioreactor for clinical-grade manufacturing of human mesenchymal stem/stromal cells. Stem Cell Rev. 14:141–143, 2018.CrossRefGoogle Scholar
  85. 85.
    Mizukami, A., T. D. Pereira Chilima, M. D. Orellana, M. A. Neto, D. T. Covas, S. S. Farid, and K. Swiech. Technologies for large-scale umbilical cord-derived MSC expansion: experimental performance and cost of goods analysis. Biochem. Eng. J. 135:36–48, 2018.CrossRefGoogle Scholar
  86. 86.
    Müller, I., S. Kordowich, C. Holzwarth, C. Spano, G. Isensee, A. Staiber, S. Viebahn, F. Gieseke, H. Langer, M. P. Gawaz, E. M. Horwitz, P. Conte, R. Handgretinger, and M. Dominici. Animal serum-free culture conditions for isolation and expansion of multipotent mesenchymal stromal cells from human BM. Cytotherapy 8:437–444, 2006.PubMedCrossRefGoogle Scholar
  87. 87.
    Ng, F., S. Boucher, S. Koh, K. S. R. Sastry, L. Chase, U. Lakshmipathy, C. Choong, Z. Yang, M. C. Vemuri, M. S. Rao, and V. Tanavde. PDGF, TGF-β, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages. Blood 112:295–307, 2008.PubMedCrossRefGoogle Scholar
  88. 88.
    Oh, S., K. S. Brammer, Y. S. J. Li, D. Teng, A. J. Engler, S. Chien, and S. Jin. Stem cell fate dictated solely by altered nanotube dimension. Proc. Natl. Acad. Sci. USA 106:2130–2135, 2009.CrossRefGoogle Scholar
  89. 89.
    Oikonomopoulos, A., W. K. van Deen, A.-R. Manansala, P. N. Lacey, T. A. Tomakili, A. Ziman, and D. W. Hommes. Optimization of human mesenchymal stem cell manufacturing: the effects of animal/xeno-free media. Sci. Rep. 5:16570, 2015.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Oka, N., A. Soeda, A. Inagaki, M. Onodera, H. Maruyama, A. Hara, T. Kunisada, H. Mori, and T. Iwama. VEGF promotes tumorigenesis and angiogenesis of human glioblastoma stem cells. Biochem. Biophys. Res. Commun. 360:553–559, 2007.PubMedCrossRefGoogle Scholar
  91. 91.
    Olsen, T. R., K. S. Ng, L. T. Lock, T. Ahsan, and J. A. Rowley. Peak MSC—are we there yet? Front. Med. 5:178, 2018.CrossRefGoogle Scholar
  92. 92.
    Pagnotto, M. R., Z. Wang, J. C. Karpie, M. Ferretti, X. Xiao, and C. R. Chu. Adeno-associated viral gene transfer of transforming growth factor-β1 to human mesenchymal stem cells improves cartilage repair. Gene Ther. 14:804, 2007.PubMedCrossRefGoogle Scholar
  93. 93.
    Parandakh, A., A. Anbarlou, M. Tafazzoli-Shadpour, A. Ardeshirylajimi, and M.-M. Khani. Substrate topography interacts with substrate stiffness and culture time to regulate mechanical properties and smooth muscle differentiation of mesenchymal stem cells. Colloids Surf. B Biointerfaces 173:194–201, 2019.PubMedCrossRefGoogle Scholar
  94. 94.
    Pittenger, M. F., A. M. Mackay, S. C. Beck, R. K. Jaiswal, R. Douglas, J. D. Mosca, M. A. Moorman, D. W. Simonetti, S. Craig, and D. R. Marshak. Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147, 1999.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Ponte, A. L., T. Ribeiro-Fleury, V. Chabot, F. Gouilleux, A. Langonné, O. Hérault, P. Charbord, and J. Domenech. Granulocyte-colony-stimulating factor stimulation of bone marrow mesenchymal stromal cells promotes CD34 cell migration via a matrix metalloproteinase-2-dependent mechanism. Stem Cells Dev 21:3162–3172, 2012.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Prasanna, S. J., S. Jyothi Prasanna, D. Gopalakrishnan, S. R. Shankar, and A. B. Vasandan. Pro-inflammatory cytokines, IFNγ and TNFα, influence immune properties of human bone marrow and wharton jelly mesenchymal stem cells differentially. PLoS ONE 5:e9016, 2010.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Quarto, R., D. Thomas, and C. T. Liang. Bone progenitor cell deficits and the age-associated decline in bone repair capacity. Calcif. Tissue Int. 56:123–129, 1995.PubMedCrossRefGoogle Scholar
  98. 98.
    Rifas, L. T-cell cytokine induction of BMP-2 regulates human mesenchymal stromal cell differentiation and mineralization. J. Cell. Biochem. 98:706–714, 2006.PubMedCrossRefGoogle Scholar
  99. 99.
    Roemeling-van Rhijn, M., F. K. F. Mensah, S. S. Korevaar, M. J. Leijs, G. J. V. M. van Osch, J. N. M. Ijzermans, M. G. H. Betjes, C. C. Baan, W. Weimar, and M. J. Hoogduijn. Effects of hypoxia on the immunomodulatory properties of adipose tissue-derived mesenchymal stem cells. Front. Immunol. 4:203, 2013.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Russell, A. L., R. C. Lefavor, and A. C. Zubair. Characterization and cost-benefit analysis of automated bioreactor-expanded mesenchymal stem cells for clinical applications. Transfusion 58:2374–2382, 2018.PubMedCrossRefGoogle Scholar
  101. 101.
    Ryan, J. M., F. Barry, J. M. Murphy, and B. P. Mahon. Interferon-γ does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin. Exp. Immunol. 149:353–363, 2007.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Salem, B., S. Miner, N. F. Hensel, M. Battiwalla, K. Keyvanfar, D. F. Stroncek, A. P. Gee, P. J. Hanley, C. M. Bollard, S. Ito, and A. John Barrett. Quantitative activation suppression assay to evaluate human bone marrow—derived mesenchymal stromal cell potency. Cytotherapy 17:1675–1686, 2015.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Saparov, A., V. Ogay, T. Nurgozhin, M. Jumabay, and W. C. W. Chen. Preconditioning of human mesenchymal stem cells to enhance their regulation of the immune response. Stem Cells Int. 2016:3924858, 2016.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Schallmoser, K., C. Bartmann, E. Rohde, A. Reinisch, K. Kashofer, E. Stadelmeyer, C. Drexler, G. Lanzer, W. Linkesch, and D. Strunk. Human platelet lysate can replace fetal bovine serum for clinical-scale expansion of functional mesenchymal stromal cells. Transfusion 47:1436–1446, 2007.PubMedCrossRefGoogle Scholar
  105. 105.
    Schallmoser, K., E. Rohde, C. Bartmann, A. C. Obenauf, A. Reinisch, and D. Strunk. Platelet-derived growth factors for GMP-compliant propagation of mesenchymal stromal cells. Biomed. Mater. Eng. 19:271–276, 2009.PubMedGoogle Scholar
  106. 106.
    Schirmaier, C., V. Jossen, S. C. Kaiser, F. Jüngerkes, S. Brill, A. Safavi-Nab, A. Siehoff, C. van den Bos, D. Eibl, and R. Eibl. Scale-up of adipose tissue-derived mesenchymal stem cell production in stirred single-use bioreactors under low-serum conditions. Eng. Life Sci. 14:292–303, 2014.CrossRefGoogle Scholar
  107. 107.
    Schmidt, A., D. Ladage, T. Schinköthe, U. Klausmann, C. Ulrichs, F.-J. Klinz, K. Brixius, S. Arnhold, B. Desai, U. Mehlhorn, R. H. G. Schwinger, P. Staib, K. Addicks, and W. Bloch. Basic fibroblast growth factor controls migration in human mesenchymal stem cells. Stem Cells 24:1750–1758, 2006.PubMedCrossRefGoogle Scholar
  108. 108.
    Sensebé, L., M. Gadelorge, and S. Fleury-Cappellesso. Production of mesenchymal stromal/stem cells according to good manufacturing practices: a review. Stem Cell Res. Ther. 4:66, 2013.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Shao, Z., X. Zhang, Y. Pi, X. Wang, Z. Jia, J. Zhu, L. Dai, W. Chen, L. Yin, H. Chen, C. Zhou, and Y. Ao. Polycaprolactone electrospun mesh conjugated with an MSC affinity peptide for MSC homing in vivo. Biomaterials 33:3375–3387, 2012.PubMedCrossRefGoogle Scholar
  110. 110.
    Shi, Y., Y. Wang, P. Zhang, and W. Liu. Fibrous scaffolds for tissue engineering Inflammation and Regeneration. Biomaterials 34:023–032, 2014.Google Scholar
  111. 111.
    Shu, Z., X. Kang, H. Chen, X. Zhou, J. Purtteman, D. Yadock, S. Heimfeld, and D. Gao. Development of a reliable low-cost controlled cooling rate instrument for the cryopreservation of hematopoietic stem cells. Cytotherapy 12:161–169, 2010.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Sivanathan, K. N., S. Gronthos, D. Rojas-Canales, B. Thierry, and P. T. Coates. Interferon-gamma modification of mesenchymal stem cells: implications of autologous and allogeneic mesenchymal stem cell therapy in allotransplantation. Stem Cell Rev. 10:351–375, 2014.CrossRefGoogle Scholar
  113. 113.
    Sobel, M. E., and S. R. Wolman. Ethical considerations in the use of human tissues in research. Cytometry 38:192–193, 1999.PubMedCrossRefGoogle Scholar
  114. 114.
    Sotiropoulou, P. A., S. A. Perez, M. Salagianni, C. N. Baxevanis, and M. Papamichail. Characterization of the optimal culture conditions for clinical scale production of human mesenchymal stem cells. Stem Cells 24:462–471, 2006.PubMedCrossRefGoogle Scholar
  115. 115.
    Spoliti, M., P. Iudicone, R. Leone, A. De Rosa, F. R. Rossetti, and L. Pierelli. In vitro release and expansion of mesenchymal stem cells by a hyaluronic acid scaffold used in combination with bone marrow. Muscles Ligaments Tendons J. 2:289–294, 2012.PubMedGoogle Scholar
  116. 116.
    Stenderup, K., J. Justesen, C. Clausen, and M. Kassem. Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone 33:919–926, 2003.PubMedCrossRefGoogle Scholar
  117. 117.
    Strojny, C., M. Boyle, A. Bartholomew, P. Sundivakkam, and S. Alapati. Interferon gamma-treated dental pulp stem cells promote human mesenchymal stem cell migration in vitro. J. Endod. 41:1259–1264, 2015.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Studeny, M., F. C. Marini, R. E. Champlin, C. Zompetta, I. J. Fidler, and M. Andreeff. Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res. 62:3603–3608, 2002.PubMedGoogle Scholar
  119. 119.
    Su, N., P.-L. Gao, K. Wang, J.-Y. Wang, Y. Zhong, and Y. Luo. Fibrous scaffolds potentiate the paracrine function of mesenchymal stem cells: a new dimension in cell-material interaction. Biomaterials 141:74–85, 2017.PubMedCrossRefGoogle Scholar
  120. 120.
    Talele, N. P., J. Fradette, J. E. Davies, A. Kapus, and B. Hinz. Expression of α-smooth muscle actin determines the fate of mesenchymal stromal cells. Stem Cell Rep. 4:1016–1030, 2015.CrossRefGoogle Scholar
  121. 121.
    Tavassoli, H., S. N. Alhosseini, A. Tay, P. P. Y. Chan, S. K. W. Oh, and M. E. Warkiani. Large-scale production of stem cells utilizing microcarriers: a biomaterials engineering perspective from academic research to commercialized products. Biomaterials 181:333–346, 2018.PubMedCrossRefGoogle Scholar
  122. 122.
    Teramura, Y., and H. Iwata. Cell surface modification with polymers for biomedical studies. Soft Matter 6:1081–1091, 2010.CrossRefGoogle Scholar
  123. 123.
    Thirumala, S., S. Zvonic, E. Floyd, J. M. Gimble, and R. V. Devireddy. Effect of various freezing parameters on the immediate post-thaw membrane integrity of adipose tissue derived adult stem cells. Biotechnol. Prog. 21:1511–1524, 2005.PubMedCrossRefGoogle Scholar
  124. 124.
    Thomas, R. J., A. D. Hope, P. Hourd, M. Baradez, E. A. Miljan, J. D. Sinden, and D. J. Williams. Automated, serum-free production of CTX0E03: a therapeutic clinical grade human neural stem cell line. Biotechnol. Lett. 31:1167–1172, 2009.PubMedCrossRefGoogle Scholar
  125. 125.
    Tsutsumi, S., A. Shimazu, K. Miyazaki, H. Pan, C. Koike, E. Yoshida, K. Takagishi, and Y. Kato. Retention of multilineage differentiation potential of mesenchymal cells during proliferation in response to FGF. Biochem. Biophys. Res. Commun. 288:413–419, 2001.PubMedCrossRefGoogle Scholar
  126. 126.
    Udalamaththa, V. L., C. D. Jayasinghe, and P. V. Udagama. Potential role of herbal remedies in stem cell therapy: proliferation and differentiation of human mesenchymal stromal cells. Stem Cell Res. Ther. 7:110, 2016.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Unger, C., H. Skottman, P. Blomberg, M. S. Dilber, and O. Hovatta. Good manufacturing practice and clinical-grade human embryonic stem cell lines. Hum. Mol. Genet. 17:R48–R53, 2008.PubMedCrossRefGoogle Scholar
  128. 128.
    Valencic, E., E. Piscianz, M. Andolina, A. Ventura, and A. Tommasini. The immunosuppressive effect of Wharton’s jelly stromal cells depends on the timing of their licensing and on lymphocyte activation. Cytotherapy 12:154–160, 2010.PubMedCrossRefGoogle Scholar
  129. 129.
    Volarevic, V., B. S. Markovic, M. Gazdic, A. Volarevic, N. Jovicic, N. Arsenijevic, L. Armstrong, V. Djonov, M. Lako, and M. Stojkovic. Ethical and safety issues of stem cell-based therapy. Int. J. Med. Sci. 15:36–45, 2018.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Wall, L., F. Burke, J. F. Smyth, and F. Balkwill. The anti-proliferative activity of interferon-γ on ovarian cancer: in vitro and in vivo. Gynecol Oncol 88:S149–S151, 2003.PubMedCrossRefGoogle Scholar
  131. 131.
    Warrier, S. R., N. Haridas, S. Balasubramanian, A. Jalisatgi, R. Bhonde, and A. Dharmarajan. A synthetic formulation, Dhanwantharam kashaya, delays senescence in stem cells. Cell Prolif. 46:283–290, 2013.PubMedCrossRefGoogle Scholar
  132. 132.
    Wehling, N., G. D. Palmer, C. Pilapil, F. Liu, J. W. Wells, P. E. Müller, C. H. Evans, and R. M. Porter. Interleukin-1β and tumor necrosis factor α inhibit chondrogenesis by human mesenchymal stem cells through NF-κB-dependent pathways. Arthritis Rheum. 60:801–812, 2009.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Windrum, P., T. C. M. Morris, M. B. Drake, D. Niederwieser, T. Ruutu, and EBMT Chronic Leukaemia Working Party Complications Subcommittee. Variation in dimethyl sulfoxide use in stem cell transplantation: a survey of EBMT centres. Bone Marrow Transpl. 36:601–603, 2005.CrossRefGoogle Scholar
  134. 134.
    Wobma, H. M., M. A. Tamargo, S. Goeta, L. M. Brown, R. Duran-Struuck, and G. Vunjak-Novakovic. The influence of hypoxia and IFN-γ on the proteome and metabolome of therapeutic mesenchymal stem cells. Biomaterials 167:226–234, 2018.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Yang, C., M. W. Tibbitt, L. Basta, and K. S. Anseth. Mechanical memory and dosing influence stem cell fate. Nat. Mater. 13:645–652, 2014.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Yeung, T., P. C. Georges, L. A. Flanagan, B. Marg, M. Ortiz, M. Funaki, N. Zahir, W. Ming, V. Weaver, and P. A. Janmey. Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell Motil. Cytoskelet. 60:24–34, 2005.CrossRefGoogle Scholar
  137. 137.
    Yim, E. K. F., and M. P. Sheetz. Force-dependent cell signaling in stem cell differentiation. Stem Cell Res. Ther. 3:41, 2012.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Yun, S. P., M. Y. Lee, J. M. Ryu, C. H. Song, and H. J. Han. Role of HIF-1α and VEGF in human mesenchymal stem cell proliferation by 17β-estradiol: involvement of PKC, PI3K/Akt, and MAPKs. Am. J. Physiol. Cell Physiol. 296:C317–C326, 2009.PubMedCrossRefGoogle Scholar
  139. 139.
    Zhao, F., R. Chella, and T. Ma. Effects of shear stress on 3-D human mesenchymal stem cell construct development in a perfusion bioreactor system: experiments and hydrodynamic modeling. Biotechnol. Bioeng. 96:584–595, 2007.PubMedCrossRefGoogle Scholar
  140. 140.
    Zhao, W., X. Li, X. Liu, N. Zhang, and X. Wen. Effects of substrate stiffness on adipogenic and osteogenic differentiation of human mesenchymal stem cells. Mater. Sci. Eng. C Mater. Biol. Appl. 40:316–323, 2014.PubMedCrossRefGoogle Scholar
  141. 141.
    Zimmermann, J. A., M. H. Hettiaratchi, and T. C. McDevitt. Enhanced Immunosuppression of T cells by sustained presentation of bioactive interferon-γ within three-dimensional mesenchymal stem cell constructs. Stem Cells Transl. Med. 6:223–237, 2017.PubMedCrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2019

Authors and Affiliations

  1. 1.Ralph E. Martin Department of Chemical EngineeringUniversity of ArkansasFayettevilleUSA
  2. 2.Department of Chemical EngineeringUniversity of Puerto Rico MayagüezMayagüezUSA

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