Progenitor Skin Cell Therapy and Evolution of Medical Applications

  • Lee Ann Applegate
  • Paris Jafari
  • Corinne Scaletta
  • Anthony de Buys Roessingh
  • Wassim Raffoul
  • Nathalie Hirt-Burri


Organs and cells can be efficiently used and transformed into intermediate or final products that propose many advances in new medical technology from skin grafting to 3D micro-tissues for biocompatibility and industry testing. For instance, cell sources that can be easily expanded and stocked from allogeneic sources would be interesting in order to avoid the biopsy from the patient and the time necessary to prepare the cells before treatments of patients. Also, cell sources used historically in medicine can provide enough banked cells not only designated for treatment of patients but also for developing innovative testing platforms with uniform primary cell populations.


Progenitor cells Stem cells Burns Musculoskeletal medicine Transplantation Cell bank Mesenchymal stem cell Hemostatic dressing Antimicrobial 



Armed Forces Institute of Regenerative Medicine


Bone marrow mesenchymal stem cell


Department of Defense


Good manufacturing Practice


Graft versus host disease


Master cell bank


Working cell bank


  1. 1.
    Gey GO, Coffman WD, Kubicek MT. Tissue culture studies of the proliferative capacity of cervical carcinoma and normal epithelium. Cancer Res. 1952;12:264–5.Google Scholar
  2. 2.
    Banatvala JE, Brown DWG. Rubella. Lancet. 2004;363:1127–37.CrossRefPubMedGoogle Scholar
  3. 3.
    Jacobs JP, Jones CM, Baille JP. Characteristics of a human diploid cell designated MRC-5. Nature. 1970;227:168–70.CrossRefPubMedGoogle Scholar
  4. 4.
    Palache AM, Brands R, van Scharrenburg GJ. Immunogenicity and reactogenicity of influenza subunit vaccines produced in MCDH cells or fertilized chicken eggs. J Infect Dis. 1997;176:520–3.CrossRefGoogle Scholar
  5. 5.
    Zimmerman RK. Ethical analyses of vaccines grown in human cell strains derived from abortion: arguments and internet search. Vaccine. 2004;22:4238–44.CrossRefPubMedGoogle Scholar
  6. 6.
    Cavallo C, Cuomo C, Fantini S, Ricci F, Tazzari PL, Lucarelli E, Donati D, Facchini A, Lisignoli G, Fornasari PM, Grigolo B, Moroni L. Comparison of alternative mesenchymal stem cell sources for cell banking and musculoskeletal advanced therapies. J Cell Biochem. 2011;112:1418–30.CrossRefPubMedGoogle Scholar
  7. 7.
    Moroni L, Fornasari PM. Human mesenchymal stem cells: a bank perspective on the isolation, characterization and potential of alternative sources for the regeneration of musculoskeletal tissues. J Cell Physiol. 2012;228:680–7.CrossRefGoogle Scholar
  8. 8.
    Tannenbaum SE, Turetsky TT, Singer O, Aizenman E, Kirshberg S, Ilouz N, Gil Y, Berman-Zaken Y, Perlman TS, Geva N, Levy O, Arbell D, Simon A, Ben-Meir A, Shufaro Y, Laufer N, Reubinoff BE. Derivations of xeno-free and GMP-grade human embryonic stem cells- platforms for future clinical applications. PLoS One. 2012;7(6):ee35325.CrossRefGoogle Scholar
  9. 9.
    Van der Valk J, Brunner D, De Smet K, Fex Svenningsen A, Honegger P, Knudsen LE, Lindl T, Noraberg J, Price A, Scarino ML, Gstraunthaler G. Optimization of chemicall defined cell culture media-replacing fetal bovine serum in mammalian in vitro methods. Toxicol In Vitro. 2010;24:1053–63.CrossRefPubMedGoogle Scholar
  10. 10.
    Rheinwald JG, Green H. Serial cultivation of strains of human epidermal keratinocytes, the formation of keratinizing colonies from single cells. Cell. 1975;6:331–44.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    de Buys Roessingh AS, Hohlfeld J, Scaletta C, Hirt-Burri N, Gerber S, et al. Development, characterization and use of a fetal skin cell bank for tissue engineering in wound healing. Cell Transplant. 2006;15:823–34.CrossRefPubMedGoogle Scholar
  12. 12.
    Hohlfeld J, de Buys Roessingh A, Hirt-Burri N, Chaubert P, Gerber S, et al. Tissue-engineered fetal skin constructs for paediatric burns. Lancet. 2005;366:840–2.CrossRefPubMedGoogle Scholar
  13. 13.
    Murry CE, Keller G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell. 2008;132:661–80.CrossRefPubMedGoogle Scholar
  14. 14.
    Quintin A, Hirt-Burri N, Scaletta C, Schizas C, Pioletti DP, Applegate LA. Consistency and safety of fetal cell banks for research and clinical use. Cell Transplant. 2007;16:675–84.CrossRefPubMedGoogle Scholar
  15. 15.
    Kebriaei P, Isola L, Bahceci E, Holland K, Rowley S, et al. Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant. 2009;15:804–11.CrossRefPubMedGoogle Scholar
  16. 16.
    Mack GS. Osiris seals billion-dollar deal with Genzyme for cell therapy. Nat Biotechnol. 2009;27:106–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Newman RE, Yoo D, LeRoux MA, Danilkovitch-Miagkova A. Treatment of inflammatory diseases with mesenchymal stem cells. Inflamm Allergy Drug Targets. 2009;8:110–23.CrossRefPubMedGoogle Scholar
  18. 18.
    Allison M. Genzyme backs Osiris, despite Prachymal flop. Nat Biotechnol. 2009;27:966–77.CrossRefPubMedGoogle Scholar
  19. 19.
    Applegate LA, Hirt-Burri N, Scaletta C, Bauen J-F, Piolotti DP. Bioengineering of human fetal tissues for clinical use. In: Bioengineering: principles, methodologies and applications, Chapter 4. Hauppauge, NY: Nova Sciences Publishers; 2009. p. 1–19. isbn:978-1-60741-7620.Google Scholar
  20. 20.
    Applegate LA, Scaletta C, Hirt-Burri N, Raffoul W, Pioletti DP. Whole-cell bioprocessing of human fetal cells for tissue engineering of skin. Skin Pharmacol Physiol. 2009;22:63–73.CrossRefPubMedGoogle Scholar
  21. 21.
    Applegate LA, Weber D, Simon J-P, Scaletta C, Hirt-Burri N, et al. Organ donation and whole-cell bioprocessing in the Swiss fetal progenitor cell transplantation platform. In: Organ donation and organ donors: issues, challenges and perspectives. Hauppauge, NY: Nova Publications; 2013.Google Scholar
  22. 22.
    Arvidson K, Abdallah BM, Applegate LA, Baldini N, Cenni E, et al. Bone regeneration and stem cells. J Cell Mol Med. 2011;15:718–46.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Darwiche S, Scaletta C, Raffoul W, Pioletti DP, Applegate LA. Epiphyseal chondroprogenitors provide a stable cell source for cartilage cell therapy. Cell Med. 2012;4:23–32.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hirt-Burri N, de Buys Roessingh AS, Scaletta C, Gerber S, Pioletti DP, et al. Human muscular fetal cells: a potential cell source for muscular therapies. Pediatr Surg Int. 2008;24:37–47.CrossRefPubMedGoogle Scholar
  25. 25.
    Hirt-Burri N, Scaletta C, Gerber S, Pioletti DP, Applegate LA. Wound-healing gene family expression differences between fetal and foreskin cells used for bioengineered skin substitutes. Artif Organs. 2008;32:509–18.CrossRefPubMedGoogle Scholar
  26. 26.
    Hirt-Burri N, Ramelet A-A, Raffoul W, de Buys RA, Scaletta C, et al. Biologicals and fetal cell therapy for wound and scar management. ISRN Dermatol. 2011;2011:549870. doi: 10.5402/2011/549870.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Krattinger N, Applegate LA, Pioletti DP, Caverzasio J. Regulation of proliferation and differentiatioon of human fetal bone cells. Eur Cell Mater. 2011;21:46–58.CrossRefPubMedGoogle Scholar
  28. 28.
    Montjovent MO, Burri N, Mark S, Federici E, Scaletta C, et al. Fetal bone cells for tissue engineering. Bone. 2004;35:1323–33.CrossRefPubMedGoogle Scholar
  29. 29.
    Montjovent M-O, Mathieu L, Schmoekel H, Silke M, Bourban P-E, et al. Repair of critical size defects in the rat cranium using ceramic-reinforced PLA scaffolds obtained by supercritical gas foaming. J Biomed Mater Res. 2007;83A:41–51.CrossRefGoogle Scholar
  30. 30.
    Montjovent M-O, Silke M, Mathieu L, Scaletta C, Scherberich A, et al. Human fetal bone cells associated with ceramic reinforced PLA scaffolds for tissue engineering. Bone. 2008;42:554–64.CrossRefPubMedGoogle Scholar
  31. 31.
    Pioletti DP, Montjovent MO, Zambelli P-Y, Applegate LA. Bone tissue engineering using foetal cell therapy. Swiss Med Wkly. 2006;136:557–60.PubMedGoogle Scholar
  32. 32.
    Quintin A, Schizas C, Scaletta C, Jaccoud S, Applegate LA, Pioletti DP. Plasticity of fetal cartilaginous cells. Cell Transplant. 2010;19:1346–57.CrossRefGoogle Scholar
  33. 33.
    Tenorio DMH, Scaletta C, Jaccoud S, Hirt-Burri N, Pioletti DP, et al. Fetal bone cells in delivery systems for bone engineering. J Tissue Eng Regen Med. 2011;5:806–14.CrossRefPubMedGoogle Scholar
  34. 34.
    Capes-Davis A, Theodosopoulos G, Atkin I, Drexler HG, Kohara A, et al. Check your cultures! A list of cross-contaminated or misidentified cell lines. Int J Cancer. 2010;127:1–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Torsvik A, Røsland GV, Svendsen A, Molven A, Immervoll H, et al. Spontaneous malignant transformation of human mesenchymal stem cells reflects cross-contamination: putting the research field on track. Cancer Res. 2010;70:6393–6.CrossRefPubMedGoogle Scholar
  36. 36.
    Mosna F, Sensebé L, Krampera M. Human bone marrow and adipose tissue mesenchymal stem cells: a user’s guide. Stem Cells Dev. 2010;19:1449–70.CrossRefPubMedGoogle Scholar
  37. 37.
    Bhattacharya N. Fetal cell/tissue therapy in adult disease: a new horizon in regenerative medicine. Clin Exp Obstet Gynecol. 2004;31:167–73.PubMedGoogle Scholar
  38. 38.
    Montjovent MO, Bocelli-Tyndal C, Scaletta C, Scherberich A, Martin I, et al. In vitro characterization of immune-related properties of human fetal bone cells for potential tissue engineering applications. Tissue Eng Part A. 2009;15:1523–32.CrossRefPubMedGoogle Scholar
  39. 39.
    Oster H, Wilson DI, Hanley NA. Human embryo and early fetus research. Clin Genet. 2006;70:98–107.CrossRefGoogle Scholar
  40. 40.
    Quintin A, Schizas C, Scaletta C, Jaccoud S, Chapuis-Bernasconi C, et al. Human fetal spine as a source of cells for intervertebral disc regeneration. J Mol Cell Med. 2009;13:1–12.CrossRefGoogle Scholar
  41. 41.
    Ramelet A-A, Hirt-Burri N, Raffoul W, Scaletta C, Pioletti DP, et al. Chronic wound healing by fetal cell therapy may be explained by differential gene profiling observed in fetal versus old skin cells. Exp. Gerontology. 2008;44:208–18.Google Scholar
  42. 42.
    Ng KW, Khor HL, Hutmacher DW. In vitro characterization of natural and synthetic dermal matrices cultured with human dermal fibroblasts. Biomaterials. 2004;25:2807–18.CrossRefPubMedGoogle Scholar
  43. 43.
    Borcard F, Godinat A, Staedler D, Comas Blanco H, Dumont A-L, et al. Covalent cell surface functionalization of human fetal osteoblasts for tissue engineering. Bioconjug Chem. 2011;22:1422–32.CrossRefPubMedGoogle Scholar
  44. 44.
    Krauss JF, Borcard F, Staedler D, Scaletta C, Applegate LA, et al. Functionalization of microstructured open-porous bioceramic scaffolds with human fetal bone cells. Bioconjug Chem. 2012;23:2278–90.CrossRefGoogle Scholar
  45. 45.
    Addor V, Narring F, Michaud P-A. Abortion trends 1990–1999 in a Swiss region and determinants of abortion recurrence. Swiss Med Wkly. 2003;133:219–26.PubMedGoogle Scholar
  46. 46.
    Wyss D, Wirthner D, Renteria SC, De Grandi P. Les demandes d’interruption de grossesse de 1988 à 2002 au CHUV. Rev Med Suisse. 2004;2503:1–8.Google Scholar
  47. 47.
    Yanow S. It is time to integrate abortion into primary care. Am J Public Health. 2013;103:14–6.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    EU. Setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells. In: Parliament E, editor. Directive 2004/23/EC; 2004.Google Scholar
  49. 49.
    EU. Implementing Directive 2004/23/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cells. In: Parliament E, editor. Directive 2006/17/EC, 2006.Google Scholar
  50. 50.
    EU. Implementing Directive 2004/23/EC of the European Parliament and of the Council as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells. In: Parliament E, editor. Directive 2006/86/EC, 2006.Google Scholar
  51. 51.
    PMP/ICH. Note for guidance on quality of biotechnological products: derivation and characterisation of cell substrates used for production of biotechnological/biological products. CPMP/ICH/294/95, 2001.Google Scholar
  52. 52.
    SwissMedics, Swiss Federal Council Transplantation Law, TxL; SR 81021, 2007.Google Scholar
  53. 53.
    Brantley JN, Verla TD. Use of placental membranes for the treatment of chronic diabetic foot ulcers. Adv Wound Care. 2015;4(9):545–59. doi: 10.1089/wound.2015.0634.CrossRefGoogle Scholar
  54. 54.
    Badylak SF, Freytes DO, Gilbert TW. Extracellular matrix as a biological scaffold material: structure and function. Acta Biomater. 2009;5:1–13.CrossRefPubMedGoogle Scholar
  55. 55.
    Gravante G, Di Fede MC, Araco A, Grimaldi M, De Angelis B, et al. A randomized trial comparing ReCell system of epidermal cells delivery versus classic skin grafts for the treatment of deep partial thickness burns. Burns. 2007;33:966–72.CrossRefPubMedGoogle Scholar
  56. 56.
    Wood FM, Giles N, Stevenson A, Rea S, Fear M. Characterisation of the cell suspension harvested from the dermal epidermal junction using a ReCell kit. Burns. 2012;38:44–51.CrossRefPubMedGoogle Scholar
  57. 57.
    Centanni JM, Straseski JA, Wicks A, Hank JA, Rasmussen CA, et al. StrataGraft skin substitutes well-tolerated and is not acutely immunogenic in patients with traumatic wounds. Ann Surg. 2011;253:1–12.CrossRefGoogle Scholar
  58. 58.
    Marra KG, Rubin JP. The potential of adipose-derived stem cells in craniofacial repair and regeneration. Birth Defects Res C Embryo Today. 2012;96:95–7.CrossRefPubMedGoogle Scholar
  59. 59.
    Cazzell SM, Lange DL, Dickerson JE, Slade HB. The management of diabetic foot ulcers with porcine small intestine submucosa tri-layer matrix: a randomized controlled trial. Adv Wound Care. 2015;4(12):711–8. doi: 10.1089/wound.2015.0645.CrossRefGoogle Scholar
  60. 60.
    Duan-Arnold Y, Gyurdieva A, Johnson A, Uveges TE, Jacobstein DA, Danilkovitch A. Retention of endogenous viable cells enhances the anti-inflammatory activity of cryopreserved amnion. Advances Wound Care. 2015;4(9):523–33. doi: 10.1089/wound.2015.0636.CrossRefGoogle Scholar
  61. 61.
    Hart CE, Loewen-Rodriguez A, Lessem J. Dermagraft : use in the treatment of chronic wounds. Adv Wound Care. 2011; doi: 10.1089/wound.2011.0282.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Soejima K, Shimoda K, Kashimura T, Yamaki T, Kono T, Sakurai H, Nakazawa H. Wound dressing material containing lyophilized allogeneic cultured cells. Cryobiology. 2013;66:210–4.CrossRefPubMedGoogle Scholar
  63. 63.
    Zhou Y, Gan SU, Lin G, Lim YT, Masilamani J, Mustafa FB, Phua ML, Rivino L, Phan TT, Lee KO, Calne R, MacAry PA. Characterization of human umbilical cord lining-derived epithelial cells and tranplantation potential. Cell Transplant. 2011;20:1827–41.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Lee Ann Applegate
    • 1
  • Paris Jafari
    • 1
  • Corinne Scaletta
    • 1
  • Anthony de Buys Roessingh
    • 2
  • Wassim Raffoul
    • 1
  • Nathalie Hirt-Burri
    • 1
  1. 1.Department of Musculoskeletal Medicine, Plastic, Reconstructive and Hand Surgery, Unit of Regenerative TherapyUniversity Hospital of LausanneEpalingesSwitzerland
  2. 2.Department of Pediatric SurgeryUniversity Hospital of LausanneLausanneSwitzerland

Personalised recommendations