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Stem Cell Applications for the Treatment of Gastrointestinal System Diseases

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Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

Gastrointestinal system is formed by organs with complex morphology and functions. Digestive tract is not a sterile medium and is exposed to external environment aggressions. As a result, its diseases are complex and encompass a broad spectrum of pathogenic mechanisms and their treatment is often challenging and frequently incurable or chronicity-tending processes are found. In this scenario, stem cells with their differentiation potential and encouraging properties could be helpful. Nowadays Stem Cells have yielded promising results in preclinical studies, some approaches have started clinical development and registered clinical trials are exponentially increasing every year. In 2011, the most advanced programs, involving Crohn’s disease and fistulous disease, have reached phase III of development. Other tested diseases include ulcerative colitis, fecal incontinence or celiac disease. If the preliminary results are confirmed, we think that this therapy may become a clinical reality in the near future. In this chapter, we summarize Stem Cells potential benefits, the current experience and the future perspectives in gastrointestinal system diseases.

Keywords

Ulcerative Colitis Celiac Disease Fibrin Glue Graft Versus Host Disease Stromal Vascular Fraction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

SCs

Stem Cells

ESCs

Embryonic Stem Cells

ASs

Adult Stem cells

iPS

Induced Pluripotent Stem

BM-MSCs

Bone Marrow derived Mesenchymal Stem Cells

MAPCS

Multipotent Adult Progenitor Cells

ASCs

Adipose derived Stem Cells

HSCs

Hematopoietic Stem Cells

GISCs

GastroIntestinal Stem Cells

LPCs

Liver Progenitor Cells

EPCs

Endothelial Progenitor Cells

CBC

Cript Base Columnar cells

BMSC

Bone Marrow Stem Cells

CDAI

Crohn’s Disease Activity Index

IBDQ

Inflammatory Bowel Disease Questionnaire

BM-MNCs

Bone Marrow Mononuclear Cells

SVF

Stromal Vascular Fraction from lipoaspirate

PDSCs

Placental Derived Stem Cells

U-MSCs

Umbilical derived Mesenchymal Stem Cells

Notes

Acknowledgments

The authors would like to express their gratitude to all the staff of the Stem Cell Therapy Laboratory of “La Paz” University Hospital (Madrid, Spain), to staff of Investigation Institute IdiPAZ (Madrid, Spain) and of both General and Digestive Surgery Department from “La Paz” University Hospital and “Nuestra Señora de Sonsoles” Hospital (Avila, Spain). We also would like to acknowledge our families for their continuous support during drafting of this chapter.

References

  1. 1.
    Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, Neutzel S, Sharkis SJ (2001) Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105(3):369–377PubMedCrossRefGoogle Scholar
  2. 2.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147PubMedCrossRefGoogle Scholar
  3. 3.
    Joannides A, Gaughwin P, Schwiening C, Majed H, Sterling J, Compston A, Chandran S (2004) Efficient generation of neural precursors from adult human skin: astrocytes promote neurogenesis from skin-derived stem cells. Lancet 364(9429):172–178PubMedCrossRefGoogle Scholar
  4. 4.
    Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH (2002) Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13(12):4279–4295PubMedCrossRefGoogle Scholar
  5. 5.
    Liu D, Wang F, Zou Z, Dong S, Shi C, Wang J, Ran X, Su Y (2010) Long-term repopulation effects of donor BMDCs on intestinal epithelium. Dig Dis Sci 55(8):2182–2193PubMedCrossRefGoogle Scholar
  6. 6.
    Rizvi AZ, Swain JR, Davies PS, Bailey AS, Decker AD, Willenbring H, Grompe M, Fleming WH, Wong MH (2006) Bone marrow-derived cells fuse with normal and transformed intestinal stem cells. Proc Nat Acad Sci USA 103(16):6321–6325PubMedCrossRefGoogle Scholar
  7. 7.
    Houlihan DD, Newsome PN (2008) Critical review of clinical trials of bone marrow stem cells in liver disease. Gastroenterology 135(2):438–450PubMedCrossRefGoogle Scholar
  8. 8.
    Yannaki E, Athanasiou E, Xagorari A, Constantinou V, Batsis I, Kaloyannidis P, Proya E, Anagnostopoulos A, Fassas A (2005) G-CSF-primed hematopoietic stem cells or G-CSF per se accelerate recovery and improve survival after liver injury, predominantly by promoting endogenous repair programs. Exp Hematol 33(1):108–119PubMedCrossRefGoogle Scholar
  9. 9.
    Uccelli A, Moretta L, Pistoia V (2006) Immunoregulatory function of mesenchymal stem cells. Eur J Immunol 36(10):2566–2573PubMedCrossRefGoogle Scholar
  10. 10.
    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy 8(4):315–317PubMedCrossRefGoogle Scholar
  11. 11.
    Planat-Benard V, Silvestre JS, Cousin B, Andre M, Nibbelink M, Tamarat R, Clergue M, Manneville C, Saillan-Barreau C, Duriez M, Tedgui A, Levy B, Penicaud L, Casteilla L (2004) Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation 109(5):656–663PubMedCrossRefGoogle Scholar
  12. 12.
    Francois S, Bensidhoum M, Mouiseddine M, Mazurier C, Allenet B, Semont A, Frick J, Sache A, Bouchet S, Thierry D, Gourmelon P, Gorin NC, Chapel A (2006) Local irradiation not only induces homing of human mesenchymal stem cells at exposed sites but promotes their widespread engraftment to multiple organs: a study of their quantitative distribution after irradiation damage. Stem Cells 24(4):1020–1029PubMedCrossRefGoogle Scholar
  13. 13.
    Mouiseddine M, Francois S, Semont A, Sache A, Allenet B, Mathieu N, Frick J, Thierry D, Chapel A (2007) Human mesenchymal stem cells home specifically to radiation-injured tissues in a non-obese diabetes/severe combined immunodeficiency mouse model. Br J Radiol 80(Spec No 1): S49–55Google Scholar
  14. 14.
    Verfaillie CM (2002) Adult stem cells: assessing the case for pluripotency. Trends Cell Biol 12(11):502–508PubMedCrossRefGoogle Scholar
  15. 15.
    Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH (2001) Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7(2):211–228PubMedCrossRefGoogle Scholar
  16. 16.
    Qiao XT, Ziel JW, McKimpson W, Madison BB, Todisco A, Merchant JL, Samuelson LC, Gumucio DL (2007) Prospective identification of a multilineage progenitor in murine stomach epithelium. Gastroenterology 133(6):1989–1998PubMedCrossRefGoogle Scholar
  17. 17.
    Cheng H, Leblond CP (1974) Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian theory of the origin of the four epithelial cell types. Am J Anat 141(4):537–561PubMedCrossRefGoogle Scholar
  18. 18.
    Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449(7165):1003–1007PubMedCrossRefGoogle Scholar
  19. 19.
    Yan L, Cai C, Li J, Xu S, Chang Q, Li Y, Wu B (2009) Present status and perspectives of stem cell-based therapies for gastrointestinal diseases. Stem Cell Rev 5(3):278–282PubMedCrossRefGoogle Scholar
  20. 20.
    Brittan M, Hunt T, Jeffery R, Poulsom R, Forbes SJ, Hodivala-Dilke K, Goldman J, Alison MR, Wright NA (2002) Bone marrow derivation of pericryptal myofibroblasts in the mouse and human small intestine and colon. Gut 50(6):752–757PubMedCrossRefGoogle Scholar
  21. 21.
    Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459(7244):262–265PubMedCrossRefGoogle Scholar
  22. 22.
    Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, Sato T, Stange DE, Begthel H, van den Born M, Danenberg E, van den Brink S, Korving J, Abo A, Peters PJ, Wright N, Poulsom R, Clevers H (2010) Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6(1):25–36PubMedCrossRefGoogle Scholar
  23. 23.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676PubMedCrossRefGoogle Scholar
  24. 24.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872PubMedCrossRefGoogle Scholar
  25. 25.
    Iwamuro M, Komaki T, Kubota Y, Seita M, Kawamoto H, Yuasa T, Shahid JM, Hassan RA, Hassan WA, Nakaji S, Nishikawa Y, Kondo E, Yamamoto K, Fox IJ, Kobayashi N (2010) Hepatic differentiation of mouse iPS cells in vitro. Cell Transplant 19(6):841–847PubMedCrossRefGoogle Scholar
  26. 26.
    Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, RingdÈn O (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371(9624):1579–1586PubMedCrossRefGoogle Scholar
  27. 27.
    Espinoza-Delgado I, Childs RW (2004) Nonmyeloablative transplantation for solid tumors: a new frontier for allogeneic immunotherapy. Expert Rev Anticancer Ther 4(5):865–875PubMedCrossRefGoogle Scholar
  28. 28.
    Lundqvist A, Childs R (2005) Allogeneic hematopoietic cell transplantation as immunotherapy for solid tumors: current status and future directions. J Immunother 28(4):281–288PubMedCrossRefGoogle Scholar
  29. 29.
    Nakagami H, Maeda K, Morishita R, Iguchi S, Nishikawa T, Takami Y, Kikuchi Y, Saito Y, Tamai K, Ogihara T, Kaneda Y (2005) Novel autologous cell therapy in ischemic limb disease through growth factor secretion by cultured adipose tissue-derived stromal cells. Arterioscler Thromb Vasc Biol 25(12):2542–2547PubMedCrossRefGoogle Scholar
  30. 30.
    Joggerst SJ, Hatzopoulos AK (2009) Stem cell therapy for cardiac repair: benefits and barriers. Expert Rev Mol Med 11:e20Google Scholar
  31. 31.
    Chen L, Tredget EE, Wu PY, Wu Y (2008) Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS ONE 3(4):e1886PubMedCrossRefGoogle Scholar
  32. 32.
    Taupin P (2006) Adult neural stem cells, neurogenic niches, and cellular therapy. Stem Cell Rev Rep 2(3):213–219CrossRefGoogle Scholar
  33. 33.
    Zani A, Pierro A, Elvassore N, De Coppi P (2009) Tissue engineering: an option for esophageal replacement? Semin Pediatr Surg 18(1):57–62PubMedCrossRefGoogle Scholar
  34. 34.
    Fascetti-Leon F, Malerba A, Boldrin L, Leone E, Betalli P, Pasut A, Zanon GF, Gamba PG, Vitiello L, De Coppi P (2007) Murine muscle precursor cells survived and integrated in a cryoinjured gastroesophageal junction. J Surg Res 143(2):253–259PubMedCrossRefGoogle Scholar
  35. 35.
    Hutchinson L, Stenstrom B, Chen D, Piperdi B, Levey S, Lyle S, Wang T, Houghton J-M (2010) Human Barrett’s adenocarcinoma of the esophagus, associated myofibroblasts and endothelium can arise from bone marrow derived cells after allogeneic stem cell transplant. Stem Cells Dev 20(1):11–17PubMedCrossRefGoogle Scholar
  36. 36.
    Askarov M, Vostrikova O, Vorobjova N, Onishenko N (2008) Effects of autologous bone marrow cells on apoptosis and regeneration of non-healing autoimmune gastric ulcers. Bull Exp Biol Med 146(5):647–651PubMedCrossRefGoogle Scholar
  37. 37.
    Hayashi Y, Tsuji S, Tsujii M, Nishida T, Ishii S, Iijima H, Nakamura T, Eguchi H, Miyoshi E, Hayashi N, Kawano S (2008) Topical transplantation of mesenchymal stem cells accelerates gastric ulcer healing in rats. Am J Physiol Gastrointest Liver Physiol 294(3):G778–G786PubMedCrossRefGoogle Scholar
  38. 38.
    Komori M, Tsuji S, Tsujii M, Murata H, Iijima H, Yasumaru M, Nishida T, Irie T, Kawano S, Hori M (2005) Efficiency of bone marrow-derived cells in regeneration of the stomach after induction of ethanol-induced ulcers in rats. J Gastroenterol 40(6):591PubMedCrossRefGoogle Scholar
  39. 39.
    Ismail A, Ramsis R, Sherif A, Thabet A, El-Ghor H, Selim A (2009) Use of human amniotic stem cells for common bile duct reconstruction: vascularized support of a free amnion graft. Med Sci Monit 15(9): BR243–BR247Google Scholar
  40. 40.
    Lin YX, Yan LN, Cheng NS (2009) Application of bone marrow cells: a novel therapy for bile leak? Med Hypotheses 73(3):374–376PubMedCrossRefGoogle Scholar
  41. 41.
    Semont A, Francois S, Mouiseddine M, Francois A, Sache A, Frick J, Thierry D, Chapel A (2006) Mesenchymal stem cells increase self-renewal of small intestinal epithelium and accelerate structural recovery after radiation injury. Adv Exp Med Biol 585:19–30PubMedCrossRefGoogle Scholar
  42. 42.
    Okamoto R, Matsumoto T, Watanabe M (2006) Regeneration of the intestinal epithelia: regulation of bone marrow-derived epithelial cell differentiation towards secretory lineage cells. Hum Cell 19(2):71–75PubMedCrossRefGoogle Scholar
  43. 43.
    Devine SM, Cobbs C, Jennings M, Bartholomew A, Hoffman R (2003) Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood 101(8):2999–3001PubMedCrossRefGoogle Scholar
  44. 44.
    Zhang J, Gong JF, Zhang W, Zhu WM, Li JS (2008) Effects of transplanted bone marrow mesenchymal stem cells on the irradiated intestine of mice. J Biomed Sci 15(5):585–594PubMedCrossRefGoogle Scholar
  45. 45.
    Sala FG, Kunisaki SM, Ochoa ER, Vacanti J, Grikscheit TC (2009) Tissue-engineered small intestine and stomach form from autologous tissue in a preclinical large animal model. J Surg Res 156(2):205–212PubMedCrossRefGoogle Scholar
  46. 46.
    Avansino JR, Chen DC, Hoagland VD, Woolman JD, Stelzner M (2006) Orthotopic transplantation of intestinal mucosal organoids in rodents. Surgery 140(3):423–434PubMedCrossRefGoogle Scholar
  47. 47.
    Agopian V, Chen D, Avansino J, Stelzner M (2009) Intestinal stem cell organoid transplantation generates neomucosa in dogs. J Gastrointest Surg 13(5):971–982PubMedCrossRefGoogle Scholar
  48. 48.
    Spence JR, Mayhew CN, Rankin SA, Kuhar MF, Vallance JE, Tolle K, Hoskins EE, Kalinichenko VV, Wells SI, Zorn AM, Shroyer NF, Wells JM (2011) Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470(7332):105–109PubMedCrossRefGoogle Scholar
  49. 49.
    Hori Y, Nakamura T, Kimura D, Kaino K, Kurokawa Y, Satomi S, Shimizu Y (2002) Experimental study on tissue engineering of the small intestine by mesenchymal stem cell seeding. J Surg Res 102(2):156–160PubMedCrossRefGoogle Scholar
  50. 50.
    Nakase Y, Hagiwara A, Nakamura T, Kin S, Nakashima S, Yoshikawa T, Fukuda K-I, Kuriu Y, Miyagawa K, Sakakura C, Otsuji E, Shimizu Y, Ikada Y, Yamagishi H (2006) Tissue engineering of small intestinal tissue using collagen sponge scaffolds seeded with smooth muscle cells. Tissue Eng 12(2):403–412PubMedCrossRefGoogle Scholar
  51. 51.
    Sirbu-Boeti MP, Chivu M, Paslaru LL, Efrimescu C, Herlea V, Pecheanu C, Moldovan L, Dragomir L, Bleotu C, Ciucur E, Vidulescu C, Vasilescu M, Boicea A, Manoiu S, Ionescu MI, Popescu I (2009) Transplantation of mesenchymal stem cells cultured on biomatrix support induces repairing of digestive tract defects, in animal model. Chirurgia (Bucur) 104(1):55–65Google Scholar
  52. 52.
    Metzger M, Caldwell C, Barlow AJ, Burns AJ, Thapar N (2009) Enteric nervous system stem cells derived from human gut mucosa for the treatment of aganglionic gut disorders. Gastroenterology 136(7): 2214–2225.e2213Google Scholar
  53. 53.
    Lindley RM, Hawcutt DB, Connell MG, Almond SN, Vannucchi MÄ, Faussone-Pellegrini MS, Edgar DH, Kenny SE (2008) Human and mouse enteric nervous system neurosphere transplants regulate the function of aganglionic embryonic distal colon. Gastroenterology 135(1): 205–216.e206Google Scholar
  54. 54.
    Tadauchi A, Narita Y, Kagami H, Niwa Y, Ueda M, Goto H (2009) Novel cell-based therapeutic strategy for ischemic colitis with use of bone marrow-derived mononuclear cells in rats. Dis Colon Rectum 52(8):1443–1451PubMedCrossRefGoogle Scholar
  55. 55.
    Lorenzi B, Pessina F, Lorenzoni P, Urbani S, Vernillo R, Sgaragli G, Gerli R, Mazzanti B, Bosi A, Saccardi R, Lorenzi M (2008) Treatment of experimental injury of anal sphincters with primary surgical repair and injection of bone marrow-derived mesenchymal stem cells. Dis Colon Rectum 51(4):411–420PubMedCrossRefGoogle Scholar
  56. 56.
    Kang SB, Lee HN, Lee JY, Park JS, Lee HS (2008) Sphincter contractility after muscle-derived stem cells autograft into the cryoinjured anal sphincters of rats. Dis Colon Rectum 51(9):1367–1373PubMedCrossRefGoogle Scholar
  57. 57.
    Saihara R, Komuro H, Urita Y, Hagiwara K, Kaneko M (2009) Myoblast transplantation to defecation muscles in a rat model: a possible treatment strategy for fecal incontinence after the repair of imperforate anus. Pediatr Surg Int 25(11):981–986PubMedCrossRefGoogle Scholar
  58. 58.
    Aghaee-Afshar M, Rezazadehkermani M, Asadi A, Malekpour-Afshar R, Shahesmaeili A, Nematollahi-mahani SN (2009) Potential of human umbilical cord matrix and rabbit bone marrow-derived mesenchymal stem cells in repair of surgically incised rabbit external anal sphincter. Dis Colon Rectum 52(10):1753–1761PubMedCrossRefGoogle Scholar
  59. 59.
    Kajbafzadeh AM, Elmi A, Talab SS, Esfahani SA, Tourchi A (2010) Functional external anal sphincter reconstruction for treatment of anal incontinence using muscle progenitor cell auto grafting. Dis Colon Rectum 53(10):1415–1421PubMedCrossRefGoogle Scholar
  60. 60.
    Gonzalez MA, Gonzalez-Rey E, Rico L, Buscher D, Delgado M (2009) Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology 136(3):978–989PubMedCrossRefGoogle Scholar
  61. 61.
    Hayashi Y, Tsuji S, Tsujii M, Nishida T, Ishii S, Iijima H, Nakamura T, Eguchi H, Miyoshi E, Hayashi N, Kawano S (2008) Topical Implantation of mesenchymal stem cells has beneficial effects on healing of experimental colitis in rats. J Pharmacol Exp Ther 326(2):523–531PubMedCrossRefGoogle Scholar
  62. 62.
    Wei Y, Nie Y, Lai J, Wan YJ, Li Y (2009) Comparison of the population capacity of hematopoietic and mesenchymal stem cells in experimental colitis rat model. Transplantation 88(1):42–48PubMedCrossRefGoogle Scholar
  63. 63.
    Khalil PN, Weiler V, Nelson PJ, Khalil MN, Moosmann S, Mutschler WE, Siebeck M, Huss R (2007) Nonmyeloablative stem cell therapy enhances microcirculation and tissue regeneration in murine inflammatory bowel disease. Gastroenterology 132(3):944–954PubMedCrossRefGoogle Scholar
  64. 64.
    Ando Y, Inaba M, Sakaguchi Y, Tsuda M, Quan GK, Omae M, Okazaki K, Ikehara S (2008) Subcutaneous adipose tissue-derived stem cells facilitate colonic mucosal recovery from 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. Inflamm Bowel Dis 14(6):826–838PubMedCrossRefGoogle Scholar
  65. 65.
    Dryden GW (2009) Overview of stem cell therapy for Crohn’s disease. Expert Opin Biol Ther 9(7):841–847PubMedCrossRefGoogle Scholar
  66. 66.
    Lanzoni G, Roda G, Belluzzi A, Roda E, Bagnara GP (2008) Inflammatory bowel disease: moving toward a stem cell-based therapy. World J Gastroenterol 14(29):4616–4626PubMedCrossRefGoogle Scholar
  67. 67.
    Deng X, Szabo S, Chen L, Paunovic B, Khomenko T, Tolstanova G, Tarnawski AS, Jones MK, Sandor Z (2011) New cell therapy using bone marrow-derived stem cells/endothelial progenitor cells to accelerate neovascularization in healing of experimental ulcerative colitis. Curr Pharm Des 17(16):1643–1651PubMedCrossRefGoogle Scholar
  68. 68.
    Jung KH, Song SU, Yi T, Jeon MS, Hong SW, Zheng HM, Lee HS, Choi MJ, Lee DH, Hong SS (2011) Human bone marrow-derived clonal mesenchymal stem cells inhibit inflammation and reduce acute pancreatitis in rats. Gastroenterology 140(3):998–1008PubMedCrossRefGoogle Scholar
  69. 69.
    Schneider G, Saur D (2011) Mesenchymal stem cells: therapeutic potential for acute pancreatitis. Gastroenterology 140(3):779–782PubMedCrossRefGoogle Scholar
  70. 70.
    Pascual I, Fernández de Miguel G, Gómez-Pinedo U, de Miguel F, García Arranz M, García-Olmo D (2008) Adipose-derived mesenchymal stem cells in biosutures do not improve healing of experimental colonic anastomoses. Br J Surg 95(9):1180–1184PubMedCrossRefGoogle Scholar
  71. 71.
    Pascual I, Fernandez de Miguel G, Garcia Arranz M, Garcia-Olmo D (2010) Biosutures improve healing of experimental weak colonic anastomoses. Int J Colorectal Dis 25(12):1447–1451PubMedCrossRefGoogle Scholar
  72. 72.
    Adas G, Arikan S, Karatepe O, Kemik O, Ayhan S, Karaoz E, Kamali G, Eryasar B, Ustek D (2011) Mesenchymal stem cells improve the healing of ischemic colonic anastomoses (experimental study). Langenbecks Arch Surg 396(1):115–126PubMedCrossRefGoogle Scholar
  73. 73.
    Tyndall A, Pistoia V (2009) Mesenchymal stem cells combat sepsis. Nat Med 15(1):18–20PubMedCrossRefGoogle Scholar
  74. 74.
    Gonzalez-Rey E, Anderson P, González MA, Rico L, Büscher D, Delgado M (2009) Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 58(7): 929–939Google Scholar
  75. 75.
    Lucas P (2007) Stem cells for mesothelial repair: an understudied modality. Int J Artif Organs 30(6):550–556PubMedGoogle Scholar
  76. 76.
    Lucas PA, Warejcka DJ, Zhang L-M, Newman WH, Young HE (1996) Effect of rat mesenchymal stem cells on development of abdominal adhesions after surgery. J Surg Res 62(2):229–232PubMedCrossRefGoogle Scholar
  77. 77.
    Lopez-Cubero SO, Sullivan KM, McDonald GB (1998) Course of Crohn’s disease after allogeneic marrow transplantation. Gastroenterology 114(3):433–440PubMedCrossRefGoogle Scholar
  78. 78.
    Ditschkowski M, Einsele H, Schwerdtfeger R, Bunjes D, Trenschel R, Beelen DW, Elmaagacli AH (2003) Improvement of inflammatory bowel disease after allogeneic stem-cell transplantation. Transplantation 75(10):1745–1747PubMedCrossRefGoogle Scholar
  79. 79.
    Oyama Y, Craig RM, Traynor AE, Quigley K, Statkute L, Halverson A, Brush M, Verda L, Kowalska B, Krosnjar N, Kletzel M, Whitington PF, Burt RK (2005) Autologous hematopoietic stem cell transplantation in patients with refractory Crohn’s disease. Gastroenterology 128(3):552–563PubMedCrossRefGoogle Scholar
  80. 80.
    Cassinotti A, Annaloro C, Ardizzone S, Onida F, Della Volpe A, Clerici M, Usardi P, Greco S, Maconi G, Porro GB, Deliliers GL (2008) Autologous haematopoietic stem cell transplantation without CD34+ cell selection in refractory Crohn’s disease. Gut 57(2):211–217PubMedCrossRefGoogle Scholar
  81. 81.
    Burt RK, Craig RM, Milanetti F, Quigley K, Gozdziak P, Bucha J, Testori A, Halverson A, Verda L, de Villiers WJ, Jovanovic B, Oyama Y (2010) Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up. Blood 116(26):6123–6132PubMedCrossRefGoogle Scholar
  82. 82.
    Duijvestein M, Vos AC, Roelofs H, Wildenberg ME, Wendrich BB, Verspaget HW, Kooy-Winkelaar EM, Koning F, Zwaginga JJ, Fidder HH, Verhaar AP, Fibbe WE, van den Brink GR, Hommes DW (2010) Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I study. Gut 59(12):1662–1669PubMedCrossRefGoogle Scholar
  83. 83.
    Taupin P (2006) OTI-010 osiris therapeutics/jcr pharmaceuticals. Curr Opin Investig Drugs 7(5):473–481PubMedGoogle Scholar
  84. 84.
    Onken JGD, Hanson J (2006) Successful outpatient treatment of refractory Crohn’s disease using adult mesenchymal stem cells. ACG 2006 Final Program Book, 121Google Scholar
  85. 85.
    Onken JJT, Custer L (2008) Long-term safety of prochymal adult mesenchymal stem cells in Crohn’s disease. Gastroenterology 134(4): A661Google Scholar
  86. 86.
    Lazebnik LB, Konopliannikov AG, Kniazev OV, Parfenov AI, Tsaregorodtseva TM, Ruchkina IN, Khomeriki SG, Rogozina VA, Konopliannikova OA (2010) Use of allogeneic mesenchymal stem cells in the treatment of intestinal inflammatory diseases. Ter Arkh 82(2):38–43PubMedGoogle Scholar
  87. 87.
    Allison M (2009) Genzyme backs osiris, despite prochymal flop. Nat Biotechnol 27(11):966–967PubMedCrossRefGoogle Scholar
  88. 88.
    Prochymal: Press release about protocols 603 and 610. (2010)Google Scholar
  89. 89.
    Rubio D, Garcia-Castro J, Martin MC, de la Fuente R, Cigudosa JC, Lloyd AC, Bernad A (2005) Spontaneous human adult stem cell transformation. Cancer Res 65(8):3035–3039PubMedGoogle Scholar
  90. 90.
    Rosland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll H, Mysliwietz J, Tonn JC, Goldbrunner R, Lonning PE, Bjerkvig R, Schichor C (2009) Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res 69(13):5331–5339PubMedCrossRefGoogle Scholar
  91. 91.
    Garcia S, Bernad A, Martin MC, Cigudosa JC, Garcia-Castro J, de la Fuente R (2010) Pitfalls in spontaneous in vitro transformation of human mesenchymal stem cells. Exp Cell Res 316(9):1648–1650PubMedCrossRefGoogle Scholar
  92. 92.
    Torsvik A, Rosland GV, Svendsen A, Molven A, Immervoll H, McCormack E, Lonning PE, Primon M, Sobala E, Tonn JC, Goldbrunner R, Schichor C, Mysliwietz J, Lah TT, Motaln H, Knappskog S, Bjerkvig R (2010) Spontaneous malignant transformation of human mesenchymal stem cells reflects cross-contamination: putting the research field on track—letter. Cancer Res 70(15):6393–6396PubMedCrossRefGoogle Scholar
  93. 93.
    Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, Montagna D, Maccario R, Villa R, Daidone MG, Zuffardi O, Locatelli F (2007) Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res 67(19):9142–9149PubMedCrossRefGoogle Scholar
  94. 94.
    He X, Tsang TC, Pipes BL, Ablin RJ, Harris DT (2005) A stem cell fusion model of carcinogenesis. J Exp Ther Oncol 5(2):101–109PubMedGoogle Scholar
  95. 95.
    Rhodes L, Muir S, Elliott S, Guillot L, Antoon J, Penfornis P, Tilghman S, Salvo V, Fonseca J, Lacey M, Beckman B, McLachlan J, Rowan B, Pochampally R, Burow M (2009) Adult human mesenchymal stem cells enhance breast tumorigenesis and promote hormone independence. Breast Cancer Res Treat 121(2):293–300PubMedCrossRefGoogle Scholar
  96. 96.
    Xu W-T, Bian Z-Y, Fan Q-M, Li G, Tang T-T (2009) Human mesenchymal stem cells (hMSCs) target osteosarcoma and promote its growth and pulmonary metastasis. Cancer Lett 281(1):32–41PubMedCrossRefGoogle Scholar
  97. 97.
    Cousin B, Ravet E, Poglio S, De Toni F, Bertuzzi M, Lulka H, Touil I, André M, Grolleau J-L, Péron J-M, Chavoin J-P, Bourin P, Pénicaud L, Casteilla L, Buscail L, Cordelier P (2009) Adult stromal cells derived from human adipose tissue provoke pancreatic cancer cell death both in vitro and in vivo. PLoS ONE 4(7):e6278PubMedCrossRefGoogle Scholar
  98. 98.
    Sun B, Roh K-H, Park J-R, Lee S-R, Park S-B, Jung J-W, Kang S-K, Lee Y-S, Kang K-S (2009) Therapeutic potential of mesenchymal stromal cells in a mouse breast cancer metastasis model. Cytotherapy 11(3):289–298PubMedCrossRefGoogle Scholar
  99. 99.
    Lamfers M, Idema S, van Milligen F, Schouten T, van der Valk P, Vandertop P, Dirven C, Noske D (2009) Homing properties of adipose-derived stem cells to intracerebral glioma and the effects of adenovirus infection. Cancer Lett 274(1):78–87PubMedCrossRefGoogle Scholar
  100. 100.
    Garcia-Olmo D, Garcia-Arranz M, Garcia LG, Cuellar ES, Blanco IF, Prianes LA, Montes JA, Pinto FL, Marcos DH, Garcia-Sancho L (2003) Autologous stem cell transplantation for treatment of rectovaginal fistula in perianal Crohn’s disease: a new cell-based therapy. Int J Colorectal Dis 18(5):451–454PubMedCrossRefGoogle Scholar
  101. 101.
    Garcia-Olmo D, Garcia-Arranz M, Herreros L (2005) A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum 48:1416–1423PubMedCrossRefGoogle Scholar
  102. 102.
    Garcia-Olmo D, Garcia-Arranz M, Herreros D (2008) Expanded adipose-derived stem cells for the treatment of complex perianal fistula including Crohn’s disease. Expert Opin Biol Ther 8(9):1417–1423PubMedCrossRefGoogle Scholar
  103. 103.
    Garcia-Olmo DMD, Herreros DMD, Pascual IMD, Pascual JAMD, Del-Valle EMD, Zorrilla JMD, De-La-Quintana PPD, Garcia-Arranz MPD, Pascual MPD (2009) Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum 52(1):79–86PubMedCrossRefGoogle Scholar
  104. 104.
    Garcia-Arranz M, Gomez-Pinedo U, Hardisson D, Herreros D, Guadalajara H, Garcia-Gomez I, Garcia-Verdugo JM, Garcia-Olmo D (2010) Histopathological analysis of human specimens removed from the injection area of expanded adipose-derived stem cells. Histopathology 56(7):979–982PubMedCrossRefGoogle Scholar
  105. 105.
    Garcia-Olmo D, Herreros D, Pascual M, Pascual I, De-La-Quintana P, Trebol J, Garcia-Arranz M (2008) Treatment of enterocutaneous fistula in Crohn’s disease with adipose-derived stem cells: a comparison of protocols with and without cell expansion. Int J Colorectal Dis 24(1):27–30CrossRefGoogle Scholar
  106. 106.
    Garcia-Olmo D, Herreros D, De-La-Quintana P, Guadalajara H, Trebol J, Georgiev-Hristov T, Garcia-Arranz M (2010) Adipose-derived stem cells in Crohn’s rectovaginal fistula. Case Report Med 2010:961758PubMedGoogle Scholar
  107. 107.
    Alvarez PD-A, Garcia-Arranz M, Georgiev-Hristov T, Garcia-Olmo D (2008) A new bronchoscopic treatment of tracheomediastinal fistula using autologous adipose-derived stem cells. Thorax 63(4):374–376PubMedCrossRefGoogle Scholar
  108. 108.
    Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C, Minelli A, Alvisi C, Vanoli A, Calliada F, Dionigi P, Perotti C, Locatelli F, Corazza GR (2011) Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut 60(6):788–798PubMedCrossRefGoogle Scholar
  109. 109.
    Garcia-Olmo D, Herreros M, Guadalajara H, DeLaQuintana P, Trebol J, Georgiev-Hristov T, Garcia-Arranz M (2011) ASCRS annual meeting abstracts: expanded adipose derived autologous stem cells for the treatment of complex cryptoglandular fistulas. A phase III clinical trial (FATT1: fistula advanced therapy trial 1) and long term evaluation (LTE). Dis Colon Rectum 54(5):e68–e69Google Scholar
  110. 110.
    Lazebnik LB, Kniazev OV, Parfenov AI, Ruchkina IN, Rogozina VA, Konopliannikov AG (2010) Transplantation of allogeneic mesenchymal stem cells from the bone marrow increases duration of remission and reduces the risk of ulcerative colitis relapse. Eksp Klin Gastroenterol (3):5–10Google Scholar
  111. 111.
    Lazebnik LB, Kniazev OV, Konopliannikov AG, Parfenov AI, Ruchkina IN, Mikhailova ZF, Tsaregorodtseva TM, Khomeriki SG, Rogozina VA, Gudkova RB, Shcherbakov PL, Konopliannikova OA (2010) Allogeneic mesenchymal stromal cells in patients with ulcerative colitis: two years of observation. Eksp Klin Gastroenterol (11):3–15Google Scholar
  112. 112.
    Van Bokkelen G (2011) Company profile: athersys. Regen Med 6(1):39–43PubMedCrossRefGoogle Scholar
  113. 113.
    Frudinger A, Kolle D, Schwaiger W, Pfeifer J, Paede J, Halligan S (2010) Muscle-derived cell injection to treat anal incontinence due to obstetric trauma: pilot study with 1 year follow-up. Gut 59(1):55–61PubMedCrossRefGoogle Scholar
  114. 114.
    Al-toma A, Visser OJ, van Roessel HM, von Blomberg BM, Verbeek WH, Scholten PE, Ossenkoppele GJ, Huijgens PC, Mulder CJ (2007) Autologous hematopoietic stem cell transplantation in refractory celiac disease with aberrant T cells. Blood 109(5):2243–2249PubMedCrossRefGoogle Scholar
  115. 115.
    Ringden O, Uzunel M, Sundberg B, Lonnies L, Nava S, Gustafsson J, Henningsohn L, Le Blanc K (2007) Tissue repair using allogeneic mesenchymal stem cells for hemorrhagic cystitis, pneumomediastinum and perforated colon. Leukemia 21(11):2271–2276PubMedCrossRefGoogle Scholar
  116. 116.
    Ball L, Bredius R, Lankester A, Schweizer J, van den Heuvel-Eibrink M, Escher H, Fibbe W, Egeler M (2008) Third party mesenchymal stromal cell infusions fail to induce tissue repair despite successful control of severe grade IV acute graft-versus-host disease in a child with juvenile myelo-monocytic leukemia. Leukemia 22(6):1256–1257PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.General and Digestive Tract Surgery DepartmentHospital “Nuestra Señora de Sonsoles”AvilaSpain
  2. 2.Laboratorio de Terapia Celular, 2ª Planta Edificio de Investigación y DesarrolloHospital Universitario La PazMadridSpain
  3. 3.General and Digestive Tract Surgery Department and Cell Therapy Laboratory, Investigation Institute IdiPAZUniversity Hospital “La Paz”MadridSpain
  4. 4. Cell Therapy Laboratory, Investigation Institute IdiPAZAutonomous UniversityMadridSpain
  5. 5.Head of Colorectal Surgery, General and Digestive Tract Surgery DepartmentUniversity Hospital “La Paz”MadridSpain
  6. 6.Associate Proffesor, Surgery Department,Autonomous UniversityMadridSpain

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