Stem Cell Therapy as an Option for Pediatric Surgical Conditions

Abstract

Regenerative medicine aims to replace, repair, or restore normal function of cells, tissues, and organs that are damaged by disease and holds a promising potential for the treatment of congenital anomalies. Herein, we present an overview of the different stem cell populations and discuss the potentials and most recent updates in stem cell therapy relevant to pediatric surgeons. In particular, we focus on stem cell applications in intestinal regeneration for necrotizing enterocolitis, liver regeneration in biliary atresia and human hepatocyte transplantation for liver failure, and pulmonary regeneration of hypoplastic lungs due to prematurity or congenital diaphragmatic hernia.

Keywords

regenerative medicine - stem cell - amniotic fluid - mesenchymal stem cells - NEC

• References

• 1 Corsello G, Giuffrè M. Congenital malformations. J Matern Fetal Neonatal Med 2012; 25 (Suppl. 01) 25-29
• 2 World Health Organization. Congenital anomalies. Fact sheet N°370. Updated January 2014. Available at: http://www.who.int/mediacentre/factsheets/fs370/en/
• 3 Kim K, Wang Y, Kirby RS, Druschel CM. Prevalence and trends of selected congenital malformations in New York State, 1983 to 2007. Birth Defects Res A Clin Mol Teratol 2013; 97 (10) 619-627
• 4 Furth ME, Atala A. Current and future perspectives of regenerative medicine. In: Atala A, Lanza R, Thompson J, Nerem R, , eds. Principles of Regenerative Medicine. 1st ed. Burlington: Elsevier; 2008: 2-15
• 5 Atala A. Regenerative medicine strategies. J Pediatr Surg 2012; 47 (1) 17-28
• 6 De Coppi P. Regenerative medicine for congenital malformations. J Pediatr Surg 2013; 48 (2) 273-280
• 7 Mimeault M, Batra SK. Concise review: recent advances on the significance of stem cells in tissue regeneration and cancer therapies. Stem Cells 2006; 24 (11) 2319-2345
• 8 Solter D. From teratocarcinomas to embryonic stem cells and beyond: a history of embryonic stem cell research. Nat Rev Genet 2006; 7 (4) 319-327
• 9 Pittenger MF, Mackay AM, Beck SC , et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284 (5411) 143-147
• 10 Yamashita YM, Mahowald AP, Perlin JR, Fuller MT. Asymmetric inheritance of mother versus daughter centrosome in stem cell division. Science 2007; 315 (5811) 518-521
• 11 Odorico JS, Kaufman DS, Thomson JA. Multilineage differentiation from human embryonic stem cell lines. Stem Cells 2001; 19 (3) 193-204
• 12 Richards M, Fong CY, Chan WK, Wong PC, Bongso A. Human feeders support prolonged undifferentiated growth of human inner cell masses and embryonic stem cells. Nat Biotechnol 2002; 20 (9) 933-936
• 13 Amit M, Shariki C, Margulets V, Itskovitz-Eldor J. Feeder layer- and serum-free culture of human embryonic stem cells. Biol Reprod 2004; 70 (3) 837-845
• 14 Lawrenz B, Schiller H, Willbold E, Ruediger M, Muhs A, Esser S. Highly sensitive biosafety model for stem-cell-derived grafts. Cytotherapy 2004; 6 (3) 212-222
• 15 Hanson C, Caisander G. Human embryonic stem cells and chromosome stability. APMIS 2005; 113 (11-12) 751-755
• 16 Maitra A, Arking DE, Shivapurkar N , et al. Genomic alterations in cultured human embryonic stem cells. Nat Genet 2005; 37 (10) 1099-1103
• 17 Teramoto K, Hara Y, Kumashiro Y , et al. Teratoma formation and hepatocyte differentiation in mouse liver transplanted with mouse embryonic stem cell-derived embryoid bodies. Transplant Proc 2005; 37 (1) 285-286
• 18 Kolossov E, Bostani T, Roell W , et al. Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium. J Exp Med 2006; 203 (10) 2315-2327
• 19 Shih CC, Forman SJ, Chu P, Slovak M. Human embryonic stem cells are prone to generate primitive, undifferentiated tumors in engrafted human fetal tissues in severe combined immunodeficient mice. Stem Cells Dev 2007; 16 (6) 893-902
• 20 Kofidis T, deBruin JL, Tanaka M , et al. They are not stealthy in the heart: embryonic stem cells trigger cell infiltration, humoral and T-lymphocyte-based host immune response. Eur J Cardiothorac Surg 2005; 28 (3) 461-466
• 21 Swijnenburg RJ, Tanaka M, Vogel H , et al. Embryonic stem cell immunogenicity increases upon differentiation after transplantation into ischemic myocardium. Circulation 2005; 112 (9, Suppl): I166-I172
• 22 Nussbaum J, Minami E, Laflamme MA , et al. Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. FASEB J 2007; 21 (7) 1345-1357
• 23 Grinnemo KH, Sylvén C, Hovatta O, Dellgren G, Corbascio M. Immunogenicity of human embryonic stem cells. Cell Tissue Res 2008; 331 (1) 67-78
• 24 Sarić T, Frenzel LP, Hescheler J. Immunological barriers to embryonic stem cell-derived therapies. Cells Tissues Organs 2008; 188 (1-2) 78-90
• 25 Daley GQ, Ahrlund Richter L, Auerbach JM , et al. Ethics. The ISSCR guidelines for human embryonic stem cell research. Science 2007; 315 (5812) 603-604
• 26 Edwards RG. A burgeoning science of embryological genetics demands a modern ethics. Reprod Biomed Online 2007; 15 (Suppl. 01) 34-40
• 27 Green RM. Can we develop ethically universal embryonic stem-cell lines?. Nat Rev Genet 2007; 8 (6) 480-485
• 28 Klimanskaya I, Chung Y, Becker S, Lu SJ, Lanza R. Human embryonic stem cell lines derived from single blastomeres. Nature 2006; 444 (7118) 481-485
• 29 Chung Y, Klimanskaya I, Becker S , et al. Embryonic and extraembryonic stem cell lines derived from single mouse blastomeres. Nature 2006; 439 (7073) 216-219
• 30 Fong H, Hohenstein KA, Donovan PJ. Regulation of self-renewal and pluripotency by Sox2 in human embryonic stem cells. Stem Cells 2008; 26 (8) 1931-1938
• 31 Lebkowski J. GRNOPC1: the world's first embryonic stem cell-derived therapy. Interview with Jane Lebkowski. Regen Med 2011; 6 (6, Suppl): 11-13
• 32 Lukovic D, Stojkovic M, Moreno-Manzano V, Bhattacharya SS, Erceg S. Perspectives and future directions of human pluripotent stem cell-based therapies: lessons from Geron's clinical trial for spinal cord injury. Stem Cells Dev 2014; 23 (1) 1-4
• 33 Schwartz SD, Hubschman JP, Heilwell G , et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 2012; 379 (9817) 713-720
• 34 Ethics Committee of the American Society for Reproductive Medicine. Human somatic cell nuclear transfer and cloning. Fertil Steril 2012; 98 (4) 804-807
• 35 Tachibana M, Amato P, Sparman M , et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell 2013; 153 (6) 1228-1238
• 36 Langerova A, Fulka H, Fulka Jr J. Somatic cell nuclear transfer-derived embryonic stem cell lines in humans: pros and cons. Cell Reprogram 2013; 15 (6) 481-483
• 37 Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126 (4) 663-676
• 38 Wernig M, Meissner A, Foreman R , et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 2007; 448 (7151) 318-324
• 39 Takahashi K, Tanabe K, Ohnuki M , et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131 (5) 861-872
• 40 Yu J, Vodyanik MA, Smuga-Otto K , et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007; 318 (5858) 1917-1920
• 41 Meissner A, Wernig M, Jaenisch R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat Biotechnol 2007; 25 (10) 1177-1181
• 42 Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse induced pluripotent stem cells without viral vectors. Science 2008; 322 (5903) 949-953
• 43 Moschidou D, Mukherjee S, Blundell MP , et al. Human mid-trimester amniotic fluid stem cells cultured under embryonic stem cell conditions with valproic acid acquire pluripotent characteristics. Stem Cells Dev 2013; 22 (3) 444-458
• 44 Obokata H, Wakayama T, Sasai Y , et al. Stimulus-triggered fate conversion of somatic cells into pluripotency. Nature 2014; 505 (7485) 641-647
• 45 Mimeault M, Hauke R, Mehta PP, Batra SK. Recent advances in cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers. J Cell Mol Med 2007; 11 (5) 981-1011
• 46 Friedenstein AJ, Deriglasova UF, Kulagina NN , et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol 1974; 2 (2) 83-92
• 47 Horwitz EM, Le Blanc K, Dominici M , et al; International Society for Cellular Therapy. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 2005; 7 (5) 393-395
• 48 Horwitz EM, Prockop DJ, Fitzpatrick LA , et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 1999; 5 (3) 309-313
• 49 Koç ON, Day J, Nieder M, Gerson SL, Lazarus HM, Krivit W. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant 2002; 30 (4) 215-222
• 50 Dalal J, Gandy K, Domen J. Role of mesenchymal stem cell therapy in Crohn's disease. Pediatr Res 2012; 71 (4 Pt 2) 445-451
• 51 Norambuena GA, Khoury M, Jorgensen C. Mesenchymal stem cells in osteoarticular pediatric diseases: an update. Pediatr Res 2012; 71 (4 Pt 2) 452-458
• 52 Zheng GP, Ge MH, Shu Q, Rojas M, Xu J. Mesenchymal stem cells in the treatment of pediatric diseases. World J Pediatr 2013; 9 (3) 197-211
• 53 Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 2001; 98 (8) 2396-2402
• 54 Guillot PV, O'Donoghue K, Kurata H, Fisk NM. Fetal stem cells: betwixt and between. Semin Reprod Med 2006; 24 (5) 340-347
• 55 Walsh DS, Adzick NS. Fetal surgical intervention. Am J Perinatol 2000; 17 (6) 277-283
• 56 Deprest JA, Done E, Van Mieghem T, Gucciardo L. Fetal surgery for anesthesiologists. Curr Opin Anaesthesiol 2008; 21 (3) 298-307
• 57 Prusa AR, Marton E, Rosner M, Bernaschek G, Hengstschläger M. Oct-4-expressing cells in human amniotic fluid: a new source for stem cell research?. Hum Reprod 2003; 18 (7) 1489-1493
• 58 Bossolasco P, Montemurro T, Cova L , et al. Molecular and phenotypic characterization of human amniotic fluid cells and their differentiation potential. Cell Res 2006; 16 (4) 329-336
• 59 Stefanidis K, Loutradis D, Koumbi L , et al. Deleted in Azoospermia-Like (DAZL) gene-expressing cells in human amniotic fluid: a new source for germ cells research?. Fertil Steril 2008; 90 (3) 798-804
• 60 Tsai MS, Hwang SM, Tsai YL, Cheng FC, Lee JL, Chang YJ. Clonal amniotic fluid-derived stem cells express characteristics of both mesenchymal and neural stem cells. Biol Reprod 2006; 74 (3) 545-551
• 61 Moschidou D, Mukherjee S, Blundell MP , et al. Valproic acid confers functional pluripotency to human amniotic fluid stem cells in a transgene-free approach. Mol Ther 2012; 20 (10) 1953-1967
• 62 De Coppi P, Bartsch Jr G, Siddiqui MM , et al. Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol 2007; 25 (1) 100-106
• 63 Zsebo KM, Williams DA, Geissler EN , et al. Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell 1990; 63 (1) 213-224
• 64 Cananzi M, De Coppi P. CD117(+) amniotic fluid stem cells: state of the art and future perspectives. Organogenesis 2012; 8 (3) 77-88
• 65 Perin L, Giuliani S, Jin D , et al. Renal differentiation of amniotic fluid stem cells. Cell Prolif 2007; 40 (6) 936-948
• 66 Ditadi A, de Coppi P, Picone O , et al. Human and murine amniotic fluid c-Kit+Lin- cells display hematopoietic activity. Blood 2009; 113 (17) 3953-3960
• 67 Piccoli M, Franzin C, Bertin E , et al. Amniotic fluid stem cells restore the muscle cell niche in a HSA-Cre, Smn(F7/F7) mouse model. Stem Cells 2012; 30 (8) 1675-1684
• 68 Fitzgibbons SC, Ching Y, Yu D , et al. Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg 2009; 44 (6) 1072-1075 , discussion 1075–1076
• 69 Zani A, Eaton S, Leon FF , et al. Captopril reduces the severity of bowel damage in a neonatal rat model of necrotizing enterocolitis. J Pediatr Surg 2008; 43 (2) 308-314
• 70 Yang J, Su Y, Zhou Y, Besner GE. Heparin-binding EGF-like growth factor (HB-EGF) therapy for intestinal injury: Application and future prospects. Pathophysiology 2014; 21 (1) 95-104
• 71 Lu J, Pierce M, Franklin A, Jilling T, Stafforini DM, Caplan M. Dual roles of endogenous platelet-activating factor acetylhydrolase in a murine model of necrotizing enterocolitis. Pediatr Res 2010; 68 (3) 225-230
• 72 Zani A, Cananzi M, Eaton S, Pierro A, De Coppi P. Stem cells as a potential treatment of necrotizing enterocolitis. J Pediatr Surg 2009; 44 (3) 659-660
• 73 Tayman C, Uckan D, Kilic E , et al. Mesenchymal stem cell therapy in necrotizing enterocolitis: a rat study. Pediatr Res 2011; 70 (5) 489-494
• 74 Zani A, Cananzi M, Fascetti-Leon F , et al. Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism. Gut 2014; 63 (2) 300-309
• 75 Brittan M, Chance V, Elia G , et al. A regenerative role for bone marrow following experimental colitis: contribution to neovasculogenesis and myofibroblasts. Gastroenterology 2005; 128 (7) 1984-1995
• 76 Komori M, Tsuji S, Tsujii M , et al. Involvement of bone marrow-derived cells in healing of experimental colitis in rats. Wound Repair Regen 2005; 13 (1) 109-118
• 77 Bamba S, Lee CY, Brittan M , et al. Bone marrow transplantation ameliorates pathology in interleukin-10 knockout colitic mice. J Pathol 2006; 209 (2) 265-273
• 78 Nakao A, Toyokawa H, Kimizuka K , et al. Simultaneous bone marrow and intestine transplantation promotes marrow-derived hematopoietic stem cell engraftment and chimerism. Blood 2006; 108 (4) 1413-1420
• 79 Khalil PN, Weiler V, Nelson PJ , et al. Nonmyeloablative stem cell therapy enhances microcirculation and tissue regeneration in murine inflammatory bowel disease. Gastroenterology 2007; 132 (3) 944-954
• 80 Hayashi Y, Tsuji S, Tsujii M , et al. Topical implantation of mesenchymal stem cells has beneficial effects on healing of experimental colitis in rats. J Pharmacol Exp Ther 2008; 326 (2) 523-531
• 81 Tanaka F, Tominaga K, Ochi M , et al. Exogenous administration of mesenchymal stem cells ameliorates dextran sulfate sodium-induced colitis via anti-inflammatory action in damaged tissue in rats. Life Sci 2008; 83 (23-24) 771-779
• 82 Wei Y, Nie Y, Lai J, Wan YJ, Li Y. Comparison of the population capacity of hematopoietic and mesenchymal stem cells in experimental colitis rat model. Transplantation 2009; 88 (1) 42-48
• 83 Burt RK, Craig RM, Milanetti F , et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up. Blood 2010; 116 (26) 6123-6132
• 84 Cassinotti A, Annaloro C, Ardizzone S , et al. Autologous haematopoietic stem cell transplantation without CD34+ cell selection in refractory Crohn's disease. Gut 2008; 57 (2) 211-217
• 85 Hommes DW, Duijvestein M, Zelinkova Z , et al. Long-term follow-up of autologous hematopoietic stem cell transplantation for severe refractory Crohn's disease. J Crohn's Colitis 2011; 5 (6) 543-549
• 86 Hawkey CJ. Stem cells as treatment in inflammatory bowel disease. Dig Dis 2012; 30 (Suppl. 03) 134-139
• 87 Good M, Siggers RH, Sodhi CP , et al. Amniotic fluid inhibits Toll-like receptor 4 signaling in the fetal and neonatal intestinal epithelium. Proc Natl Acad Sci U S A 2012; 109 (28) 11330-11335
• 88 Siggers J, Ostergaard MV, Siggers RH , et al. Postnatal amniotic fluid intake reduces gut inflammatory responses and necrotizing enterocolitis in preterm neonates. Am J Physiol Gastrointest Liver Physiol 2013; 304 (10) G864-G875
• 89 Engelmann G, Schmidt J, Oh J , et al. Indications for pediatric liver transplantation. Data from the Heidelberg pediatric liver transplantation program. Nephrol Dial Transplant 2007; 22 (Suppl. 08) viii23-viii28
• 90 Masson S, Harrison DJ, Plevris JN, Newsome PN. Potential of hematopoietic stem cell therapy in hepatology: a critical review. Stem Cells 2004; 22 (6) 897-907
• 91 Alison MR, Poulsom R, Jeffery R , et al. Hepatocytes from non-hepatic adult stem cells. Nature 2000; 406 (6793) 257
• 92 Lagasse E, Connors H, Al-Dhalimy M , et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 2000; 6 (11) 1229-1234
• 93 Theise ND, Nimmakayalu M, Gardner R , et al. Liver from bone marrow in humans. Hepatology 2000; 32 (1) 11-16
• 94 Gehling UM, Willems M, Dandri M , et al. Partial hepatectomy induces mobilization of a unique population of haematopoietic progenitor cells in human healthy liver donors. J Hepatol 2005; 43 (5) 845-853
• 95 Gehling UM, Willems M, Schlagner K , et al. Mobilization of hematopoietic progenitor cells in patients with liver cirrhosis. World J Gastroenterol 2010; 16 (2) 217-224
• 96 Fausto N, Campbell JS. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech Dev 2003; 120 (1) 117-130
• 97 Omori M, Evarts RP, Omori N, Hu Z, Marsden ER, Thorgeirsson SS. Expression of alpha-fetoprotein and stem cell factor/c-kit system in bile duct ligated young rats. Hepatology 1997; 25 (5) 1115-1122
• 98 Davenport M. Biliary atresia: clinical aspects. Semin Pediatr Surg 2012; 21 (3) 175-184
• 99 Khan AA, Parveen N, Mahaboob VS , et al. Management of hyperbilirubinemia in biliary atresia by hepatic progenitor cell transplantation through hepatic artery: a case report. Transplant Proc 2008; 40 (4) 1153-1155
• 100 Sharma S, Kumar L, Mohanty S, Kumar R, Datta Gupta S, Gupta DK. Bone marrow mononuclear stem cell infusion improves biochemical parameters and scintigraphy in infants with biliary atresia. Pediatr Surg Int 2011; 27 (1) 81-89
• 101 Hughes RD, Mitry RR, Dhawan A. Current status of hepatocyte transplantation. Transplantation 2012; 93 (4) 342-347
• 102 Fitzpatrick E, Wu Y, Dhadda P , et al. Co-culture with mesenchymal stem cells results in improved viability and function of human hepatocytes. Cell Transplant 2013;
• 103 Fung ME, Thébaud B. Stem cell-based therapy for neonatal lung disease: it is in the juice. Pediatr Res 2014; 75 (1-1) 2-7
• 104 Herriges M, Morrisey EE. Lung development: orchestrating the generation and regeneration of a complex organ. Development 2014; 141 (3) 502-513
• 105 Filippone M, Sartor M, Zacchello F, Baraldi E. Flow limitation in infants with bronchopulmonary dysplasia and respiratory function at school age. Lancet 2003; 361 (9359) 753-754
• 106 Cutz E, Chiasson D. Chronic lung disease after premature birth. N Engl J Med 2008; 358 (7) 743-745 , author reply 745–746
• 107 Wong PM, Lees AN, Louw J , et al. Emphysema in young adult survivors of moderate-to-severe bronchopulmonary dysplasia. Eur Respir J 2008; 32 (2) 321-328
• 108 Alphonse RS, Rajabali S, Thébaud B. Lung injury in preterm neonates: the role and therapeutic potential of stem cells. Antioxid Redox Signal 2012; 17 (7) 1013-1040
• 109 Pierro M, Thébaud B. Mesenchymal stem cells in chronic lung disease: culprit or savior?. Am J Physiol Lung Cell Mol Physiol 2010; 298 (6) L732-L734
• 110 Tropea KA, Leder E, Aslam M , et al. Bronchioalveolar stem cells increase after mesenchymal stromal cell treatment in a mouse model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2012; 302 (9) L829-L837
• 111 Aslam M, Baveja R, Liang OD , et al. Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease. Am J Respir Crit Care Med 2009; 180 (11) 1122-1130
• 112 van Haaften T, Byrne R, Bonnet S , et al. Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am J Respir Crit Care Med 2009; 180 (11) 1131-1142
• 113 Balasubramaniam V, Ryan SL, Seedorf GJ , et al. Bone marrow-derived angiogenic cells restore lung alveolar and vascular structure after neonatal hyperoxia in infant mice. Am J Physiol Lung Cell Mol Physiol 2010; 298 (3) L315-L323
• 114 Chang YS, Oh W, Choi SJ , et al. Human umbilical cord blood-derived mesenchymal stem cells attenuate hyperoxia-induced lung injury in neonatal rats. Cell Transplant 2009; 18 (8) 869-886
• 115 Carraro G, Perin L, Sedrakyan S , et al. Human amniotic fluid stem cells can integrate and differentiate into epithelial lung lineages. Stem Cells 2008; 26 (11) 2902-2911
• 116 Ruttenstock E, Doi T, Dingemann J, Puri P. Insulinlike growth factor receptor type 1 and type 2 are downregulated in the nitrofen-induced hypoplastic lung. J Pediatr Surg 2010; 45 (6) 1349-1353
• 117 Pederiva F, Ghionzoli M, Pierro A, De Coppi P, Tovar JA. Amniotic fluid stem cells rescue both in vitro and in vivo growth, innervation, and motility in nitrofen-exposed hypoplastic rat lungs through paracrine effects. Cell Transplant 2013; 22 (9) 1683-1694
• 118 Garcia O, Carraro G, Turcatel G , et al. Amniotic fluid stem cells inhibit the progression of bleomycin-induced pulmonary fibrosis via CCL2 modulation in bronchoalveolar lavage. PLoS ONE 2013; 8 (8) e71679