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Stem Cell Therapy as an Option for Pediatric Surgical Conditions Augusto Zani1

Paolo De Coppi1,2

1 Department of Paediatric Surgery, University College London

Institute of Child Health, London, United Kingdom 2 Department of Surgery, Great Ormond Street Hospital for Children, London, United Kingdom

Address for correspondence Paolo De Coppi, MD, PhD, Department of Paediatric Surgery, University College London Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom (e-mail: [email protected]).

Abstract Keywords

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

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.

Introduction With an incidence of 1 in 33 (3%) live births, congenital anomalies result in approximately 3.2 million birth defectrelated disabilities every year and represent a major cause of disease and death during the 1st year of life.1,2 Despite advancements in pre- and postnatal treatment and primary prevention based on controlling environmental risk factors, in the last decade some congenital anomalies have shown an increasing incidence.3 Regenerative medicine aims to replace, repair, or restore normal function of cells, tissues, and organs that are damaged by disease,4 and holds a promising potential for the treatment of congenital anomalies. In fact, while organ transplantation remains a mainstay of treatment for patients with severely compromised organ function, the number of patients in need of treatment far exceeds the organ supply, and this shortfall is expected to worsen as the global population ages.5,6 Regenerative medicine techniques include injection of functional cells into a nonfunctional site to stimulate regeneration (stem cell therapy) and/or the use of biocompatible materials to create new tissues and organs (tissue engineering).5

received April 19, 2014 accepted April 23, 2014 published online June 19, 2014

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.

Stem Cells The term “stem cell” identifies a cell that shares the dual ability to proliferate indefinitely (self-renewal) and to differentiate into one or more types of specialized cells (potency).7 Based on their differentiation potential, stem cells are classified into four groups. Totipotent stem cells are cells with the highest differentiation potential; by definition, the only type of totipotent stem cell is the fertilized egg (zygote) and descendent cells that derive from it in the first two cellular divisions. These cells can give rise to all cells and tissues of the developing embryo and its annexes (trophoblast). Pluripotent stem cells retain the ability to differentiate into all derivatives of the three primary germ layers (ectoderm, mesoderm, and endoderm), but not into extraembryonic cell types. Pluripotent stem cells were first recognized in the inner cell mass of mouse blastocyst at the embryonic day

© 2014 Georg Thieme Verlag KG Stuttgart · New York

DOI http://dx.doi.org/ 10.1055/s-0034-1378150. ISSN 0939-7248.

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Eur J Pediatr Surg 2014;24:219–226.

Stem Cell Therapy as an Option for Pediatric Surgical Conditions 3.5 and are present at least as late as the pregastrulating embryo. Multipotent stem cells give rise to multiple cell types deriving from a single germ layer.8 A classical example of multipotent stem cell is the mesenchymal stem cell (MSC) that originates from mesoderm and gives rise to bone, muscle, and adipose tissue.9 Unipotent stem cells indicate a cell population, usually present in adult tissues, capable of differentiating along only one lineage (i.e., epidermal stem cells in the basal layer that produce only keratinized squames).10 Stem cells can also be classified according to their origin.

Embryonic Stem Cells Embryonic stem (ES) cells are derived from the inner cell mass of a blastocyst stage embryo, and can be expanded in vitro indefinitely.11 They are pluripotent cells as they can give rise to all derivatives of the three primary germ layers: ectoderm, endoderm, and mesoderm.12,13 Owing to their enormous regenerative potential, ES cells (ESCs) are the ones that could provide unlimited supplies of a wide variety of cell types for use in new therapies. However, ES research has been limited by a series of factors, including teratogenicity, immunogenicity, and ethics. ESCs raise safety concerns due to their tendency to form teratomas when injected undifferentiated or only partially differentiated in vivo.14–19 Moreover, a host immune rejection of ES cellular allografts might be developed as ES are allogenic and therefore require immunosuppression.20–24 Finally, ES raised ethical considerations concerning their harvest from human embryos,25–27 although some studies have shown that nowadays it is possible to harvest ESC lines without destroying embryos.28,29 Mouse-derived ES cells are grown on a layer of gelatin and require the presence of leukemia inhibitory factor (LIF), whereas human-derived ES (hES) cells are grown on a feeder layer of mouse embryonic fibroblasts and require the presence of basic fibroblast growth factor (FGF). 13 Pluripotency in hES cells is maintained by gene suppressing factors that lead to differentiation, such as Oct-4, Nanog, and SOX2.30 hES cell identification is achieved by targeting surface antigens such as the glycolipids stem cells embryonic antigen-3 and -4 and the keratan sulfate antigens Tra1–60 and Tra-1–81. Some clinical trials have tested hES cell safety in clinical applications. The world’s first ES cell-derived therapy evaluating the safety of GRNOPC1 (hES cell–derived oligodendrocyte progenitor cells) administered to patients with neurologically complete spinal cord injuries was discontinued in November 2011 and results on the patients treated are still awaited.31,32 On the contrary, Schwartz et al preliminarily reported promising results on the first two patients with Stargardt macular dystrophy and dry age-related macular degeneration, whose eyes had been injected with retinal pigmented epithelial cells derived from hES cells.33 Moreover, phase I/II clinical trials involving retinal pigment epithelial cells derived from hES cells for the treatment of severe myopia were approved in February 2013. European Journal of Pediatric Surgery

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Somatic Cell Nuclear Transfer Somatic cell nuclear transfer (SCNT) is a procedure that removes an oocyte nucleus in culture and replaces it with a nucleus derived from a somatic cell obtained from a patient biopsy. The cell obtained is genetically identical to somatic cells and would not be rejected by the donor. Although promising, SCNT raises ethical considerations, due to the potential use of SCNT for reproduction. In 2012, the Ethics Committee of the American Society for Reproductive Medicine has produced a new document where they declared unethical to use SCNT for infertility treatment due to concerns about safety, the unknown impact of SCNT on children, families, and society, and the availability of other ethically acceptable means of assisted reproduction.34 On the contrary, SCNT can be used for therapeutic purposes, generating blastocysts for stem cell derivation, and their use in research and regenerative medicine. This is important for the future of ES therapies, allowing the production of nonimmunogenic ES lines. Recently, Tachibana et al reported an optimized approach for the production of human SCNT ESCs.35 However, there is an ongoing debate whether, in the era of induced pluripotent stem (iPS) cells, the production of these cells is indeed necessary.36

Induced Pluripotent Stem Cells In 2006, a new type of pluripotent stem cells was produced in the laboratory from nonpluripotent mouse cells: iPS cells.37 The discovery that mature cells can be reprogrammed to become pluripotent earned Shinya Yamanaka, the 2012 Nobel Prize for Physiology or Medicine. iPS cells are typically derived from adult somatic cells by inducing forced expression of genetic sequences such as Oct4 (POU5F1), the transcription factor Sox2, c-Myc proto-oncogene protein, and Klf4 (Krueppel-like factor 4) as key genes, sufficient to reprogram fibroblasts which are able to produce viable chimeras if injected into developing embryos and teratomas in immunocompromised mice.37,38 This makes iPS cells similar to natural pluripotent stem cells, such as hES cells. iPS cells show morphological resemblance to hES cells, express typical hES cell-specific surface antigens and genes, give rise to multiple lineages in vitro, and form teratomas when injected into immunocompromised mice. In 2007, successful iPS cells were obtained from human fibroblasts both using Oct3/4, Sox2, Klf4, and c-Myc via retroviral transfection, and using OCT4, SOX2, NANOG, and a different gene LIN28 using a lentiviral system, improving transduction output.39,40 To avoid the risk of teratogenesis due to the use of viral transfection systems, Meissner et al described the use of adenoviruses to transport the four sequences into the DNA of mouse somatic cells,41 while Okita et al demonstrated that reprogramming can be accomplished via plasmids without any virus transfection system at all, although at very low efficiencies.42 Moreover, fetal cells can be fully reprogrammed to pluripotency without ectopic factors, by simply adding the histone deacetylase inhibitor valproic acid.43 In the last few months, during the preparation of this article, an innovative way to reprogrammed somatic cells, defined as stimulus-triggered acquisition of pluripotency, has also been described. If

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confirmed by independent studies, this technique could represent a safer way to generate pluripotent cells, which require neither nuclear transfer nor the introduction of transcription factors. Simply adding strong external stimuli such as a transient low-pH stressor to purified lymphocytes, pluripotent cells could be generated and efficiently contribute to chimeric embryos and to offspring via germline transmission.44

Adult Stem Cells Stem cells that are present in the postnatal life are more committed and classified as either multipotent or unipotent. Contrarily to ESCs, adult stem cells do not raise clinical concerns as their derivation can be performed in an autologous setting and does not involve destruction of human embryos.45 For this reason, at present, they represent a best resource both for research and medical purposes.45 MSCs are multipotent stromal cells with fibroblast-like morphology that can differentiate in vitro into a variety of cell types, including osteogenic, chondrogenic, and adipogenic lineages.46 MSCs have been isolated from a variety of sources, including the fetus, amniotic fluid, umbilical cord blood, Wharton jelly, placenta and postnatally from blood, liver, bone marrow, lung, pancreas, dental pulp, and periosteum.6 MSCs can be distinguished from hematopoietic stem cells because of their capacity to grow in adherent culture. According to the International Society for Cellular Therapy, MSCs can be considered as such if they express CD73 (ecto 5′-nucleotidase), CD90 (Thy-1) and CD105 (SH2 or MCAM or endoglin), LNGFR (low-affinity nerve growth factor receptor), CD166, ALCAM adhesion protein, CD146 (P1H12), CD29, CD106 (vascular cell adhesion molecule-1), and if they are negative for hematopoietic cell surface antigens, such as CD45 (panleukocyte marker), CD34 (marker of primitive hematopoietic progenitors and endothelial cells), CD11b or CD14 (monocyte markers), CD19 or CD79a (B-cells markers), and human leukocyte antigen class 2.47 MSC therapy has been proposed for several pediatric conditions, including several pediatric osteoarticular disorders, Crohn disease, inborn errors of metabolism, osteogenesis imperfect, graft-versus-host diseases, etc.48–52

Amniotic Fluid Stem Cells To overcome the limitations associated with both embryonic and adult stem cells, attempts have been made to identify alternative sources of stem cells. The discovery of fetal stem cell populations opened new horizons to regenerative medicine offering a promising alternative source for clinical applications. Although more lineage committed than ESCs, fetal stem cells show better proliferation and differentiation capacities in comparison to adult progenitors, do not seem to form teratomas in vivo as ESCs, and are less associated with rejection when transplanted in immunocompetent mice.7,53,54 However, the collection of fetal tissue during gestation can be associated with high morbidity and mortal-

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ity both for the fetus and the mother.55,56 In 2003, Prusa et al first described the presence of a distinct subpopulation of proliferating amniotic fluid cells (0.1–0.5% of the total nucleated cell count present in the amniotic fluid) that express the pluripotency marker Oct4 at both transcriptional and protein levels.57 Similarly, other groups confirmed the expression of Oct4 and its transcriptional targets (e.g., Rex-1) in amniotic fluid cells.58,59 Although the presence of stem cells in the amniotic fluid cells had been reported by other authors,60 the isolation of a stem cell population able to differentiate into lineages representative of all three embryonic germ layers which in specific conditioned acquired characteristics of pluripotency was demonstrated later.61,62 These cells, named amniotic fluid stem (AFS) cells, are characterized by the expression of the surface antigen c-kit (CD117), which is the type III tyrosine kinase receptor of the stem cell factor.63 AFS cells can be isolated from the amniotic fluid of humans and rodents.64 Human AFS cells can be derived either from small volumes (5 mL) of second-trimester amniotic fluid (14– 20 weeks) or from confluent back up of amniocentesis cultures and can be expanded in mesenchymal conditions or reprogrammed to generate iPS cells.43 Murine AFS cells are obtainable from the amniotic fluid collected during week 2 of pregnancy (E11.5–14.5).60–62 AFS cell isolation is based on a two-step protocol consisting in immunomagnetic selection of c-kit positive cells from the amniotic fluid (
1% of total amniotic fluid cells) followed by expansion and subsequent culture.62,65 Isolated AFS cells can be expanded in feeder layer-free, serum-rich conditions without evidence of spontaneous differentiation in vitro. In contrast with mesenchymal cells, AFS cells show hematopoietic engraftment and a functional and stable integration into the skeletal muscle stem cell niche, so that they could be a cell source for the treatment of muscular pathologies and skeletal muscle defects.66,67

Cell Therapy Relevant to Pediatric Surgery Pediatric stem cell transplant is a treatment modality used for some patients with hematological, oncological, immunological, and/or genetic diseases. Several other therapeutic stem cell applications in various pediatric areas also exist either at a laboratory or clinical experimental stage. Following, we report the recent achievements in stem cell applications in clinical conditions of interest to pediatric surgeons.

Intestinal Regeneration Necrotizing enterocolitis (NEC) is one of the most devastating and life-threatening diseases affecting preterm neonates. Despite extensive research and advancement in medical and surgical treatment, mortality from NEC remains as high as 40% especially in very low-birth-weight infants.68 Several experimental studies have reported a variety of strategies for prevention and/or treatment of NEC. These include captopril,69 heparin-binding epidermal growth factor (EGF)-like growth factor,70 platelet-activating factor antagonists,71 and recently stem cells.72–74 Cell therapy for NEC came about only recently due to the complexity of the European Journal of Pediatric Surgery

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Stem Cell Therapy as an Option for Pediatric Surgical Conditions

Stem Cell Therapy as an Option for Pediatric Surgical Conditions intestine as an organ and the variety of its cell populations. The foundation of this approach has to be found in the successful results using bone marrow or peripheral blood stem cells to treat inflammatory bowel disease in experimental colitis,75–82 a condition that shares common features with NEC. Given the promising results in experimental models, several studies attempted cell therapy in patients with Crohn disease and reported clinical improvement and disease remission.83–85 The Autologous Stem Cell Transplantation International Crohn’s Disease (ASTIC) Trial using MSCs reported promising results in decreasing the disease activity index and the disease endoscopic index of severity, and concluded that in human case of refractory Crohn disease, hemopoietic stem cell transplantation appears to be an effective treatment.86 Given these data and the limited clinical management options in NEC, Zani et al first reported the use of AFS cells in a well-established neonatal rat model of NEC.72,73 In this study, initial experiments with bone marrow–derived MSCs (BM-MSCs) were not successful in improving survival of rats with NEC. Conversely, AFS cells integrated in the bowel wall and improved rat survival and clinical conditions, decreased NEC incidence and macroscopic gut damage, improved intestinal function, decreased bowel inflammation, increased enterocyte proliferation, and reduced apoptosis.74 To understand the mechanism responsible for AFS cell beneficial effects, gut expression profiles were studied on duplicated complementary DNA arrays. Rats injected with AFS cells showed an upregulation of the genes involved in the proliferative response, namely, genes of the Wnt/β-catenin pathway, which regulate intestinal epithelial stem cell function, cell migration, and growth factors known to maintain gut epithelial integrity and reduce mucosal injury.74 AFS cells were found to act by modulating stromal cells present in the lamina propria expressing cyclooxygenase 2 in the lamina propria, as shown by survival studies using selective and nonselective cyclooxygenase 2 inhibitors.74 Similar beneficial results with the use of amniotic fluid were reported by Good et al, who demonstrated that enteral administration of amniotic fluid per se attenuates the severity of experimental NEC in mice through activation of the EGF receptor.87 In this study, amniotic fluid was administered by gavage and proved to attenuate the severity of intestinal damage via inhibition of Toll-like receptor 4 signaling. Recently, Siggers et al demonstrated that postnatal amniotic fluid administration reduces inflammatory responses and NEC in preterm piglets.88 In this study, piglets receiving amniotic fluid showed decreased bacterial colonization in the colon and intestinal inflammation-related genes were downregulated. The pathway through which AFS cell therapy reported by Zani et al exerts a positive effect on the intestine of rats with experimental NEC might be the same or part of the pathway described by Good et al. Cell therapy for NEC was reported also by Tayman et al in neonatal rats.73 In this study, intraperitoneally injected human BM-MSCs, labeled with iron oxide particles, were found home to injured sites in the bowel and to decrease microscopic gut damage. Moreover, rats injected with BMEuropean Journal of Pediatric Surgery

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MSCs had a higher body weight and better behavior, assessed with a clinical sickness score, than untreated rats with NEC. More studies are needed to translate these preliminary results onto clinical practice. Potentially, stem cell therapy could be considered in the future for infants with milder forms of NEC, where the inflammation could be limited and the established damage repaired. Conversely, in infants with advanced disease, surgery would still play a vital role, for the resection of the perforated or necrotic bowel. However, given the notable effect in the stimulation of cell repopulation, stem cell therapy could be imagined for the postoperative period, to help the bowel recover. Finally, stem cell therapy could play a role in patients who develop intestinal failure secondary to short gut, as it could promote mucosal repopulation and facilitate bowel adaptation.

Liver Regeneration In the past years, several studies have looked into the role of stem cells in liver regeneration. Currently, the only curative option for end-stage liver disease is liver transplantation. Donor organ availability cannot meet current demand and many patients die while waiting for a suitable organ.5 Alternative therapeutic strategies are urgently required for the treatment of advanced liver disease. Indications for liver transplantation in infants and children include acute liver failure, chronic liver failure with pruritus, complications of cholestasis, and failure to thrive. Several pediatric liver conditions can progress to liver failure and necessitate transplant, including inborn errors of metabolism, drug-induced or viralinduced acute liver failure, and biliary atresia which alone accounts for approximately 50% of all liver transplants in children.89 Hematopoietic stem cell therapy through fusion or transdifferentiation can contribute to hepatic epithelial lineages.90 Several studies have reported that after transplantation, circulating bone marrow–derived stem cells migrate into the liver and contribute to liver regeneration.91–93 In 2005, Gehling et al demonstrated that partial hepatectomy in healthy human liver donors induces a significant mobilization of CD133þ hematopoietic progenitor cells into the peripheral blood.94 The same group later reported another study demonstrating that liver cirrhosis leads to recruitment of various populations of hematopoietic progenitor cells that display markers of intrahepatic progenitor cells.95 Liver regeneration occurs through division of mature hepatocytes. However, when the liver is affected by severe fibrosis, mature hepatocytes lose their ability and liver regeneration happens through hepatic progenitor cells.96 These are intrahepatic precursor cells also called oval cells that can give rise to both hepatocytes and biliary epithelium. In an experimental study, Omori et al showed that the expression of stem cell factor was significantly increased in bile duct–ligated rats up to 5 weeks of age, thus demonstrating that the bile ductular epithelium in young rats responds to bile stasis similarly to activated hepatic stem cells in adult livers.97

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The paradigm of liver disease for pediatric surgeons is biliary atresia, a destructive inflammatory obliterative cholangiopathy, with an average 5-year native liver survival of 50%.98 Currently, there is no effective pharmacologic method to control the early onset of liver fibrosis, which is a characteristic feature of biliary atresia, so that alternative strategies are under investigation. So far, cell therapy in this area has been almost anecdotal. In 2008, Khan et al reported the case of a 1year-old infant with biliary atresia and end-stage liver disease, who was treated with hepatic progenitor cell infusion through the hepatic artery.99 The treatment resulted in an eightfold decrease of conjugate bilirubin and increased liver cell function at scintigraphy. In 2011, Sharma et al reported a study on 30 infants with biliary atresia who received BM-MSC infusion either at the time of or after Kasai portoenterostomy.100 These infants with biliary atresia treated with stem cell therapy had early biochemical and scintigraphic improvement and a reduction in the number of episodes of cholangitis. Since BM-MSC infusion prolonged survival in patients with liver cirrhosis probably thanks to their anti-inflammatory action, Sharma et al speculated that this therapeutic approach might have a potential role in patients awaiting a liver transplant.100 Recently, an alternative cell therapy using human hepatocyte has become an accepted therapy for acute liver failure, either as a bridge to liver regeneration or to organ transplantation.101 Human hepatocytes are isolated from liver tissues rejected or not used for transplantation, digested by collagenase perfusion technique and purified by centrifugation.101 Storage of human hepatocyte has posed concerns regarding their viability and function, especially because cryopreservation can have detrimental effects on their viability and metabolic function. To overcome this issue, Fitzpatrick et al recently described a technique where human MSCs cocultured with cryopreserved human hepatocytes improved both hepatocytes viability and function, as indicated by increased levels of albumin and urea production.102 This study confirms the beneficial role that MSCs have providing structural and trophic support to hepatocytes.

Lung Regeneration Lung regeneration using a cell therapy approach has been explored in the last few years for various conditions. In pediatric surgery, the clinical paradigms where lung regeneration would be envisaged are the hypoplastic lungs of infants born with congenital diaphragmatic hernia and those of preterm infants in general. The lung has extensive abilities to repair and regenerate after damage and this is particularly true in children where its development continue in the postnatal life.103 In fact, it is known that in human, the alveolar stage of lung development continues after birth up to 2 years of age. One can speculate that early intervention in children affected by hypoplastic or fibrotic lungs might help restoring normal function. As in other tissues, attention has been focused on understanding the mechanisms of lung development with the hope of getting more insight to possible therapeutic actions.104 Children and adolescents born preterm show impaired lung function, which in many cases leads to the development of

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chronic respiratory disorders.105–107 There is increasing evidence of the value of stem cells as a potential treatment for neonatal lung disorders,108 especially of cord blood and bone marrow stem cells, which have been used in newborn murine models.109,110 Adult MSCs are likely to represent the ideal candidate from their pleiotropic effects because of the multifactorial disease. In experimental oxygen-induced BPD in newborn rodents, intravenous or intratracheal delivery of BM-MSCs healed inflammation, prevented lung vascular and alveolar damage, and rose exercise tolerance and survival.111,112 Promotion of angiogenesis could also be a strategy to improve recovery of damaged lung. Indeed bone marrow myeloid progenitor cells have been shown to be able to restore impaired alveolar and vascular lung growth in hyperoxia-exposed newborn mice.113 Umbilical cord blood, in particular, is an easily accessible, ethically feasible, and readily available source of MSCs. Chang et al demonstrated that MSCs from human cord blood, delivered using intratracheal or intraperitoneal routes, prevent alveolar growth arrest and decrease fibrotic changes in the lungs of oxygenchallenged neonatal rats.114 Fetal cells such as AFS cells have also been successfully adopted. AFS cells are able to integrate into developing as well as injured lung tissue, influencing its recovery from injury, and differentiate into lung epithelial lineages.61,62,115 To study lung hypoplasia in congenital diaphragmatic hernia, a well-established model based on nitrofen exposure of pregnant rats has been used.116 In hypoplastic nitrofen-exposed lung explants cocultured with AFS cells, the size and the number of terminal buds were restored.117 Moreover, the frequency of peristaltic waves, which was decreased in nitrofen-exposed lungs, as expected, normalized after adding AFS cells to the medium.117 Despite the minimal indication of engraftment, the main therapeutic effect produced by AFS cells seems to be mediated by paracrine mechanisms elicited through trophic mediators, as evident by the coculture experiments. Among the various factors that could be driving this effect, FGF-10, which is essential for lung branching morphogenesis, was considered to have a possible role in the regeneration mediated by AFS cells. Finally, Garcia et al recently demonstrated that AFS cells are able to inhibit the progression of bleomycin-induced pulmonary fibrosis via modulation of the profibrotic cytokine CCL2, whose expression is increased in bleomycin-injured bronchoalveolar lavage.118

Conclusion Stem cells technologies are advancing very rapidly and it is possible that we will be able to offer more therapies derived from applications in the field. Basic knowledge in stem cell and regenerative medicine is mandatory both to be able to translate to patients these innovative treatments and to dialogue with basic scientist facilitating implementation and reverse translation.

Conflict of Interest None. European Journal of Pediatric Surgery

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Stem Cell Therapy as an Option for Pediatric Surgical Conditions

22 Nussbaum J, Minami E, Laflamme MA, et al. Transplantation of

References 1 Corsello G, Giuffrè M. Congenital malformations. J Matern Fetal

Neonatal Med 2012;25(Suppl 1):25–29 2 World Health Organization. Congenital anomalies. Fact sheet N°

3

4

5 6 7

8

9

10

11

12

13

14

15 16

17

18

19

20

21

370. Updated January 2014. Available at: http://www.who.int/ mediacentre/factsheets/fs370/en/ 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 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 Atala A. Regenerative medicine strategies. J Pediatr Surg 2012; 47(1):17–28 De Coppi P. Regenerative medicine for congenital malformations. J Pediatr Surg 2013;48(2):273–280 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 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 Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284(5411): 143–147 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 Odorico JS, Kaufman DS, Thomson JA. Multilineage differentiation from human embryonic stem cell lines. Stem Cells 2001;19(3): 193–204 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 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 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 Hanson C, Caisander G. Human embryonic stem cells and chromosome stability. APMIS 2005;113(11-12):751–755 Maitra A, Arking DE, Shivapurkar N, et al. Genomic alterations in cultured human embryonic stem cells. Nat Genet 2005;37(10): 1099–1103 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 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 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 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 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

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29

30

31

32

33

34

35

36

37

38

39

40

41

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undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. FASEB J 2007;21(7): 1345–1357 Grinnemo KH, Sylvén C, Hovatta O, Dellgren G, Corbascio M. Immunogenicity of human embryonic stem cells. Cell Tissue Res 2008;331(1):67–78 Sarić T, Frenzel LP, Hescheler J. Immunological barriers to embryonic stem cell-derived therapies. Cells Tissues Organs 2008; 188(1-2):78–90 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 Edwards RG. A burgeoning science of embryological genetics demands a modern ethics. Reprod Biomed Online 2007;15 (Suppl 1):34–40 Green RM. Can we develop ethically universal embryonic stemcell lines? Nat Rev Genet 2007;8(6):480–485 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 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 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 Lebkowski J. GRNOPC1: the world’s first embryonic stem cellderived therapy. Interview with Jane Lebkowski. Regen Med 2011;6(6, Suppl):11–13 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 Schwartz SD, Hubschman JP, Heilwell G, et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 2012;379(9817):713–720 Ethics Committee of the American Society for Reproductive Medicine. Human somatic cell nuclear transfer and cloning. Fertil Steril 2012;98(4):804–807 Tachibana M, Amato P, Sparman M, et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell 2013;153(6): 1228–1238 Langerova A, Fulka H, Fulka J Jr. Somatic cell nuclear transferderived embryonic stem cell lines in humans: pros and cons. Cell Reprogram 2013;15(6):481–483 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 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 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 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 Meissner A, Wernig M, Jaenisch R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat Biotechnol 2007;25(10):1177–1181 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 Moschidou D, Mukherjee S, Blundell MP, et al. Human midtrimester amniotic fluid stem cells cultured under embryonic stem cell conditions with valproic acid acquire pluripotent characteristics. Stem Cells Dev 2013;22(3):444–458

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conversion of somatic cells into pluripotency. Nature 2014; 505(7485):641–647 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 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 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 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 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 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 Norambuena GA, Khoury M, Jorgensen C. Mesenchymal stem cells in osteoarticular pediatric diseases: an update. Pediatr Res 2012;71(4 Pt 2):452–458 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 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 Guillot PV, O’Donoghue K, Kurata H, Fisk NM. Fetal stem cells: betwixt and between. Semin Reprod Med 2006;24(5):340–347 Walsh DS, Adzick NS. Fetal surgical intervention. Am J Perinatol 2000;17(6):277–283 Deprest JA, Done E, Van Mieghem T, Gucciardo L. Fetal surgery for anesthesiologists. Curr Opin Anaesthesiol 2008;21(3):298–307 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 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 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 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 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 De Coppi P, Bartsch G Jr, Siddiqui MM, et al. Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol 2007; 25(1):100–106 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 Cananzi M, De Coppi P. CD117(þ) amniotic fluid stem cells: state of the art and future perspectives. Organogenesis 2012;8(3): 77–88

225

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

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

fluid c-KitþLin- cells display hematopoietic activity. Blood 2009; 113(17):3953–3960 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 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 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 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 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 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 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 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 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 Komori M, Tsuji S, Tsujii M, et al. Involvement of bone marrowderived cells in healing of experimental colitis in rats. Wound Repair Regen 2005;13(1):109–118 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 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 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 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 Tanaka F, Tominaga K, Ochi M, et al. Exogenous administration of mesenchymal stem cells ameliorates dextran sulfate sodiuminduced colitis via anti-inflammatory action in damaged tissue in rats. Life Sci 2008;83(23-24):771–779 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 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 Cassinotti A, Annaloro C, Ardizzone S, et al. Autologous haematopoietic stem cell transplantation without CD34þ cell selection in refractory Crohn’s disease. Gut 2008;57(2):211–217 Hommes DW, Duijvestein M, Zelinkova Z, et al. Long-term followup of autologous hematopoietic stem cell transplantation for severe refractory Crohn’s disease. J Crohn’s Colitis 2011;5(6): 543–549 European Journal of Pediatric Surgery

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This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

44 Obokata H, Wakayama T, Sasai Y, et al. Stimulus-triggered fate

Zani, De Coppi

Stem Cell Therapy as an Option for Pediatric Surgical Conditions 86 Hawkey CJ. Stem cells as treatment in inflammatory bowel 87

88

89

90

91 92

93 94

95

96

97

98 99

100

101 102

disease. Dig Dis 2012;30(Suppl 3):134–139 Good M, Siggers RH, Sodhi CP, et al. Amniotic fluid inhibits Tolllike receptor 4 signaling in the fetal and neonatal intestinal epithelium. Proc Natl Acad Sci U S A 2012;109(28):11330–11335 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 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 8): viii23–viii28 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 Alison MR, Poulsom R, Jeffery R, et al. Hepatocytes from nonhepatic adult stem cells. Nature 2000;406(6793):257 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 Theise ND, Nimmakayalu M, Gardner R, et al. Liver from bone marrow in humans. Hepatology 2000;32(1):11–16 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 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 Fausto N, Campbell JS. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech Dev 2003;120(1): 117–130 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 Davenport M. Biliary atresia: clinical aspects. Semin Pediatr Surg 2012;21(3):175–184 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 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 Hughes RD, Mitry RR, Dhawan A. Current status of hepatocyte transplantation. Transplantation 2012;93(4):342–347 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

European Journal of Pediatric Surgery

Vol. 24

No. 3/2014

Zani, De Coppi

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

105

106 107

108

109

110

111

112

113

114

115

116

117

118

generation and regeneration of a complex organ. Development 2014;141(3):502–513 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 Cutz E, Chiasson D. Chronic lung disease after premature birth. N Engl J Med 2008;358(7):743–745, author reply 745–746 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 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 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 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 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 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 Balasubramaniam V, Ryan SL, Seedorf GJ, et al. Bone marrowderived 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 Chang YS, Oh W, Choi SJ, et al. Human umbilical cord bloodderived mesenchymal stem cells attenuate hyperoxia-induced lung injury in neonatal rats. Cell Transplant 2009;18(8):869–886 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 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 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 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

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