Biochemical Society Transactions

Engineering tissue for the fetus: stem cells and matrix signalling Paolo De Coppi*1 *Surgery Unit, University College London, 30 Guilford Street, London WC1N 1EH, U.K.

Abstract Congenital malformations are major causes of disease and death during the first years of life and, most of the time, functional replacement of the missing or damaged organs remains an unmet clinical need. Particularly relevant for the treatment of congenital malformation would be to collect the stem cells at diagnosis, before birth, to be able to intervene during the gestation or in the neonatal period. Human AFSCs (amniotic fluid stem cells), which have characteristics intermediate between those of embryonic and adult stem cells, have been isolated. c-Kit + Lin − cells derived from amniotic fluid display a multilineage haemopoietic potential and they can be easily reprogrammed to a pluripotent status. Although, in the future, we hope to use cells derived from the amniotic fluid, we and others have proved recently that simple organs such as the trachea can be engineered using adult progenitors utilizing decellularized cadaveric matrices. A similar approach could be used in the future for more complex organs such as the muscles, intestines or lungs.

Introduction The repair of congenital malformations can be often challenged by the fact that autologous tissue is missing [1]. Major cardiac anomalies, bladder exstrophy, omphaloceles, diaphragmatic hernia or long gap oesophageal atresia are only some of the situations in which we have to use prostheses or adopt solutions associated with a significant degree of morbidity and mortality. Since these children have, overall, good survival rates and mostly normal schooling, it is important to avoid using solutions that are not ideal, as this may limit their options in the future. However, at the moment, we are still limited and therefore if, for example, we put a prosthesis in the diaphragm, it will not grow with the child, so there is more chance of muscle traction with possible scoliosis, hernia recurrence or patch infections resulting in a poor quality of life for the child and his or her family [2]. For all of these reasons, many surgeons dealing with congenital malformations have been interested in tissue regeneration [3–5]. The possibility of making new tissue in vitro would

Key words: amniotic fluid, congenital malformation, decellularization, regenerative medicine, stem cell, tissue engineering. Abbreviations: AFSC, amniotic fluid stem cell; BM-MSC, bone marrow mesenchymal stem cell; ECM, extracellular matrix; ESC, embryonic stem cell; iPSC, induced pluripotent stem cell; IUSCT, in utero stem cell therapy; NEC, necrotizing enterocolitis; PGA, poly(glycolic acid); SC, satellite cell. 1 email [email protected]

Biochem. Soc. Trans. (2014) 42, 631–635; doi:10.1042/BST20140069

indeed completely change the way we treat these children and transform their lives.

Background to stem cells and regenerative medicine

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The recent progress in regenerative medicine has been possible, mainly thanks to the advancement in stem cell technologies. We can probably date this back to the work of Charles Lindbergh, who was the first solo flyer over the Atlantic Ocean, and Alexis Carrel, who was the Nobel Prize winner for vascular anastomosis and who is considered the father of transplantation. They began working together in 1935 because Charles Lindbergh’s sister had died due to a severe cardiac anomaly [6]. Lindbergh could not believe that technology could take humans over the Atlantic on a flight, but could not build a new heart. It is interesting to note that, almost 80 years later, we cannot build a new biological heart in the laboratory as such, although we can now routinely adopt mechanical hearts as a bridge to transplantation and, in so doing, have already saved thousands of lives [7]. However, we now know that stem cells are present in our body. A stem cell is defined by the capacity of undergoing an asymmetric division while maintaining selfrenewal and lineage commitment towards one or more tissues [8].  C The

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Only stem cells have these characteristics; however, their potential is to vary from the totipotency of cells derived from the first few divisions of the fertilized egg to the unipotency of somatic cells present in peripheral tissue [9,10]. To regenerate large amounts of tissues, pluripotent cells would be ideal because they can be expanded and are able to generate any tissue [9]. However, they are still limited in their clinical use because, besides ethical concerns and immunogenicity, which have been partially overcome with the discovery of iPSCs (induced pluripotent stem cells), they are so powerful that they can be tumorigenic [11]. On the other side, we have multipotent cells, which are limited to the generation of tissues within the same germ layer, but they are safer and indeed they have already been adopted to correct some of these malformations [10,12].

Embryonic stem cells ESCs (embryonic stem cells) would be ideally positioned to build tissues for children with congenital malformations [9]. However, besides their tumorigenic potential and the ethical issues, immunosuppressive treatment should also be adopted to avoid their rejection by the transplanted patient. It is believed that ESCs are less immunogenic, but this is only true if you consider them before differentiation. Once they are terminally differentiated and express all of the MHCs, they would be rejected if immunosuppression therapy was not adopted. There is only one exception to this paradigm: injection into the retina, as demonstrated by the preliminary results of injection of ESCs in patients affected by macular degeneration [13]. Only a limited number of cells can be therapeutic and therefore can be more efficiently monitored before transplantation. Secondly, the retina is an immuneprivileged site so ESC injection does not need to be associated with immunosuppression.

Adult stem cells On the opposite side of the picture, there are the adult stem cells [10]. Somatic stem cells can be expanded from different postnatal tissues and could be useful for therapy, particularly in newborns and children where they are generally more abundant and probably more potent than in adults [14]. Classically, the bone marrow contains, beside haemopoietic stem cells, mesenchymal stem cells, but somatic cells with different potentials can be isolated and grown in good quantities. These cells can be used in autologous settings, avoiding immunogenic problems, as far as we know they are not tumorigenic, and their use does not raise any ethical issues [15]. Some 15 years ago, a cover of Nature Biotechnology celebrated the first artificial bladder taking shape in dogs [16]. The whole dome of the bladder could be successfully replaced using smooth muscle and urothelial cells expanded from the recipient and this established the basis for treating the first patients affected by bladder exstrophy. The group co-ordinated by Dr Atala described in The Lancet in 2006 a pilot study of seven patients who  C The

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had received implanted tissue engineering bladders from 1998 onwards [3]. Similarly to the animal model, they reported the use of either collagen scaffolds seeded with cells or a combined PGA [poly(glycolic acid)]–collagen scaffold seeded with cells for bladder replacement. These engineered tissues were implanted with or without omental coverage. Patients reconstructed with engineered bladder tissue created with cell-seeded PGA–collagen scaffolds and omental coverage showed increased compliance, decreased end-filling pressures, increased capacities and longer dry periods over time [3]. More recently, the same group showed that in five boys who had urethral defects, tubularized urethras could be engineered and remain functional in a clinical setting for up to 6 years [17]. A tissue biopsy was taken from each patient, and the muscle and epithelial cells were expanded and seeded on to tubularized PGA–poly(lactide-co-glycolide acid) scaffolds. Patients (10–14 years of age), who had surgery between March 2004 and July 2007, were followed up until July 2010 showing maintenance of a normal function and tissue architecture after biopsy [17]. So why do we not always use adult stem cells? First, because the number of cells are small and decrease with age. Secondly, these cells are multipotent not pluripotent, so they cannot give rise to all lineages. Finally, they can be exposed to viruses and toxins during their lifetime [10]. That means that we have cells in our body that continuously accumulate deletions and mutations [18]. Our immune system normally destroys them; however, if they are replicated in large numbers in the laboratory and transplanted back into the recipient, they may be able to fight against our immune system and generate a tumour.

Induced pluripotent stem cells In 2006, a seminal paper published by Takahashi and Yamanaka [11] described how some of the limitations of both embryonic and adult stem cells were overcome. His group found, first in mice and subsequently in humans, that pluripotent stem cells could be generated from adult counterparts using defined transcription factors [19]. The findings were confirmed by independent groups and it is now possible to derive iPSCs using different methodologies [20]. Although iPSCs, when compared with ESCs, eliminate the immunogenic problem since you can use them in an autologous setting, and reduce the ethical concerns, iPSCs are still tumorigenic and their clinical use has still not been adopted.

Amniotic fluid stem cells Fetal stem cells should also be considered. They are distinct both from adult stem cells and ESCs, they can be used in an autologous setting, their use is not controversial and they are not tumorigenic [8]. Moreover, they are more na¨ıve than adult stem cells and can be superior in terms of both proliferation and differentiation. Isolation of stem cells from amniotic fluid

Biochemical Society Annual Symposium No. 81: Biochemical Determinants of Tissue Regeneration

is easy to perform, at low risk for the mother and the fetus, and it is a widely accepted method for prenatal diagnosis. So, AFSCs (amniotic fluid stem cells) are ideal for prenatal and neonatal application [21]. AFSCs are immunoselected by the stem cell factor receptor c-kit (CD117) and give rise to lineages representing the three germ layers both in vitro and in vivo [22]. The cells express markers of all three germ layers and have been easily reprogrammed not only by DNA-integrating systems [23], but also without any genetic manipulation by means of the histone deacetylase inhibitor VPA (valproic acid) [24,25]. Both human and rodent AFSCs display multilineage haemopoietic potential [26] and can exert a beneficial paracrine action in models of bladder [27], heart [28], kidney [29] and lung [30] disease. AFSCs could also have a role for IUSCT (in utero stem cell therapy) [31]. IUSCT in humans has been successful only for the treatment of congenital SCID (severe combined immunodeficiency) [32]. Rejection of allogeneic cells in utero could be at least partially explained by the migration of the in utero injected cells into maternal circulation and mounting of a rejection response, which could diminish the engraftment. In mice, this is most likely to be due to activated maternal T-cells which can cross the placenta and destroy engrafted allogeneic cells [33]. In order to avoid this response, stem cells matched to the mother could be used. Alternatively, in monogenic disease, AFSCs derived from the fetus could be used for therapy after genetic modification since they would not trigger an immunogenic response either from the fetus or from the mother. Regarding their applications for the treatment of acquired conditions, we and others have tested various disease models. HSA-Cre, SmnF7/F7 mice receiving intravenous injection of a small number of AFSCs were able to survive with drastic improvement of their muscle force [34]. Histopathological evaluation of the treated animals revealed integration of AFSCs not only in the skeletal muscle fibres, but also in the stem cell compartment of the muscle. Indeed, following secondary transplants of SCs (satellite cells) derived from treated mice, it was found that AFSCs integrate into the muscle stem cell compartment and have long-term muscle regeneration capacity indistinguishable from that of wildtype-derived SCs [34]. In other disease models, AFSCs do not fully integrate into the differentiated tissues, but promote their regeneration. NEC (necrotizing enterocolitis) remains a major cause of neonatal morbidity and mortality despite changes in medical and surgical treatment [35]. Since there are no specific medical therapies which are of clinical benefit in infants with NEC, current management is characterized by supportive medical treatment and surgical resection of affected intestine in severe cases; survivors may develop intestinal failure and/or short bowel syndrome. Using a well-established NEC model in neonatal rats, we demonstrated that intraperitoneal injection of AFSCs improved survival compared with animals injected with BM-MSCs (bone marrow mesenchymal stem cells). In contrast with other models of bowel disease, in which BM-

MSCs are effective, the benefit we obtained in experimental NEC was specific to AFSCs and was not observed with BMMSCs. This could be due to differences in pathogenesis; in NEC, the enterocolitis is associated with ischaemia and bowel immaturity, whereas in IBD (inflammatory bowel disease), the pathological changes are primarily related to immune dysregulation [36]. Interestingly, AFSCs also improved clinical status and MRI images acquired immediately after death indicated a reduction in fluid within the peritoneal cavity following AFSC treatment. Gut motility was restored when AFSCs were injected into the affected animals, which did not differ from breastfed rats and had significantly less macroscopic gut damage than NEC animals. In this animal model, AFSC injected into the peritoneal cavity migrated and integrated in the damaged intestine. These cells were consistently present, but their low degree of tissue engraftment suggested a paracrine mechanism of action. It appears that AFSCs diminish apoptosis and inflammation, and promote enterocyte proliferation, and could act via a COX-2 (cyclooxygenase 2)-related mechanism [36]. AFSCs, however, have not yet been used clinically. Therefore attempts to generate tissues or organs in the laboratory for the correction of congenital malformations have been made using adult somatic cells.

Recent developments in organ tissue engineering Trachea engineering, first attempted to correct the left main bronchus of an adult [37], has been successfully applied to substitute the entire trachea of a 10-year-old child [12] born with a congenital tracheal stenosis who underwent several operations for attempting surgical reconstruction using traditional techniques. The engineered trachea was prepared using bone marrow mononuclear cells and tracheal epithelium taken from the recipient and seeded in a decellularized trachea derived from a cadaver. Although in vivo regeneration occurs only with time since initially there were difficulties related mainly to epithelial regeneration and cilia formation, engineering organs using decellularized tissue is an option closer and closer to patients. The examples are multiplying in the literature and they are proven in both small and larger animals. From relatively simple organs such as the oesophagus [38] to more complex organs such as the intestine [39], decellularized tissues have been engineered to provide new functional organs. Functional kidneys, livers or lungs have also been generated using this type of technique. The lungs have been engineered thanks to the ability to maintain matrices, which resemble as close as possible the tissue of origin. Early protocols used simple immersion of the lungs in a series of detergents for an extended period of time until cells were removed [40]. More recently, the focus has shifted towards dynamic protocols in which the trachea and the pulmonary artery are used to infuse the decellularization solutions [41,42]. Other laboratories have used both ports of entry with complex systems, which, if translated to  C The

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clinical practice, could be prone to contamination. Others omitted the vascular access and used only the trachea to decellularize rat and sheep lungs [43,44]. Kidneys have been particularly challenging. They have now been successfully decellularized in the rodent [45], pig [46] and rhesus monkey [47], preserving the ECM (extracellular matrix) and vascular supply. Preliminary data showed that the renal ECM may contribute towards the differentiation of the injected cells, since seeding of ESCs adjacent to the renal artery and ureter led to a loss of cellular embryonic appearance, expression of differentiation markers and proliferation within the vascular, tubular and glomerular structures [48]. Regarding the liver, methodologies involving increasing concentrations of SDS, followed by Triton X-100, led to a successful liver decellularization in the rat [49]. Variations of this method described an increasing concentration of Triton X-100, followed by SDS [50], a combination of trypsin, EDTA and Triton X-100 [51], or Triton X-100 and ammonium hydroxide [52]. The general methodology based on detergents has also been scaled up in larger animals such as the rabbit and pig [53,54] and hopefully may in the future lead to obtain ideal matrices to functionally engineer new liver for transplantation. However, when we consider the newborn, we have additional problems related to size-matching. Even if we consider only obtaining cadaveric organs, it would be very difficult to obtain consent from carers to obtain tissue from a deceased newborn. For this reason, it may become an opportunity to collect tissue and organs from animals and utilize them to engineer tissue for humans. It has been shown that decellularized rabbit muscles can be implanted in rats without generating any rejection [55]. Moreover, the ECM could partially protect transplanted xenogeneic cells from rejection. In conclusion, regenerative medicine is changing the way we do things for patients born affected by a congenital malformation. Although science needs time to elucidate the mechanism of actions and determine the safety of stem cell products, we need to be ready to advance these techniques for the benefit of patients.

Note added in proof (received 17 April 2014) While this paper was in proof, it was reported that ¨ four young females affected by Mayer–Rokitansky–Kuster– Hauser syndrome were each transplanted with a tissueengineered vagina [56]. The organs, engineered from the patient’s own cells and implanted, showed normal structural and functional variables with a follow-up of up to 8 years [56].

Funding P.D.C. is supported by the Great Ormond Street Hospital Children’s Charity.

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Biochemical Society Annual Symposium No. 81: Biochemical Determinants of Tissue Regeneration

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Received 31 March 2014 doi:10.1042/BST20140069

 C The

C 2014 Biochemical Society Authors Journal compilation 


Engineering tissue for the fetus: stem cells and matrix signalling.

Congenital malformations are major causes of disease and death during the first years of life and, most of the time, functional replacement of the mis...
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