Journal of Medical Hypotheses and Ideas (2012) 6, 7–11
Available online at www.sciencedirect.com Journal of Medical Hypotheses and Ideas
journal homepage: www.elsevier.com/locate/jmhi
REGULAR ARTICLES The human umbilical cord: A novel substitute for reconstruction of the extrahepatic bile duct
Yao Cheng 1, Yixin Lin 1, Xianze Xiong, Sijia Wu, Jiong Lu, Nansheng Cheng *
Department of Bile Duct Surgery, West China Hospital, Sichuan University, Chengdu, China
Received 9 January 2012; revised 10 February 2012; accepted 28 February 2012
Abstract Reconstruction of the extrahepatic bile duct following bile duct injury or defect is one of the most common challenges for hepatobiliary surgeons. There are currently a number of surgical strategies such as biliary-enteric anastomosis, end-to-end anastomosis and autologous tissue substi- tute. However, sphincter of Oddi dysfunction as well as biliary stricture may occur after surgical anastomosis. Also, insufficient tissue quantity remains a problem associated with the application of tissue substitute. Therefore, considerable attention has been attracted to explore a new replace- ment material of the bile duct for biliary reconstruction. The human umbilical cord (HUC) is abun- dant in resource and is convenient to collect, including two arteries and one vein, whose diameters are close to that of the common bile duct. In order to reduce immunogenicity (foreign-body reac- tion), cells and major histocompatibility complex (MHC) antigens can be removed from the HUC and the remaining tissue (extracellular matrix, ECM) can be used as a scaffold. The HUC provides a rich source of mesenchymal stem cells (MSCs). A current study has demonstrated that MSCs are able to differentiate into biliary epithelial cells in vivo and in vitro with low immunogenicity, which can be used as seed cells. The HUC might be a promising composite material of a scaffold (ECM) and seed cells (biliary epithelial cells), for bile duct replacement in situ without removal of sphincter of Oddi, or biliary stricture. In addition, the patients’ own umbilical cord without any foreign-body reaction can be directly banked for possible future use in bile duct reconstruction. Therefore, we hypothesise that the HUC may be a novel substitute for reconstruction of the extrahepatic bile duct. ª 2012 Tehran University of Medical Sciences. Published by Elsevier Ltd. Open access under CC BY-NC-ND license.
* Corresponding author. Address: Department of Bile Duct Surgery, West China Hospital, Sichuan University, 37# Guoxue Road, Chengdu 610041, China. Tel./fax: +86 28 85422465. E-mail address: [email protected] (N. Cheng). 1 They contributed equally to the submission.
2251-7294 ª 2012 Tehran University of Medical Sciences. Published by Elsevier Ltd. Open access under CC BY-NC-ND license. URL: www.tums.ac.ir/english/ doi:http://dx.doi.org/10.1016/j.jmhi.2012.03.001 8 Y. Cheng et al.
Introduction [25]. HUC, with such a composition of bio-scaffolds, living cells and growth factors, might be a promising material for restoration of the function of bile duct. Bile duct, as a conduit for bile flow, has a poor intrinsic healing 2. Autologous substitute: The patient’s own umbilical cord, capacity [1,2]. Once bile duct has been affected by carcinoma, which was banked after birth for future use, could be cyst, stricture or atresia, most patients require resection of the applied to directly reconstruct the patient’s own bile duct. affected segment, if applicable, resulting in iatrogenic bile duct Some autologous tissues (e.g., vein, ileum and gallbladder) defect [3]. Iatrogenic bile duct injury occurs more frequently in have been suggested as substitutes for biliary reconstruc- the era of laparoscopic cholecystectomy. The overall incidence tion. Similarly, we hypothesise that the autologous HUC of biliary lesion following laparoscopic cholecystectomy varies may also be used to reconstruct the bile duct. The autolo- between 0.3% and 0.7% in different series [4–7]. Reconstruc- gous HUC offers the following advantages: First, the tion of the extrahepatic bile duct is often performed on the pa- HUC-MSCs might differentiate into biliary epithelial cells tients suffering from the bile duct injury or defect [8,9]. in vivo after transplantation, which might promote the bile Biliary-enteric anastomosis (anastomosis between bile duct duct regeneration (see below). Second, reconstruction of the and small intestine) is regarded as the ‘golden standard’ tech- extrahepatic bile duct can be achieved without any immu- nique for reconstruction of the extrahepatic bile duct [8,9]. nologic graft rejection. However, this operation alters the normal biliary anatomy and removes the sphincter of Oddi function, which may lead Both allogenic substitute and autologous substitute can be to the reflux of pancreatic juice and bacteria from the intestine used to reconstruct the extrahepatic bile duct in situ without into the biliary tree [8–10]. Biliary-enteric anastomosis has long altering the normal biliary anatomy. This operation does pre- been associated with some severe complications (e.g., cholangi- serve the sphincter of Oddi function. Furthermore, the HUC is tis, anastomotic stricture, intra-hepatic stone and biliary long enough to reconstruct the extrahepatic bile duct more cirrhosis) and an increased risk for cholangiocarcinoma than once, if necessary (e.g., in case of postoperative anasto- [8–10]. Therefore, the best way to treat bile duct injury or de- motic stricture). fect is to preserve the sphincter of Oddi function and recon- struct the bile duct in situ without altering the normal biliary anatomy. However, on account of the present lack of viable Evaluation of the hypothesis replacement materials with the capacity of growth and regen- eration, a sphincter of Oddi-preserving biliary reconstruction The feasibility of this hypothesis is based on the following five remains a challenge for hepatobiliary surgeons [8,9]. Identify- facts: ing an ideal material that can promote bile duct regeneration has been an active area of research [8–14]. 1. Scaffolds: The diameters of umbilical vessel and common Recently, the human umbilical cord (HUC) has been bile duct are similar. Mature HUC attains an average diam- broadly studied in tissue engineering. Current studies have sug- eter of 1.7 cm and a length of 50–60 cm [26,27]. The diam- gested that the HUC has the potential to be used as a substi- eter of umbilical artery varies between 3 and 4 cm, and the tute for vessel [15–18], ligament, tendon [19] and bone diameter of umbilical vein ranges from 6 to 8 cm [26,27]. [20,21]. Furthermore, the use of autologous umbilical vein The normal common bile duct has a diameter of 6 mm or patch from ligamentum teres hepatis (round ligament of liver) less, with a range of 4–8 mm in adults [28,29]. After choos- for reconstruction of the injured bile duct has been reported in ing the umbilical vessels with the appropriate diameter, cells two small clinical trials [22,23]. Therefore, it may be feasible and major histocompatibility complex (MHC) antigens can that the HUC may be used as a substitute for reconstruction be removed to reduce immunogenicity. The decellularisa- of the extrahepatic bile duct. tion process can be performed via various methods (e.g., chemical treatments and enzymatic treatments) [30]. The Hypothesis remaining tissue consists of mainly extracellular matrix (ECM). Consequently, tubular scaffold with appropriate We hypothesise that the HUC may be an effective novel sub- diameter and low immunogenicity can be generated from stitute for reconstruction of the extrahepatic bile duct. Our the primary HUC. Moreover, the scaffold is biodegradable hypothesis can be summarised as follows: and can provide a suitable environment for the growth and proliferation of stem cells [31]. 1. Allogenic substitute: An HUC, as a tissue-engineered prod- 2. Seed cells: The HCU, especially the part of Wharton’s jelly uct for reconstruction of the extrahepatic bile duct, is and HUC vein, is an abundant resource of mesenchymal donated from one person and transplanted into another per- stem cells (HUC-MSCs) [32,33]. It is generally accepted son. A key in the revolutionary field of tissue engineering is that HUC-MSCs are poorly immunogenic with multilin- the development of the suitable scaffolds for seeding cells, eage differentiation potential [32,33]. Recently, growth factors and subsequent growth of tissues. It is well HUC-MSCs have successfully differentiated into osteocytes established that the HUC is rich in conduits (vessels), con- [21], hepatocytes [24], etc. We have proposed the possibility taining two arteries and one vein. Intriguingly, the HUC of application of bone marrow-derived MSCs in bile leak has been demonstrated to be a new source for mesenchymal [1]. Likewise, the ability of HUC-MSCs to differentiate into stem cells (HUC-MSCs) which can differentiate into multi- biliary epithelial cells can be postulated. ple lineage-specific cells that form bone, cartilage, liver, etc 3. Growth factors: Growth factors are responsible for prolif- [21,24]. Furthermore, the Wharton’s jelly that surrounds eration and differentiation of cells. For example, epidermal the human umbilical vein (HUV) is rich in growth factors growth factor (EGF) exerts a wide variety of biological The human umbilical cord: A novel substitute 9
effects, including the promotion of proliferation and differ- Discussion entiation of MSCs [34,35]; transforming growth factor beta (TGF-b) plays important roles in cellular differentiation, Our strategies of making allogenic substitutes and autologous hormone secretion and immune function [34,36]. Fibroblast substitutes are shown in Figs. 1 and 2. Vascularisation (blood growth factor (FGF), EGF and TGF-b have been detected supply) is a key factor to warrant the long-term viability of the in the extracts of Wharton’s jelly [25]. graft [38]. Various methods have been suggested: incorpora- 4. Animal experiments and clinical trials: An animal experi- tion of vascular endothelial growth factor (VEGF) in the scaf- ment has demonstrated the reconstruction of the extrahe- fold for slow release; co-cultivation of target tissue cells, patic bile duct in dogs by using human amniotic endothelial cells and angiogenesis signalling cells; and decellu- membrane [14]. As described above, autologous umbilical larisation of the whole organ and its blood vessels [38]. In addi- vein patch form ligamentum tere hepatis could be used to tion, wrapping the graft in vascularised great omentum may reconstruct the injured bile duct [22,23]. support the survival of the graft [14]. 5. Sources: The HUC is abundant in resource without ethical issues. It is usually discarded after delivery. Collecting the HUC after birth does not carry any risk to the mother or Conclusion newborn. Furthermore, some investigators have suggested the importance of banking the whole umbilical cord unit We hypothesise that the HUC may be a novel substitute for for research or future therapeutic use [37]. reconstruction of the extrahepatic bile duct. Continued
Figure. 1 Strategy of making allogenic substitute. ECM: extracellular matrix; MSCs: mesenchymal stem cells. 10 Y. Cheng et al.
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