Elsevier

The Lancet

Volume 380, Issue 9838, 21–27 July 2012, Pages 230-237
The Lancet

Articles
Transplantation of an allogeneic vein bioengineered with autologous stem cells: a proof-of-concept study

https://doi.org/10.1016/S0140-6736(12)60633-3Get rights and content

Summary

Background

Extrahepatic portal vein obstruction can have severe health consequences. Variceal bleeding associated with this disorder causes upper gastrointestinal bleeding, leading to substantial morbidity and mortality. We report the clinical transplantation of a deceased donor iliac vein graft repopulated with recipient autologous stem cells in a patient with extrahepatic portal vein obstruction.

Methods

A 10 year old girl with extrahepatic portal vein obstruction was admitted to the Sahlgrenska University Hospital in Gothenburg, Sweden, for a bypass procedure between the superior mesenteric vein and the intrahepatic left portal vein (meso Rex bypass). A 9 cm segment of allogeneic donor iliac vein was decellularised and subsequently recellularised with endothelial and smooth muscle cells differentiated from stem cells obtained from the bone marrow of the recipient. This graft was used because the patient's umbilical vein was not suitable and other strategies (eg, liver transplantation) require lifelong immunosuppression.

Findings

The graft immediately provided the recipient with a functional blood supply (25–30 cm/s in the portal vein and 40 mL/s in the artery was measured intraoperatively and confirmed with ultrasound). The patient had normal laboratory values for 9 months. However, at 1 year the blood flow was low and, on exploration, the shunt was patent but too narrow due to mechanical obstruction of tissue in the mesocolon. Once the tissue causing the compression was removed the graft dilated. We therefore used a second stem-cell populated vein graft to lengthen the previous graft. After this second operation, the portal pressure was reduced from 20 mm Hg to 13 mm Hg and blood flow was 25–40 cm/s in the portal vein. With restored portal circulation the patient has substantially improved physical and mental function and growth. The patient has no anti-endothelial cell antibodies and is receiving no immunosuppressive drugs.

Interpretation

An acellularised deceased donor vein graft recellularised with autologous stem cells can be considered for patients in need of vascular vein shunts without the need for immunosuppression.

Funding

Swedish Government.

Introduction

Extrahepatic portal vein obstruction leads to impaired hepatopedal blood flow from the superior mesenteric vein, splenic vein, and coronary veins through the portal vein. The disorder is by definition not associated with intrinsic liver disease, and can be congenital or acquired.1, 2 Its pathogenesis in children is unexplained. Various factors such as hereditary thrombophilias, neonatal abdominal surgery, sepsis, umbilical vein catheterisation, and dehydration are known to predispose development of extrahepatic portal vein obstruction. The initial clinical manifestation is characterised either by episodes of upper gastrointestinal bleeding or by splenomegaly on routine clinical examination. The disorder can result in complications such as variceal haemorrhage, enlarged spleen, biliopathy, or developmental retardation, and neurocognitive disability.3 Upper gastrointestinal bleeding in children and adults with extrahepatic portal vein obstruction can even be asymptomatic and results in high mortality and morbidity. Almost 80% of children diagnosed with the disorder will have at least one episode of such bleeding in their lifetime.2 Episodes are characterised by high morbidity, including frequent hospital admissions, an increase in school absenteeism, and emotional stress for the children and their families. Thus, appropriate diagnosis and treatment are needed to reduce morbidity and mortality. Diagnosis is made by abdominal Doppler ultrasonography and CT angiography. Surgical guidelines recommend restoration of the portal blood flow by use of autologous veins for bypass between the superior mesenteric vein and the left intrahepatic portal vein, which is known as the meso Rex bypass.1

Use of umbilical veins for the bypass has produced varied results.4, 5 When this technique is not adequate, other vessels such as the internal jugular veins or even the internal iliac, splenic, inferior mesenteric, or saphenous veins can be used. The recommended technique is the use of the internal jugular vein.1 Other attempts, including use of artificial grafts and cryopreserved veins, have shortcomings and are associated with little success.1, 6, 7 The ideal solution would be to use an autologous vein to repair the damage,1 which would avoid dependence on artificial grafts or allografts.

If the meso Rex procedure fails, patients are often referred back for palliative treatment, with the aforementioned risks, or—if lifethreatening complications occur—are referred for liver transplantation, which sometimes includes a portocaval hemitransposition8 or a multivisceral organ transplantation.9 These procedures lead to a need for lifelong treatment with immunosuppressive drugs and have a high rate of morbidity and mortality due to the treatment itself.

We report a meso Rex procedure that aimed to address the aforementioned issues by using a decellularised donor vein, recellularised with autologous stem cells.

Section snippets

Patient

A 1-year-old girl developed thrombocytopenia and splenomegaly and was diagnosed with idiopathic thrombocytopenic purpura and followed up for several years at a local hospital. When the patient was 9·5 years old she was reassessed and was referred to the Sahlgrenska University Hospital in Gothenburg, Sweden. Oesophageal varicose veins and splenomegaly were confirmed. The patient's international normalised ratio was slightly elevated (1·4), concentrations of protein S and protein C were normal,

Results

Histological analysis of the first vein graft showed it was successfully decellularised after seven cycles of decellularisation. Figure 3 shows the gross morphology and histology of the iliac vein used in the first transplantation before and after decellularisation. The architecture of the decellularised vein was different from the native control. We noted no nuclei or expression of HLA class I or II antigens on the decellularised vein graft at the end of cycle seven and no anti-endothelial

Discussion

We show that recellularisation of a decellularised human iliac vein with autologous stem cells is possible, and subsequent use in a bypass procedure can result in good blood flow rates and normal laboratory test values. A previous study in a sheep model showed that endothelial cell coverage is a prerequisite for successful patency and function of vein valves.11 The investigators of that study noted a significant reduction of thrombogenicity in the decellularised vein as a result of

Cited by (144)

View all citing articles on Scopus
View full text