Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Cell Transplantation
Introduction
For numerous liver diseases of childhood, liver transplantation (LT) is a lifesaving procedure. However, it requires scarce organs, a highly experienced team to manage the surgical procedure, complications, and follow-up and lifelong immunosuppression for the recipient. Living donor organs and split livers gave us the proof of concept that a partial organ is sufficient to restore liver metabolic functions. Liver cell therapy (LCT), where cells rather than organs are transplanted in the patient, was first evaluated in acute liver failure to support liver function while awaiting spontaneous recovery or as a bridge to transplantation. Recently, LCT has been proposed as a treatment in itself to overcome LT barriers with an off the shelf, easily injectable, and reversible procedure. In addition, it has the advantage of not inducing a strong immunogenic response. Initially, LCT was performed for liver-based inborn errors of metabolism (IEM) with hepatocytes isolated from livers not suitable for LT, but stem cells are increasingly of interest for acquired liver diseases.
Hepatocyte Transplantation
Clinical Application
Hepatocyte transplantation (HT) was translated to human medicine in the 1990s to overcome the limitations of LT—lack of donors, intensive surgery, cost, immunosuppression. In 1994, Habibullah et al. reported on intraperitoneal fetal hepatocytes administration in seven patients with acute liver failure; one child was included in the study and survived the acute decompensation. The next year, Grossman et al. published the first intraportal injection of autologous hepatocytes transduced with a low-density lipoprotein (LDL) receptor in five patients (three children) with familial hypercholesterolemia; LDL cholesterol decreased in three of them. The autologous procedure was developed to avoid immunosuppression and the allogenic variable. Finally, in 1997, an intraportal heterologous hepatocyte infusion in a 5-year-old boy diagnosed with ornithine transcarbamylase (OTC) deficiency was reported. His ammonia and glutamine levels returned to normal values at discharge. Unfortunately, the child died 43 days post-HT of liver biopsy complications. Since the first report in 1994, HT has been evaluated in 58 children for indications ranging from biliary atresia by acute liver failure ( Table 32.1 ) to liver-based IEM ( Table 32.2 ), with variable clinical success. At least 52% of them (30/58) received LT after HT. Currently, HT may be considered a bridge to transplantation, especially for patients with liver-based IEM who usually face a long waiting time before LT.
Table 32.1
Clinical Hepatocyte Transplantation in Pediatric Acute Liver Failure
(From Gramignoli R, et al. Clinical hepatocyte transplantation: practical limits and possible solutions. Eur Surg Res. 2015;54(3-4):162-177; Puppi J, Dhawan A. Human hepatocyte transplantation overview. Methods Mol Biol. 2009;48:11-16; Hansel MC, et al. The history and use of human hepatocytes for the treatment of liver diseases: the first 100 patients. Curr Protoc Toxicol. 2014;62:14.12.1-23; Khan Z, Strom SC. Hepatocyte transplantation in special populations: clinical use in children. Methods Mol Biol. 2017;1506:3-16.)
| Cause | Age | Effect, Outcome | Reference |
|---|---|---|---|
| Drug-induced | 16 years 12 years 10 years |
Ammonia reduction, death, 2 days post-HT Ammonia reduction, death, 7 days post-HT Ammonia reduction, death, 7 days post-HT |
|
| 6 months | Ammonia reduction, life support withdrawal and death, 7 days post-HT | ||
| 13 years | Death, 4 days post-HT | ||
| 14 years | Ammonia reduction and improved encephalopathy, LT 1 day post-HT | ||
| Idiopathic | 8 years | Intraperitoneal injection of fetal hepatocytes, full recovery | |
| 3 years 5 years |
Ammonia reduction and improved encephalopathy in both Full recovery and immunosuppression weaned; successful bridge to LT 4 days post-HT |
||
| 3.5 months | No clear benefit, LT 1 day post-HT | ||
| Virus-induced | 4 years | Ammonia reduction and improved encephalopathy, intracranial hypertension on day 2 | |
| 3 weeks | Ammonia reduction, death, 11 days post-HT |
HT, Hepatocyte transplantation; LT, liver transplantation.
Table 32.2
Clinical Hepatocyte Transplantation in Pediatric Liver-Based Inborn Errors of Metabolism
(From Gramignoli R, et al. Clinical hepatocyte transplantation: practical limits and possible solutions. Eur Surg Res. 2015;54(3-4):162-177; Pareja E, Gomez-Lechon ML, Tolosa L. Alternative cell sources to adult hepatocytes for hepatic cell therapy. Methods Mol Biol. 2017;1506:17-42; Puppi J, Dhawan A. Human hepatocyte transplantation overview. Methods Mol Biol. 2009;48:11-16; Hansel MC, et al. The history and use of human hepatocytes for the treatment of liver diseases: the first 100 patients. Curr Protoc Toxicol. 2014;62:14.12.1-23; Khan Z, Strom SC. Hepatocyte transplantation in special populations: clinical use in children. Methods Mol Biol. 2017;1506:3-16.)
| Cause | Age | Effect, Outcome | Reference |
|---|---|---|---|
| Crigler-Najjar syndrome type 1 | 10 years | 50% reduction in bilirubin, reduction in phototherapy, LT 4 years post-HT | |
| 8 years | 40% reduction in bilirubin, LT 20 months post-HT | ||
| 9 years | 30% reduction in bilirubin, 35% reduction in phototherapy, LT 5 months post-HT | ||
| 1.5 years
3 years |
> 50% reduction in bilirubin, reduction in phototherapy, LT 8 months post-HT 30% reduction in bilirubin, LT 18 months post-HT |
||
| 3.5 years | Lowered serum bilirubin, outcome unknown | ||
| 8 years | 35% reduction in bilirubin, 50% reduction in phototherapy, LT 11 months post-HT | ||
| 9 years 1 year |
20% reduction in bilirubin, LT 6 months post-HT 25% reduction in bilirubin, LT 4 months post-HT |
, | |
| 2 years | 50% reduction in bilirubin, outcome unknown | ||
| 11 years | 20% reduction in bilirubin, LT waiting list | ||
| 7 months | 50% reduction in bilirubin and in phototherapy, psychomotor improvement, bilirubin stable at 1-year follow-up | ||
| 13 years
11 years |
50% reduction in bilirubin, presence of bile glucuronides in bile, LT 19 months post-HT 50% reduction in bilirubin, presence of bile glucuronides in bile, LT 31 months post-HT |
||
| Alpha-1 antitrypsin deficiency | 18 weeks | LT 2 days post-HT, cirrhosis on explant | |
| Familial hypercholesterolemia | 12 years 7 years 11 years |
Ex vivo gene therapy with autologous cells. No benefit; 6% reduction in total cholesterol and LDL cholesterol 19% reduction in total cholesterol and LDL cholesterol |
|
| 12 years | 13% reduction in total cholesterol and LDL cholesterol | ||
| Factor VII deficiency | 3 months 35 months |
70% reduction in rFVII requirement, LT 7 months post-HT 70% reduction in rFVII requirement, LT 8 months post-HT |
|
| 4 months | Reduction in rFVII requirement, outcome unknown | ||
| Progressive familial intrahepatic cholestasis type 2 | 32 months 16 months |
No benefit (cirrhosis established):, LT 5 months post-HT No benefit (cirrhosis established), LT 14 months post-HT |
|
| Phenylketonuria | 6 years | Reduction in phenylalanine levels and improved dietary tolerance up to 3 months post-HT (cells from “domino” GSD1b liver), PAH activity on liver biopsy at 11 months post-HT | |
| Tyrosinemia type 1 | 59 days | Improved coagulopathy and bilirubin, LT 45 days post-HT (cirrhosis on explant) | |
| Glycogen storage disease type 1a | 6 years | Reduction in hypoglycemic episodes and cholesterol and triglycerides levels, no hypoglycemic admission at 1-year follow-up | |
| Glycogen storage disease type 1b | 18 years | Improved blood glucose, decreased epistaxis, normal G6Pase activity on liver biopsy at 8 months post-HT | |
| Mild Zellweger spectrum disorder | 4 years | 40% reduction in pipecolic acid for 18 months, decreased cholestasis and abnormal bile acid, psychomotor improvement, outcome unknown | |
| Primary hyperoxaluria type 1 | 15 months | Reduction un plasma oxalate, liver-kidney transplant 13 months post-HT | |
| Urea cycle defects | |||
| Ornithine transcarbamylase deficiency | 5 years | Ammonia reduction and protein tolerance, death by sepsis 43 days post-HT | |
| 5 years | Ammonia reduction, normal glutamine, death 45 days post-HT | ||
| 10 hours | Ammonia reduction and protein tolerance, LT 6 months post-HT | ||
| 1 day | Ammonia reduction, increased urea, protein tolerance, auxiliary partial LT 7 months post-HT and neurologically normal | ||
| 14 months | Ammonia reduction, increased urea, psychomotor improvement, LT 6 months post-HT | , | |
| 1 day | Ammonia reduction, increased urea, protein tolerance, auxiliary partial LT 7 months post-HT | ||
| 6 hours
9 days |
Ammonia reduction, increased urea, normal urine orotic acid, death 4 months post-HT Ammonia reduction, protein tolerance, normal urine orotic acid, LT waitlist 6 months post-HT |
||
| 12 years | Ammonia reduction, increased urea, normal glutamine, septic death 30 days post-HT | ||
| 11 days | Ammonia reduction, neurologically normal 3 months post-HT | ||
| 7 months | No effect, LT 4 months post-HT | ||
| Argininosuccinate lyase deficiency | 3.5 years | Ammonia reduction, psychomotor improvement, LT 18 months post-HT | , |
| Carbamoyl phosphate synthase I deficiency | 2.5 months | Ammonia reduction and increased urea, LT 15 months post-HT | , |
| 4 months | No effect, LT 3.5 months post-HT | ||
| Citrullinemia | 25 months | Ammonia reduced and increased urea, outcome unknown | (Lee et al., unpublished) |
| 3 years | Ammonia reduction, increased urea, protein tolerance, outcome unknown | ||
G6Pase, Glucose-6-phosphatase; GSD1b, glycogen storage disease type 1b; HT, hepatocyte transplantation; LDL, low-density lipoprotein; LT, liver transplantation; rFVII, recombinant factor VII; PAH, phenylalanine hydroxylase.
Material Source
The first HT procedure was performed with using fetal hepatocytes, generating some ethical considerations. One team used magnetic activated cell sorting to purify hepatic progenitor cells from fetal hepatocyte based on the CD326 expression.
Today, the main source of cells for HT are the livers unsuitable for LT, such as reduction remnants or unused split livers, damaged livers, or livers from young donors. Steatotic livers are of lesser quality for hepatocytes. Hepatocytes seem to tolerate ischemia well in comparison with cholangiocytes. Yet, their viability has been shown to be inversely correlated to ischemia time. Hepatocytes can also be isolated from segment IV, with or without caudate lobe during a split-liver procedure or from non-heart-beating donors. As for domino liver transplantation, hepatocytes collected from an explanted liver affected by a specific IEM are suitable for HT in patients with another IEM. A 6-year-old child with tetrahydrobiopterin unresponsive phenylketonuria received hepatocytes isolated from the native liver of a patient transplanted for glycogen storage disease type 1b. Phenylalanine levels returned to normal, and their half-life decreased significantly after the procedure. To date, no difference in clinical outcome has been reported based on the hepatocyte origin.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here