Hepatocyte-Like Cells Can Be Derived from Human Umbilical Cord Blood and Embryonic Stem Cells: Tested in a Novel Mouse Model
Notice bibliographique
Résumé
Abstract Liver transplantation remains the only therapeutic option for many acute and chronic end-stage liver diseases. However, this approach is limited by a serious shortage of donor organs required for transplantation. Hepatocytes have been reported to be generated from cells not originated from liver, such as hematopoietic stem cells, mesenchymal stem cells and most recently embryonic stem cells. However, the frequency of these stem cell-derived hepatocytes is very low in most studies. Therefore, the significance of stem cell contribution to the repair of liver damage is still controversial. To further explore this potential, we used the beta-glucuronidase (GUSB)-null NOD/SCID/MPSVII mouse model for better identification of engrafted human cells. Enriched cord blood primitive cells (lineage depleted cells with high aldehyde dehydrogenase activity, ALDHhiLin−) were transplanted into irradiated NOD/SCID/MPSVII mice. One month after transplantation, carbon tetrachloride (CCl4) was administrated into the mice twice a week for 4 weeks to induce liver damage. In this model, ALDHhiLin− cells efficiently engrafted in the recipient mouse livers as demonstrated by GUSB positive immunohistological staining and the presence of human Alu DNA using PCR. The percentage of human cells in these livers ranged between 3% and 14.2% using quantitative real-time PCR. These engrafted cells improved recovery of the mice from toxic insult, and significantly increased the numbers of surviving mice. Furthermore, human liver-specific a-1-antitrypsin mRNA and albumin protein were expressed in the recipient livers. Interestingly, human vs. murine centromeric fluorescent in situ hybridization analysis on the liver sections demonstrated that most human cells were not fused to mouse cells. However, mouse nuclei were detected in the majority of the albumin-expressing cells, suggesting that fusion had occurred and was responsible for the appearance of donor derived hepatocyte-like cells. With the goal of achieving higher levels of liver reconstitution than had been possible using the adult stem cells, we began studying engraftment of human embryonic stem cells (hESC), which theoretically have the potential to regenerate any tissue. The H1 cell line was cultured on mouse embryonic fibroblasts then allowed to form embryoid bodies (EBs) in suspension culture for 7 days with or without further expansion and differentiation in attached culture for another month. EBs were dissociated into a single cell suspension and transplanted into NOD/SCID/MPSVII mice or NOD/SCID/IL2Rγ−/− mice via the tail vein after 300 RADs sublethal radiation with or without CCl4 administration. Two months post-transplantation, the human EB-derived cells were found to be well engrafted in the NOD/SCID/MPSVII mouse livers, spleens and kidneys, using the clear-cut enzymatic identification method for cells expressing normal levels of beta-glucuronidase in the mice, which are null for the enzyme. Human DNA was also detected in the recipient mouse liver. Most interestingly, human albumin-expressing cells were also found in the livers of engrafted mice. Our data indicate that the progeny of cord blood stem cells can significantly enhance survival of mice with severe liver damage, and that fusion can occur between transplanted and recipient cells. This could be a normal mechanism of liver repair, since hepatocytes exist normally as multinucleate cells. We also demonstrate that the progeny of hESC can be effectively dissociated and transplanted intravenously, then home to the liver and differentiate to the hepatocyte lineage in an immune deficient mouse model of liver damage.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».