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Human pluripotent stem cell-derived mesenchymal stem cells regenerate injured GUNN rat liver

ABSTRACT: Gunn rats bear a mutation within the uridine diphosphate glucuronosyltransferase-1A1 (Ugt1A1) gene resulting in high serum bilirubin levels as seen in Crigler-Najjar syndrome. In the present study, the Gunn rat was used as an animal model for heritable liver dysfunction. Human pluripotent stem cell-derived mesenchymal stem cells (iMSCs) were transplanted into Gunn rats after partial hepatectomy. The iMSCs engrafted and survived in the liver for up to 2 months without the need for immunosuppression. The transplanted iMSCs differentiated into functional hepatocytes and partially suppressed hyperbilirubinemia. Furthermore, human Albumin as well as the human immunomodulatory factors, RANTES and SERPINE1, were detected in the rat serum upon iMSC transplantation. The differentiation of iMSCs into hepatocytes was confirmed by qPCR and/or immunohistochemistry, detecting expression of human hepatocyte nuclear factor 4α, UGT1A1, cytokeratin 18, α-fetoprotein and Albumin. These findings indicate transplanted iMSCs differentiated into hepatocytes and thus contributed to tissue repair in an injury model of hepatocyte-based liver regeneration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97692 | GEO | 2019/04/30

REPOSITORIES: GEO

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Project description:Neonatal hyperbilirubinemia (jaundice) is common in infants, with extremely preterm infants (EPT, <28 weeks gestational age) being at high risk for bilirubin-induced neurotoxicity, resulting in neurodevelopmental impairment. Hyperbilirubinemia is treated using phototherapy to lower unconjugated bilirubin levels. However, the benefits and risks of phototherapy in EPTs have not been well studied, and bilirubin at low levels may be protective as an antioxidant. Phototherapy is associated with markers of oxidative stress in the plasma, but the effects of phototherapy on the hippocampus (HPC) are not known. Bilirubin and insults associated with EPTs impair hippocampal development, a brain structure critical for cognitive function, but their underlying mechanisms remain unknown. The effects of hyperbilirubinemia and phototherapy on the HPC were studied using a Gunn rat model. Jaundiced (jj) and non-jaundiced (Nj) pups were subjected to phototherapy from postnatal day 4 (P4) through P6. The HPC was harvested and processed for RNA sequencing. Serum bilirubin levels were elevated in jj compared to Nj control rats. Phototherapy significantly lowered serum bilirubin levels in jj rats. Compared to Nj rats, 1294 genes were differentially expressed in the jj hippocampal transcriptome and mapped onto the nervous system development, inflammation, and ferroptosis signaling pathways. Phototherapy induces 3297 differentially-expressed genes (DEGs) in rat hippocampal transcriptome compared to untreated rats. These DEGs were annotated to pathways regulating synaptogenesis, long-term potentiation, and neurogenesis. Both hyperbilirubinemia and phototherapy altered expression of 407 genes, which mapped onto hippocampal plasticity functions, including neuritogenesis and long-term potentiation. Our study demonstrates a model for investigating molecular effects of hyperbilirubemia and phototherapy in an EPT-equivalent Gunn rat pup. Our data revealed the effects of hyperbilirubinemia and phototherapy on signaling pathways critical for hippocampal development and plasticity.

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Human pluripotent stem cell-derived mesenchymal stem cells regenerate injured GUNN rat liver

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