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Vascularised and functional human liver from an iPSC-derived organ bud transplant

ABSTRACT: Critical shortage of donor organs for treating end-stage organ failure highlights the urgent need for generating organs from induced pluripotent stem cells (hiPSCs). Despite many reports describing functional cell differentiation, no studies have succeeded in generating a three-dimensional vascularised organ such as liver. Here, we show the generation of vascularised and functional human liver from hiPSCs by transplantation of liver buds created in vitro (hiPSC-LBs). Specified hepatic cells self-organised into three-dimensional hiPSC-LBs by recapitulating organogenetic interactions between endothelial and mesenchymal cells. Immunostaining and gene expression analyses revealed resemblance between in vitro grown hiPSC-LBs and in vivo liver buds. Human vasculatures in hiPSC-LB transplants became functional by connecting to the host vessels within 48 hours. The formation of functional vasculatures stimulated the maturation of hiPSC-LBs into tissue resembling the adult liver. Highly metabolic hiPSC-derived tissue performed liver-specific functions such as protein production and human-specific drug metabolism without recipient liver replacement.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE46631 | GEO | 2013/07/01

SECONDARY ACCESSION(S): PRJNA201333

REPOSITORIES: GEO

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Project description:Cell-based models of many neurological and psychiatric diseases, established by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), have now been reported. While numerous reports have demonstrated that neuronal cells differentiated from hiPSCs are electrophysiologically active mature neurons, the âageâ of these cells relative to cells in the human brain remains unresolved. Comparisons of gene expression profiles of hiPSC-derived neural progenitor cells (NPCs) and neurons to the Allen BrainSpan Atlas indicate that hiPSC neural cells most resemble first trimester neural tissue. Consequently, we posit that hiPSC-derived neural cells may most accurately be used to model the early developmental defects that contribute to disease predisposition rather than the late features of the disease. Though the characteristic symptoms of schizophrenia SZ generally appear late in adolescence, it is now thought to be a neurodevelopmental condition, often predated by a prodromal period that can appear in early childhood. Postmortem studies of SZ brain tissue typically describe defects in mature neurons, such as reduced neuronal size and spine density in the prefrontal cortex and hippocampus, but abnormalities of neuronal organization, particularly in the cortex, have also been reported. We postulated that defects in cortical organization in SZ might result from abnormal migration of neural cells. To test this hypothesis, we directly reprogrammed fibroblasts from SZ patients into hiPSCs and subsequently differentiated these disorder-specific hiPSCs into NPCs. SZ hiPSC differentiated into forebrain NPCs have altered expression of a number of cellular adhesion genes and WNT signaling. Methods: We compared global transcription of forebrain NPCs from six control and four SZ patients by RNAseq. Results: Multi-dimensional scaling (MDS) resolved most SZ and control hiPSC NPC samples; 848 genes were significantly differentially expressed (FDR<0.01) Conclusions: The WNT signaling pathway was enriched 2-fold (fisher exact test p-value = 0.031). 1-2 independent differentiations (biological replicates) for each of four control and four schizophrenia patients were analyzed; samples were generated in parallel to neuron RNAseq data.

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Vascularised and functional human liver from an iPSC-derived organ bud transplant

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