Instruct: Identify the main category of Biorxiv papers based on the titles and abstracts
Query: Thyroid hormone and ALK5 inhibitor improve maturation of human pluripotent stem cell derived hepatocytes Hepatocytes derived from human pluripotent stem cells (PSCs) hold great promise for modeling human liver disease, in vitro hepatotoxicity testing, and future cellular therapy. However, current protocols generate hepatocyte-like cells (HLCs) that resemble fetal hepatocytes, and thus do not accurately recapitulate the molecular identity and functions of the adult liver. To address this, we compared the transcriptomes of human fetal and adult liver to PSC-derived HLCs during progressive stages of in vitro differentiation. This revealed that during the final stages of in vitro differentiation the hepatic transcription factors HNF4A and CEBPA were sub-optimally expressed. Computational analyses predicted that ALK5i II (TGF-{beta} receptor inhibitor) and thyroid hormone (T3) would be able to rectify this and improve HLC maturation. We next show that application of these molecules during hepatocyte differentiation indeed increases CEBPA and HNF4A mRNA and protein expression, and that these HLCs show enhanced albumin secretion, a 25-fold increase in CYP3A4 activity, and 10 to 100-fold increased expression of mature hepatic markers. We demonstrate that this improved maturation is effective across different cell lines and HLC differentiation protocols, and exemplifies that our approach provides a tractable template for identifying and targeting additional factors that that will fully mature human liver cells from human pluripotent stem cells.
28
The categories of this paper are: communication
24
The categories of this paper are: cancer
0
The categories of this paper are: genetics
9
The categories of this paper are: synthetic
26
The categories of this paper are: biochemistry
32
The categories of this paper are: zoology
6
The categories of this paper are: plant
1
The categories of this paper are: bioinformatics
31
The categories of this paper are: paleontology
11
The categories of this paper are: cognition
30
The categories of this paper are: scientific
25
The categories of this paper are: bioengineering
3
The categories of this paper are: evolutionary
27
The categories of this paper are: pathology
29
The categories of this paper are: education
8
The categories of this paper are: genomics