Human hepatocytes and uses thereof
Inventors
Lee, Jau-Nan • LEE, Tony Tung-Yin • Lee, Yuta • Tsai, Eing-Mei
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11026979-B2
Publication Date
2021-06-08
Expiration Date
Abstract
Disclosed herein are human hepatocytes for example isolated human hepatic progenitor cells, artificial tissue or organ thereof, and kits or compositions thereof. Also disclosed herein are various methods of using a human hepatocyte disclosed herein.
Core Innovation
The invention describes induced hepatocytes, including human hepatocytes and hepatocyte-like lineages, that are used for cell therapy and pharmaceutical compositions with targeted delivery and intravenous administration. The disclosure also characterizes therapeutic protein production by induced hepatocytes, including major plasma proteins, hormones, and cytokines, and supports liver regeneration via ex vivo perfusion and/or 3D bioprinting with scaffold generation on 2D/3D biocompatible substrates.
The disclosed subject matter differentiates trophoblast stem cells into induced hepatocytes that present hepatocyte traits including endogenous transforming growth factor beta 1 (TGFβ1) expression, fibronectin expression, and collagen IV expression. The induced hepatocytes are further characterized by human leukocyte antigen G (HLA-G) expression, immune-privilege-related features, and recruitment of CD4+ Foxp3+ Treg cells.
The disclosure additionally describes diagnostic options for determining biomarker expression and includes example differentiation and functional liver-like activities supported by hepatic marker expression, extracellular matrix scaffold formation, and functional readouts. Mechanistic findings are described for definitive endoderm specification using a signaling pathway sequence and downregulation of MIXL1, consistent with the generation of hepatocyte-like lineages and their expression profiles.
Claims Coverage
The claim coverage centers on two independent claims with four main inventive features: an isolated human hepatocyte endogenously expressing TGFβ1, fibronectin, and collagen IV; an isolated human hepatocyte characterized by HLA-G expression; an isolated human hepatocyte characterized by recruiting CD4+ Foxp3+ Treg cells; and an artificial tissue or organ comprising hepatocytes expressing HLA-G together with selected biomarkers.
Isolated human hepatocyte with endogenous TGFβ1, fibronectin, and collagen IV
An isolated human hepatocyte wherein the isolated human hepatocyte endogenously expresses transforming growth factor beta 1 (TGFβ1), fibronectin, and collagen IV.
HLA-G expression in the isolated human hepatocyte
The isolated human hepatocyte is characterized by expression of human leukocyte antigen G (HLA-G).
Recruitment of CD4+ Foxp3+ Treg cells
The isolated human hepatocyte is characterized by recruiting CD4+ Foxp3+ Treg cells.
Artificial tissue or organ with HLA-G-expressing hepatocytes and selected biomarkers
An artificial tissue or organ comprising human hepatocytes that endogenously express human leukocyte antigen G (HLA-G) and one or more biomarkers selected from CXCR4, FOXA2, HHEX, CYP7A1, BSEP, SERPINA1, ABCC2, C/EBPβ, HNF1α, and any combination thereof.
Overall, the claims tie therapeutic and regenerative concepts to defined hepatocyte formats, with core cell identity supported by endogenous expression of TGFβ1, fibronectin, and collagen IV, and immune-privilege-associated HLA-G together with recruitment of CD4+ Foxp3+ Treg cells. The artificial tissue or organ claim adds HLA-G with selected hepatocyte biomarkers.
Stated Advantages
Enables treatment and prevention of liver diseases and liver injury scenarios associated with immune response and liver injury.
Supports liver regeneration via ex vivo perfusion and/or 3D bioprinting with scaffold generation on 2D/3D biocompatible substrates.
Allows production of therapeutic proteins, including major plasma proteins, hormones, and cytokines.
Provides immune-privilege-related features associated with HLA-G and TGFβ1, including recruitment of CD4+ Foxp3+ Treg.
Enables screening of therapeutic compounds by contacting isolated human hepatocytes with a compound and detecting biomarker expression level in hepatocytes.
Documented Applications
Treating or preventing a condition associated with liver disease and liver injury by using induced hepatocytes and/or hepatocyte-containing compositions or tissues.
Screening therapeutic compounds by contacting isolated human hepatocytes with the compound and detecting biomarker expression levels for therapeutic use in treating or preventing a condition.
Producing therapeutic proteins, including major plasma proteins, hormones, and cytokines, using induced hepatocytes.
Liver regeneration using ex vivo perfusion and/or 3D bioprinting and scaffold generation on 3-dimensional biocompatible substrates.
Intravenous cell therapy using induced hepatocytes.
Generating tissue scaffolds by culturing an isolated human hepatocyte in a medium on a three-dimensional biocompatible substrate.
Ex vivo gene therapy using induced-hepatocyte-derived approaches to replace defective or missing gene products, reduce rejection, and repopulate a host liver.
Interested in licensing this patent?