Inducing Hepatocyte Plasticity via FGF2-MAPK-EZH2 Axis
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Solution Overview
Problem
Current methods for inducing hepatic progenitor cells from rodent hepatocytes cannot be applied to human cells, and induced human hepatic progenitor cells lack high proliferative ability and pluripotency, with no effective regulation of human hepatocyte plasticity or aging.
Innovation Solution
A novel method involving the FGF2-MAPK-EZH2 axis to convert human hepatocytes into hepatic progenitor cells with proliferative and pluripotent capabilities, using histone deacetylase inhibitors to improve the plasticity of old hepatocytes, allowing them to be passaged multiple times and maintain functionality.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional methods for inducing hepatic progenitor cells from rodent hepatocytes are applied to human cells, then the induction process can be performed, but the induced human hepatic progenitor cells cannot be passaged three times or more and lack high proliferative ability
Solution Approach 1:
The invention changes the chemical parameters of the culture medium by incorporating specific small molecule compounds (YAC, Y-27632, A83-01, CHIR99021) at optimized concentrations to induce hepatic progenitor cells from human hepatocytes while maintaining high proliferative ability and enabling passage for 20 times or more, resolving the contradiction between proliferative ability and passaging capability
Solution Approach 2:
The invention uses small molecule compounds as intermediaries to mediate the conversion of human hepatocytes into hepatic progenitor cells, enabling controlled induction while preserving both proliferative capacity and long-term passaging capability, thus resolving the reliability issue of conventional methods
2Adaptability or versatility
If conventional methods are used to induce human hepatic progenitor cells, then cell induction can occur, but pluripotency for differentiation into human hepatocytes and cholangiocytes is not maintained
Solution Approach 1:
The invention optimizes cultural parameters including the addition of specific small molecule compounds (YAC, Y-27632, A83-01, CHIR99021) and growth factors (FGF2, HGF) to maintain pluripotency while preserving differentiation capability into hepatocytes and cholangiocytes, resolving the contradiction between pluripotency and differentiation capability
Solution Approach 2:
The induced hepatic progenitor cells acquire universal properties, enabling them to differentiate into multiple cell types (hepatocytes and cholangiocytes) while maintaining high proliferative ability, thus achieving multi-functionality that resolves the reliability issue of conventional single-purpose induction methods
3Adaptability or versatility
If histone deacetylase inhibitors are added to culture medium, then plasticity of old hepatocytes is improved, but the complexity of the culture system increases
Solution Approach 1:
The invention modifies the chemical composition parameter of the culture medium by adding histone deacetylase inhibitors (trichostatin A, sodium butyrate, valproic acid) to enhance plasticity of old hepatocytes, enabling them to be converted into proliferative hepatic progenitor cells while managing the increased complexity through systematic optimization of the culture system
Data Source
AI summary
The disclosure provides a method for producing hepatocytes or hepatic progenitor cells; a method for suppressing hepatocyte aging using a drug causing histone hyperacetylation; a hepatocyte anti-aging agent; a method for increasing hepatocyte plasticity; and a drug for increasing hepatocyte plasticity.