| abstract |
The disclosure provides materials and methods useful in forming at least one bile duct or treating cholestatic disease or injury by transdifferentiating hepatocytes to cholangiocytes by delivery of an effective amount of an expressible Transforming Growth Factor β Type I Receptor (TGFBR1), Transforming Growth Factor β Type II Receptor (TGFBR2), SMAD3, SMAD1, SMAD2, SMAD5 or SMAD8/9, in either in vivo or in vitro environments. Another aspect provides a method of forming at least one bile duct or treating a cholestatic disease or injury by delivering an effective amount of JAG1, JAG2, DLL1, DLL3, DLL4, NOTCH1, NOTCH2, NOTCH3, NOTCH4 or the respective NOTCH intracellular domains either in vivo or in vitro. Also provided are methods for correcting mutant alleles of genes in the ΤGFβ and/or Notch pathways, e.g., JAG1 or NOTCH2, using ZFNs, TALENs, CRISPR or any other genome editing technique. Additionally, methods are provided for inducing increased expression of a normal, or wild-type, allele of a ΤGFβ or Notch pathway gene such as TGFBR1 or JAG1 using CRISPRa technology. Yet another aspect is drawn to a method of forming at least one bile duct or treating a cholestatic disease or injury by delivering an effective amount of a wild-type hepatocyte or a hepatocyte that has not been engineered to overexpress a gene product. |