A small molecule Hedgehog agonist HhAg1.5 mediated reprogramming breaks the quiescence of noninjured liver stem cells for rescuing liver failure

Transl Res. 2019 Mar;205:44-50. doi: 10.1016/j.trsl.2018.10.004. Epub 2018 Oct 19.

Abstract

Liver is the second most transplanted organ according to United network for organ sharing. Due to shortage of compatible donors, surgical difficulties, immunological hindrance, and high postoperative cost, stem cell therapy is an attractive substitute of liver transplant for millions of patients suffering from hepatic failure. Due to several technical limitations such as viral integration, inefficient differentiation, and adult phenotypes and epigenetic memory of fibroblasts, induced pluripotent stem cells, mesenchymal stem cells, or induced hepatocyte may not present a great clinical substitute for liver transplant. We pioneered a novel technology for robust expansion of quiescent liver stem cells (LSCs) from mice via utilizing of Hedgehog agonist HhAg1.5 for 3 weeks. These expanded LSCs retained stem-like properties after multiple passaging and differentiated to hepatocytes and cholangiocytes. Grafting of ex vivo expanded LSCs in Fah-/- Rag2-/- Il2rg-/- knockout mice, significantly increased life span compared to control group (P < 0.001). Thus in this study, we provide a promising viable substitute for primary hepatocytes for regenerative medicine and for life-threatening metabolic liver diseases.

Keywords: ((fumarylacetoacetate hydrolase)  Fah(−/−)  Rag2(−/−) Il2rg(−/−)); FRG; Hedgehog agonist 1.5; HhAg1.5; LSCs; LT; MSCs; iPSCs; induced pluripotent stem cells; liver stem cells; liver transplant; mesenchymal stem cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AC133 Antigen / immunology
  • Adult Stem Cells / cytology*
  • Adult Stem Cells / immunology
  • Animals
  • Biliary Tract / cytology
  • Cell Differentiation
  • Hedgehog Proteins / agonists*
  • Hepatocytes / cytology
  • Leukocyte Common Antigens / immunology
  • Liver / cytology*
  • Liver / immunology
  • Liver Failure / therapy*
  • Longevity
  • Mice
  • Mice, Knockout
  • Regenerative Medicine
  • Small Molecule Libraries / pharmacology*

Substances

  • AC133 Antigen
  • Hedgehog Proteins
  • Prom1 protein, mouse
  • Small Molecule Libraries
  • Leukocyte Common Antigens
  • Ptprc protein, mouse