Romo, A. | Search bioRxiv

bioRxiv2023

Liver regeneration by a population of midzone-located mesenchymal-hepatocyte hybrid cells

Regenerative medicine relies on deep understanding of the mechanisms of organ repair and regeneration. The liver, an organ with critical metabolic functions carried out by hepatocytes located in zones 1-3 of liver lobules, has the capacity to fully regenerate itself, which is mainly attributable to midzone hepatocytes. Yet, how differentiated midzone hepatocytes execute transzone regeneration and quickly recover most of the liver mass remains a myth. Here, we uncover a mesenchymal-hepatocyte population (13.7% of total hepatocytes) that are derived from Twist2-lineage EpCAM+ progenitors, midzone-located, highly polyploidy, and equipped with great mitogenic and migratory capabilities to the detriment of metabolism. They regenerate about 50% of new hepatocytes and repopulate zones 1 and 3 in liver regeneration. Mechanistically, expansion of these cells is negatively controlled by Notch1 signaling. This study has thus uncovered a hepatocyte subpopulation with great proliferation potential and important mechanisms of liver regeneration.

cell biology↗

bioRxiv2021

A novel splice variant of human TGF-β type II receptor encodes a soluble protein and its Fc-tagged version prevents liver fibrosis in vivo.

We describe, for the first time, a new splice variant of the human TGF-{beta} type II receptor (T{beta}RII). The new transcript lacks 149 nucleotides, causing a frameshift with the appearance of an early stop codon, rendering a truncated mature protein of 57 amino acids. The predicted protein, lacking the transmembrane domain and with a distinctive 13 amino acid stretch in the C-terminus, was named T{beta}RII-Soluble Endogenous (T{beta}RII-SE). Binding predictions indicated that the novel 13 amino acid stretch interacts with all three TGF-{beta} cognate ligands and generate a more extensive protein-protein interface than T{beta}RII. T{beta}RII-SE and human IgG1 Fc-domain, were fused in frame in a lentiviral vector (Lv) for further characterization. With this vector, we transduced 293T cells and purified T{beta}RII-SE/Fc by A/G protein chromatography from conditioned medium. Immunoblotting revealed homogeneous bands of approximately 37 kDa (reduced) and 75 kD (non-reduced), indicating that T{beta}RII-SE/Fc is secreted as a disulphide-linked homodimer. Moreover, high affinity binding of T{beta}RII-SE to the three TGF-{beta} isoforms was confirmed by Surface Plasmon Resonance (SPR) analysis. Also, intrahepatic delivery of Lv.T{beta}RII-SE/Fc in a carbon tetrachloride-induced liver fibrosis model revealed amelioration of liver injury and fibrosis. Our results indicate that T{beta}RII-SE is a novel member of the TGF-{beta} signaling pathway with distinctive characteristics. This novel protein offers an alternative for the prevention and treatment of pathologies caused by the overproduction of TGF-{beta} ligands.

cell biology↗