Protection of liver sinusoids by intravenous administration of human Muse cells in a rat extra-small partial liver transplantation model

Abstract

Small‐for‐size syndrome (SFSS) has a poor prognosis due to excessive shear stress and sinusoidal microcirculatory disturbances in the acute phase after living‐donor liver transplantation (LDLT). Multilineage‐differentiating stress enduring (Muse) cells are reparative stem cells found in various tissues and currently under clinical trials. These cells selectively home to damaged sites via the sphingosine‐1‐phosphate (S1P)–S1P receptor 2 system and repair damaged tissue by pleiotropic effects, including tissue protection and damaged/apoptotic cell replacement by differentiating into tissue‐constituent cells. The effects of intravenously administered human bone marrow‐Muse cells and ‐mesenchymal stem cells (MSCs) (4 × 105) on liver sinusoidal endothelial cells (LSECs) were examined in a rat SFSS model without immunosuppression. Compared with MSCs, Muse cells intensively homed to the grafted liver, distributed to the sinusoids and vessels, and delivered improved blood chemistry and Ki‐67(+) proliferative hepatocytes and ‐LSECs within 3 days. Tissue clearing and three‐dimensional imaging by multiphoton laser confocal microscopy revealed maintenance of the sinusoid continuity, organization, and surface area, as well as decreased sinusoid interruption in the Muse group. Small‐interfering RNA‐induced knockdown of hepatocyte growth factor and vascular endothelial growth factor‐A impaired the protective effect of Muse cells on LSECs. Intravenous injection of Muse cells might be a feasible approach for LDLT with less recipient burden.

Downregulation of Augmenter of Liver Regeneration Impairs the Therapeutic Efficacy of Liver Epithelial Progenitor Cells Against Acute Liver Injury by Enhancing Mitochondrial Fission

“…Cell labeling offers great advantages of in vivo tracking and investigating the homing ability of transplanted cells by using noninvasive imaging techniques 33–36 . Transplanted LEPCs were labeled with the fluorescent lipophilic tracer DiR and imaged by IVIS.…”

“…As Cell labeling offers great advantages of in vivo tracking and investigating the homing ability of transplanted cells by using noninvasive imaging techniques. [33][34][35][36] Transplanted LEPCs were labeled with the fluorescent lipophilic tracer DiR and imaged by IVIS. At 0 hour post-treatment, the cells were confined inside the spleen and then gradually moved into the liver.…”

Mobilization of multilineage-differentiating stress-enduring cells into the peripheral blood in liver surgery

“…Administering human bone marrow-derived MSCs and human bone marrow-derived Muse cells to a small-for-size rat model after liver transplantation showed that Muse cells migrated to the transplanted liver, and Ki-67-positive hepatocytes and sinusoidal endothelial cells were significantly higher in the Muse cell group. Furthermore, this study found that Muse cells could protect sinusoidal endothelial cells by expressing hepatocyte growth factor and vascular endothelial growth factor-A [ 25 ]. These studies suggest that Muse cells contribute to promoting liver function and regeneration.…”

The hepatic sinusoid: The “muse” in small-for-size liver transplantation

“…In the arts, a “muse” is a source of inspiration. In this issue of American Journal of Transplantation , Shono and colleagues were inspired by the cells lining the hepatic sinusoids to explore the use of muse cells—“multilineage‐differentiating, stress‐enduring” pluripotent‐like stem cells—to regrow these target cell populations in and improve outcomes using SFS grafts 4 . Muse cells reside endogenously in the bone marrow and peripheral blood as well as the connective tissue of nearly every organ.…”