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

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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.

Original languageEnglish
JournalAmerican Journal of Transplantation
DOIs
Publication statusAccepted/In press - 2020

Keywords

  • animal models: murine
  • basic (laboratory) research/science
  • cellular transplantation (non-islet)
  • donors and donation: living
  • liver transplantation/hepatology
  • liver transplantation: living donor
  • regenerative medicine
  • stem cells
  • tissue injury and repair

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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