International Journal of Physical Medicine & Rehabilitation
Open Access

Abstract

Activated Frozen Mesenchymal Stem Cells in Humanized Mice after Induction of Acute Liver Injury through Alcohol Binging

Juan Carlos Hernandez1, Yicheng Aiden Zhu1, Sean P. Martin2, Nathan Kohrman2, Da-Wei Yeh1, Joel Marh3,Karina Zaragoza3, Hye Yeon Choi1, Julia Kim3, Shefali Chopra4, Li Ding5, Matthew Thornton2,6, Brendan Grubbs2,6, Leonard Makowka3, Linda Sher2,3*, Keigo Machida1,7*

Background: After acute injury there are a variety both modifiable and unknown factors that contribute to the liver’s ability to recover. This group previously demonstrated that treatment with activated umbilical cord Mesenchymal Stem Cells (MSCs) increased the survival of mice with humanized livers who developed alcoholinduced liver injury. Objective: This study’s primary objective was to evaluate the safety and efficacy of various doses of frozen-thawed activated MSCs compared to placebo in the treatment of acute alcohol-induced liver injury in humanized mouse livers. Secondary objectives included evaluating hepatic chemistries, biomarkers and pathology at various doses. Methods: Sixty-two humanized mice that were fed high fat diets and alcohol binge drinking for 24 days were randomized to receive 1 million, 500,000, 250,000, 100,000 or 28,000 activated umbilical cord MSCs, or vehicle (plasmalyte) only injections via tail vein three times in the first week and weekly for two additional weeks. Mice were followed for survival at 4 weeks with surviving mice euthanized. Results: At the highest administered dose, 1 million activated umbilical cord MSCs, there was a statistically significant survival increase compared to placebo (p=0.03). Histologic findings correlated with survival with 27 surviving animals demonstrating 1 to 2+ steatosis with no necrosis. Of the 35 animals that died, 23 demonstrated necrosis and 9 showed various degrees of steatosis. Using food consumption and body weight as measures of safety showed no statistical differences between study groups. Conclusion: Treatment with high-dose frozen-thawed activated umbilical cord MSCs can result in improved survival and histology in mice with humanized livers and alcohol-induced liver injury. Additionally, this therapy does not appear to be associated with adverse effects.

Published Date: 2024-03-22; Received Date: 2024-02-16