Off-the-shelf GMP-grade UC-MSCs as therapeutic drugs for the amelioration of CCl4-induced acute-on-chronic liver failure in NOD-SCID mice.

Abstract

Umbilical cord-derived mesenchymal stem/stromal cells (UC-MSCs) are advanced therapy medicinal products (ATMPs) and thus act as an alternative to liver transplantation for acute-on-chronic liver failure (ACLF). Therewith, we are aiming to evaluate the pharmacologyandpharmacokinetics of GMP-grade UC-MSCs products on carbon tetrachloride (CCl4)-induced ACLF mouse model and the concomitant therapeutic dose for intravenous administration. For the purpose, the GMP-grade UC-MSCs products were transplanted intravenously into the aforementioned CCl4-induced ACLF NOD-SCID mouse model, and the therapeutic effect was evaluated with the aid of serological, biochemical and histological assessments. Meanwhile, the correlationshipbetween the treatment groups and other characteristics were determined by conducting principal component analysis (PCA). To further verify the spatio-temporal pharmacokinetics of UC-MSCs products on ACLF treatment, we took advantage of the bioluminescence imaging (BLI) technology with the dual-color fluorescence reporter construct (pLV-Fluc-eGFP). The biological characteristics of UC-MSCs products were in conformity with the International Society of Cell Therapy (ISCT) criteriaand the GMP requirements. ACLF mice with high dose of UC-MSCs treatment revealed significantly alleviated pathological manifestations with a dramatically improved survival rate, the alleviation of liver injury with reduced hepatic enzyme, inflammatory infiltration and inflammatory cytokines. Notably, UC-MSCs in ACLF mice displayed preferable homing and delayed attenuation in the damaged liver tissue. Collectively, our data indicated the feasibility of UC-MSC-based cytotherapy for ACLF model administration. Our findings have provided new references for pharmacologyandpharmacokinetics assessments, which will provide overwhelming evidence for pre-clinical study in vivo.