Human Umbilical Cord-Derived Mesenchymal Stem Cells in Combination with Small Extracellular Vesicles Prevent the Development of Fibrosis and Cirrhosis and Improve Survival in Wistar Rats Receiving CCl_₄

Objective: Umbilical Cord-derived Mesenchymal Stem Cells (UC-MSCs) and Small Extracellular Vesicles (SEVs) independently exert anti-inflammatory properties and have shown antifibrotic effects in animal models of liver fibrosis and cirrhosis. In this proof-of-concept study, we examined the effects of human UC-MSCs combined with SEVs on liver fibrosis in a rat model of fibrosis and cirrhosis. Additionally, we studied the efficacy of UC-MSC and SEVs in improving survival.

Methods: Two groups of 14 male Wistar rats received six doses of oral CCl4. Starting at week 4, one group received three weekly IV doses of UC-MSC+SEV at a dose of 1 million MSCs and 5 billion SEV each. Fourteen animals who received CCl4 alone were used as control animals. All animals that survived until week seven were sacrificed.

Results: Liver fibrosis stage was significantly lower in the UCMSC+ SEV group (p<0.001). No animals in the UC-MSC+SEV group had cirrhosis, in contrast to the 12 animals in the control group with cirrhosis (p<0.001). Corresponding favorable changes in liver morphology, biochemistry, and immunohistochemistry were observed in the UC-MSC+SEV group. The difference in survival at 6 weeks was significant between the two groups (100% vs. 57%, p<0.01).

Conclusion: In this first animal trial, human UC-MSCs in combination with SEV prevented liver fibrosis and cirrhosis development in CCl4 induced liver disease and significantly improved animal survival. Further studies are needed to validate our observations and to test the combination of UCMSC+ SEV in other animal models and in humans with fibrotic liver diseases and liver failure.