Mesenchymal stromal cell administration promotes macrophage-mediated bile duct regeneration

TL;DR

This study shows that mesenchymal stromal cells help regenerate bile ducts by promoting macrophage activity in mice with bile duct injury.

Contribution

The study is the first to demonstrate MSC therapy's role in bile duct regeneration and its dependence on macrophages.

Findings

MSC administration increased body weight and liver-to-body weight ratio in mice.

MSCs enhanced the number of cholangiocytes and macrophages in the liver.

Macrophage removal negated the regenerative effects of MSCs.

Abstract

Mesenchymal stromal cell (MSC) therapy is used in cirrhosis models of chronic hepatocellular damage and represents a novel therapeutic approach for liver regeneration. However, no studies have examined MSC therapy for bile duct injury and its effects on bile duct regeneration. This study aimed to elucidate the mechanism underlying bile duct regeneration by establishing a regeneration model and administering MSCs.

A model of bile duct regeneration was developed by feeding mice a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing diet to induce bile duct injury, followed by a normal diet to promote bile duct regeneration. MSCs were administered concurrently with the normal diet, and the livers were analyzed after 2 days. An experimental system was also developed in which clodronate liposomes were administered alongside MSCs to eliminate the influence of macrophages.

MSC administration significantly increased the rate of body weight gain and the liver-to-body weight ratio on day 2 after the change to a normal diet. Immunostaining revealed an increase in the number of CK19+ cholangiocytes. The numbers of Hnf4α+ and Sox9+ cells were significantly elevated in the MSC-treated group. Flow cytometric analysis of liver lymphocytes showed a significant increase in the number of Ly6C− macrophages in the MSC-treated group. Furthermore, analysis of liver lymphocyte populations and cap analysis of gene expression revealed alterations in the immune response and macrophage-related genes, whereas macrophage removal during MSC treatment abolished the bile duct regenerative effects observed with MSC treatment.

Macrophages play a crucial role in bile duct regeneration, and MSC administration has regenerative effects. This approach has potential as a novel treatment modality for bile duct injuries.

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