Interleukin-4-mediated Pro-Regenerative Cellular Reprogramming in 3-dimensional Liver Culture

Area of Science:

• Hepatology
• Immunology
• Regenerative Medicine

Background:

• Interleukin-4 (IL-4) is crucial for liver regeneration, but its precise mechanisms are unclear due to limited suitable models.
• Existing models often fail to replicate the complex cellular interactions within the liver microenvironment.

Purpose of the Study:

• To investigate the role of IL-4 in hepatic cell reprogramming using murine precision-cut liver slices (PCLS).
• To elucidate the pro-regenerative effects of IL-4 through longitudinal single-cell transcriptomics and protein validation.

Main Methods:

• Longitudinal single-nucleus RNA sequencing of PCLS cultured with and without IL-4.
• Assessment of slice viability via intracellular ATP output and Ki67 protein expression.
• Orthogonal validation using immunohistochemistry (IHC) and evaluation in thioacetamide-induced liver injury models.

Main Results:

• IL-4 upregulated tissue repair markers in myeloid cells and promoted hepatocyte/cholangiocyte progenitor expansion.
• IL-4 inhibited fibroblast activation and significantly increased Ki67 expression, indicating enhanced proliferation.
• IL-4 improved cellular viability and regenerative potential in PCLS from injured livers.

Conclusions:

• IL-4 effectively modulates the liver microenvironment to promote regeneration.
• Cytokine-based therapies targeting IL-4 offer a promising strategy for immune-mediated hepatic regeneration.
• PCLS serve as a valuable 3D model for studying liver regeneration and immune cell interactions.