Mechanically preconditioned stem cells therapy using bioinspired liver-mimetic microspheres for functional liver...

Area of Science:

• Biomaterials Science
• Regenerative Medicine
• Mechanobiology

Background:

• Acute liver failure (ALF) presents a critical unmet medical need, with limited therapeutic options.
• Hepatocyte-like cells (HLCs) show promise for ALF treatment but require optimization for efficacy.
• The liver's mechanical microenvironment is increasingly recognized as a key factor in cellular function and disease.

Purpose of the Study:

• To investigate the impact of ALF-induced mechanical changes on HLC-based cell therapy.
• To design bioinspired hydrogel microspheres that mimic healthy and ALF liver viscoelasticity.
• To enhance HLC differentiation and therapeutic efficacy by controlling the mechanical niche.

Main Methods:

• Fabrication of tunable viscoelastic hydrogel microspheres.
• Differentiation of human adipose-derived mesenchymal stem cells (hADSCs) into HLCs within engineered niches.
• Assessment of HLC function and therapeutic efficacy in ALF mouse models (CCl4-induced and partial hepatectomy).
• Analysis of cellular mechanotransduction pathways (ROCK axis, YAP nuclear translocation, stress fibers).

Main Results:

• A fast-relaxation hydrogel niche mimicking healthy liver promoted efficient hADSC differentiation into functional HLCs.
• This niche suppressed abnormal stress fiber formation and pathological YAP nuclear translocation via the ROCK axis.
• Mechanically preconditioned HLCs demonstrated significant therapeutic efficacy in ALF mouse models, promoting liver regeneration.
• These HLCs modulated host mechanotransduction and remodeled the diseased microenvironment.

Conclusions:

• Tailoring the mechanical microenvironment using bioinspired hydrogels is a viable strategy to enhance HLC differentiation and function.
• Disease mechanobiology-oriented approaches can significantly improve cell therapy outcomes for acute liver failure.
• This work provides insights into designing viscoelastic biomaterials for regenerative medicine applications in liver disease.