Biomaterial-Based Regulation of Mesenchymal Stromal Cell Hepatic Differentiation for Liver Regeneration

Liver failure and advanced chronic liver disease remain major causes of morbidity and mortality, while donor organ shortages, procedural complexity, cost, and the need for lifelong management after transplantation limit the availability of liver transplantation. Mesenchymal stromal cells (MSCs) have attracted substantial interest as a cell source for liver regeneration because of their accessibility, expansion capacity, immunomodulatory properties, and regenerative secretome. MSC-based hepatic differentiation, however, remains challenging, and cells generated in vitro frequently display an incomplete hepatocyte phenotype and limited maturation. Increasing evidence indicates that soluble differentiation factors alone are insufficient to reproduce the complex microenvironmental cues that regulate hepatic cell fate. Biomaterials can provide three-dimensional architecture, extracellular matrix (ECM) ligands, mechanical cues, cell-adhesive sites, and controlled presentation of growth factors, thereby acting as more than passive carriers of cells. In this mini-review, we summarize studies investigating natural and synthetic biomaterials for MSC hepatic differentiation, with emphasis on collagen-, gelatin-, heparin-, alginate-, and decellularized ECM-based systems as well as synthetic polymeric scaffolds such as poly(lactic-co-glycolic acid) and poly(L-lactic acid)-co-poly(ε-caprolactone). We discuss how biomaterial composition and three-dimensional organization may cooperate with hepatic differentiation media to promote hepatic phenotype and function. We also highlight an important distinction between expression of hepatic markers and acquisition of mature hepatocyte function, and identify opportunities for biomaterial systems that integrate biochemical, biophysical, and paracrine cues to achieve more reproducible hepatic maturation and clinically relevant liver regeneration.