Enhancing mesenchymal stem cell function with epiregulin in tissue engineering: From tissue regeneration to gut microbiota modulation

Table 1 Research on epiregulin and mesenchymal stem cells in regenerative medicine (2020–2026)

Tissue/organ	Methodology	Results	Ref.
Bone	In vitro: Osteogenic differentiation of BMSCs in the presence of TNF-α. In vivo: Model rats with periodontitis	EREG enhances osteogenesis via the EGFR/ERK1/2 pathway, accelerating mineralization and bone formation in periodontal bone defects	[1,27,29]
Skin	Multi-omics analysis of UVB-induced photoaging in human keratinocytes treated with hUC-MSC-CM	hUC-MSC-CM reduced apoptosis by ~4.5%, decreased ROS production, enhanced keratinocyte migration, and modulated EREG expression through EGFR-dependent signaling pathways	[30]
Liver	In vitro: Human hepatocyte cell line (THLE-2) treated with EREG; CCK-8 proliferation assays. In vivo: Mouse ALPPS model; PHLF model; CCl4-induced acute/chronic liver injury; MSC administration [(1–5) × 106 cells/kg]; MSC-EV delivery (109–1012 particles/kg). Analysis: ScRNA-seq and CyTOF of the liver immune microenvironment; ELISA for growth factors	EREG was found to significantly promote hepatocyte proliferation (THLE-2) and improve survival in PHLF mice (median survival increased from 22 hours to 36 hours). THBS1+ monocytes were identified as the source of EREG. MSCs suppressed hepatocyte apoptosis and reduced inflammatory cytokines. They also enhanced liver regeneration via the secretion of HGF, IGF-1, IL-6, and VEGF; reduced fibrosis via the downregulation of TGF-β1; and improved liver function	[31,32]
Intestinal tissue	In vitro: HIOs cultured with EREG; scRNA-seq. In vivo: Transplantation of HIOs under the murine kidney capsule and injection of tomato lectin into the tail vein	EREG promotes the simultaneous differentiation of the epithelium, mesenchyme, enteric neuroglial cells, endothelial cells, and organized smooth muscle. EREG-HIOs form functional neuromuscular units that exhibit spontaneous, peristaltic-like contractions	[15,16]

ALPPS: Associating liver partition and portal vein ligation for staged hepatectomy; EGFR: Epidermal growth factor receptor; ELISA: Enzyme-linked immunosorbent assay; EREG: Epiregulin; ERK1/2: Extracellular signal-regulated kinase 1/2; HGF: Hepatocyte growth factor; HIOs: Human induced pluripotent stem cell-derived intestinal organoids; hUC-MSC-CM: Human umbilical cord mesenchymal stem cell-conditioned medium; IGF-1: Insulin-like growth factor-1; IL-6: Interleukin-6; MSC: Mesenchymal stem cell; MSC-EV: Mesenchymal stem cell derived extracellular vesicle; PHLF: Post-hepatectomy liver failure; ROS: Reactive oxygen species; scRNA-seq: Single-cell RNA sequencing; TGF-β1: Transforming growth factor β; TNF-α: Tumor necrosis factor-α; VEGF: Vascular endothelial growth factor.