Work

Pancreatic stellate cells promote pancreatic regeneration in chronic pancreatitis via exosomal lncRNA MALAT1-Induced acinar-ductal metaplasia

Year: 2025

Type: article

Abstract: Chronic pancreatitis (CP) is defined by ongoing inflammation and scarring within the pancreas, leading to loss of pancreatic function. Activation of pancreatic stellate cells (PSCs) plays a central regulatory role in acinar-to-ductal metaplasia (ADM), but the specific mechanisms behind it are not well understood. This study aims to explore the impact of PSCs on pancreatic regeneration through exosome-mediated lncRNA MALAT1 in ADM. We established a stable cell line overexpressing Gli1 and an in vitro co-culture model with PSCs; extracted PSC exosomes for biological analysis; identified differentially expressed lncRNA-MALAT1 using lncRNA chips; and explored the functional and mechanistic changes following exosome entry into cells using molecular biology methods, confirming its regulatory effect on downstream RBPJ using dual-luciferase and FISH. Finally, we validated our findings in animal models and human specimens. Our results showed that overexpression of Gli1 in PSCs significantly increased their activation and upregulated markers related to pancreatic fibrosis. The differentially expressed lncRNA MALAT1 in exosomes suppressed ADM by binding RBPJ. Conversely, downregulating MALAT1 significantly promoted ADM, thereby protecting pancreatic function. After PSCs overexpress Gli1, they regulate the expression of RBPJ through lncRNA MALAT1 in exosomes to inhibit ADM pathology, thus inhibiting pancreatic regeneration, providing new insights underlying the molecular mechanisms of pancreatic regeneration in chronic pancreatitis. • Exosomal lncRNA MALAT1 from Gli1-activated pancreatic stellate cells (PSCs) inhibits acinar-ductal metaplasia (ADM). • PSC-derived exosomes serve as critical vehicles, transporting MALAT1 to acinar cells to suppress ADM. • Gli1 overexpression in PSCs activates the Hedgehog pathway, promoting fibrosis markers (α-SMA/TGFβ) while paradoxically inhibiting ADM via exosomal MALAT1, highlighting context-dependent Hh signaling effects. • LncRNA MALAT1 knockdown reverses ADM suppression, demonstrating its pivotal role in pancreatic regeneration. • In vivo studies confirm that MALAT1-downregulating exosomes enhance ADM and pancreatic repair in CP models, supported by human tissue analyses.

Source: Biochemical and Biophysical Research Communications

DOI: 10.1016/j.bbrc.2025.152468