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

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.