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Heterozygous Spink1 Deficiency Promotes Trypsin-dependent Chronic Pancreatitis in Mice
Alexandra Demcsák1, Miklós Sahin-Tóth1
1Department of Surgery, University of California Los Angeles, Los Angeles, California.
Background & Aims:
Heterozygous SPINK1 mutations are strong risk factors for chronic pancreatitis in humans, yet heterozygous disruption of mouse Spink1 yielded no pancreatic phenotype. To resolve this contradiction, we used CRISPR/Cas9-mediated genome editing to generate heterozygous Spink1-deleted mice (Spink1-KOhet) in the C57BL/6N strain and studied the effect of this allele in trypsin-independent and trypsin-dependent pancreatitis models.
Methods:
We investigated severity of acute pancreatitis and progression to chronic pancreatitis in Spink1-KOhet mice after transient (10 injections) and prolonged (2 × 8 injections) cerulein hyperstimulation. We crossed Spink1-KOhet mice with T7D23A and T7D22N,K24R mice that carry strongly autoactivating trypsinogen mutants and exhibit spontaneous chronic pancreatitis.
Results:
Prolonged but not transient cerulein stimulation resulted in increased intrapancreatic trypsin activity and more severe acute pancreatitis in Spink1-KOhet mice relative to the C57BL/6N control strain. After the acute episode, Spink1-KOhet mice developed progressive disease with chronic pancreatitis-like features, whereas C57BL/6N mice recovered rapidly. Trypsinogen mutant mice carrying the Spink1-KOhet allele exhibited strikingly more severe chronic pancreatitis than the respective parent strains.
Conclusions:
Heterozygous Spink1 deficiency caused more severe acute pancreatitis after prolonged cerulein stimulation and promoted chronic pancreatitis after the cerulein-induced acute episode, and in two strains of trypsinogen mutant mice with spontaneous disease. In contrast, acute pancreatitis induced with limited cerulein hyperstimulation was unaffected by heterozygous Spink1 deletion, in agreement with recent observations that trypsin activity does not mediate pathologic responses in this model. Taken together, the findings strongly support the notion that loss-of-function SPINK1 mutations in humans increase chronic pancreatitis risk in a trypsin-dependent manner.
Insights
Heterozygous SPINK1 deficiency exacerbates pancreatitis in mice, particularly chronic pancreatitis, confirming its role in trypsin-dependent disease progression. This research clarifies SPINK1
Area of Science:
- Gastroenterology and Hepatology
- Genetics and Molecular Biology
- Disease Modeling
Background:
- Heterozygous SPINK1 mutations are established human risk factors for chronic pancreatitis.
- Previous mouse models with heterozygous Spink1 disruption showed no pancreatic phenotype, creating a contradiction.
- CRISPR/Cas9 genome editing was employed to generate a novel heterozygous Spink1-deleted mouse model (Spink1-KOhet).
Purpose of the Study:
- To resolve the contradiction between human genetic data and mouse models regarding SPINK1's role in pancreatitis.
- To investigate the effect of heterozygous Spink1 deficiency in both trypsin-independent and trypsin-dependent pancreatitis models.
- To assess the impact of the Spink1-KOhet allele on acute and chronic pancreatitis development and severity.
Main Methods:
- Generated heterozygous Spink1-deleted mice (Spink1-KOhet) using CRISPR/Cas9.
- Investigated pancreatitis severity in Spink1-KOhet mice subjected to transient and prolonged cerulein hyperstimulation.
- Crossed Spink1-KOhet mice with autoactivating trypsinogen mutant strains (T7D23A, T7D22N,K24R) to study spontaneous chronic pancreatitis.
Main Results:
- Prolonged cerulein stimulation led to increased intrapancreatic trypsin activity and more severe acute pancreatitis in Spink1-KOhet mice.
- Spink1-KOhet mice developed progressive chronic pancreatitis features after acute episodes, unlike rapidly recovering controls.
- Spink1-KOhet allele significantly worsened chronic pancreatitis in trypsinogen mutant mouse strains.
Conclusions:
- Heterozygous SPINK1 deficiency exacerbates acute pancreatitis under prolonged stimulation and promotes chronic pancreatitis.
- The findings support SPINK1's role in trypsin-dependent pancreatitis, aligning with human genetic risk factors.
- Limited cerulein-induced pancreatitis was unaffected, consistent with models where trypsin activity is not pathogenic.
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