Local hyperthyroidism promotes pancreatic acinar cell proliferation during acute pancreatitis
Malagola, E and Chen, R and Bombardo, M and Saponara, E and Dentice, M and Salvatore, D and Reding, T and Myers, S and Hills, AP and Graf, R and Sonda, S, Local hyperthyroidism promotes pancreatic acinar cell proliferation during acute pancreatitis, Journal of Pathology, 248 pp. 217-229. ISSN 0022-3417 (2019) [Refereed Article]
Proliferation of pancreatic acinar cells is a critical process in the pathophysiology of pancreatic diseases,because limited or defective proliferation is associated with organ dysfunction and patient morbidity. Inthis context, elucidating the signalling pathways that trigger and sustain acinar proliferation is pivotal todevelop therapeutic interventions promoting the regenerative process of the organ.In this study we usedgenetic and pharmacological approaches to manipulate both local and systemic levels of thyroid hormones toelucidate their role in acinar proliferation following caerulein-mediated acute pancreatitis in mice. In addition,molecular mechanisms mediating the effects of thyroid hormones were identified by genetic and pharmacologicalinactivation of selected signalling pathways. In this study we demonstrated that levels of the thyroid hormone3,3′,5-triiodo-L-thyronine (T3) transiently increased in the pancreas during acute pancreatitis. Moreover, by usinggenetic and pharmacological approaches to manipulate both local and systemic levels of thyroid hormones, weshowed that T3 was required to promote proliferation of pancreatic acinar cells, without affecting the extentof tissue damage or inflammatory infiltration.Finally, upon genetic and pharmacological inactivation of selectedsignalling pathways, we demonstrated that T3 exerted its mitogenic effect on acinar cells via a tightly controlledaction on different molecular effectors, including histone deacetylase, AKT, and TGFsignalling.In conclusion, ourdata suggest that local availability of T3 in the pancreas is required to promote acinar cell proliferation and providethe rationale to exploit thyroid hormone signalling to enhance pancreatic regeneration.