β-Cells Are Not Generated in Pancreatic Duct Ligation–Induced Injury in Adult Mice

Abstract

The existence of adult β-cell progenitors remains the most controversial developmental biology topic in diabetes research. It has been reported that β-cell progenitors can be activated by ductal ligation–induced injury of adult mouse pancreas and apparently act in a cell-autonomous manner to double the functional β-cell mass within a week by differentiation and proliferation. Here, we demonstrate that pancreatic duct ligation (PDL) does not activate progenitors to contribute to β-cell mass expansion. Rather, PDL stimulates massive pancreatic injury, which alters pancreatic composition and thus complicates accurate measurement of β-cell content via traditional morphometry methodologies that superficially sample the pancreas. To overcome this potential bias, we quantified β-cells from the entire pancreas and observed that β-cell mass and insulin content are totally unchanged by PDL-induced injury. Lineage-tracing studies using sequential administration of thymidine analogs, rat insulin 2 promoter–driven cre-lox, and low-frequency ubiquitous cre-lox reveal that PDL does not convert progenitors to the β-cell lineage. Thus, we conclude that β-cells are not generated in injured adult mouse pancreas.

Long-term evolution of acinar-to-ductal metaplasia and β-cell mass after radiofrequency-assisted transection of the pancreas in a controlled large animal model

“…Since complete duct occlusion should prevent duct cells regenerating into acinar cells after PDL [16] and some morphometric results could have been biased by including injured pancreas [7,11], the present study implemented six key differences from conventional PDL mouse models in order to ensure efficient and reliable pancreatic duct occlusion and accurate evaluation:…”

“…PDL has been extensively used to study the conversion of ADM into PDAC [1,3] as well as a method of duct-to-islet differentiation [6,[8][9][10][11][12] in order to increase beta-cell mass. However, contradictory results have been obtained from the conventional mouse models [6,7,11,26].…”

“…However, the validity of PDL as a model of endocrine regeneration has now been called into question [5][6][7]11,13,14]. Recent results from PDL in mouse models have shown that some acinar cells can escape death [7] and that acinar compartment can regenerate in a long-term evolution after PDL (over 6 months), probably by restoration of pancreatic drainage [6].…”

“…Pancreatic duct ligation (PDL) in mouse models has been extensively used as a model of chronic pancreatitis in order to study the evolution of ADM into PDAC [1,3,7], and also as a model of duct-to-islet differentiation [6,[8][9][10][11][12] to increase beta-cell mass. However, the validity of PDL as a model of endocrine regeneration has now been called into question [5][6][7]11,13,14].…”

Quelles cellules souches pour une réparation du pancréas endocrine ?

“…Ces données constituent donc un faisceau d'arguments en faveur de l'existence de cellules souches canalaires dans le pancréas adulte. Néanmoins, ce débat n'est pas clos, car les équipes de Sander et Kushner ont remis en cause cette théorie [32,33]. En effet, l'équipe de Sander montre qu'une ligature du canal pancréatique induit l'expression de Ngn3 sans pour autant aboutir à une différenciation complète des progéniteurs en cellules β.…”