Preexisting pancreatic acinar cells contribute to acinar cell, but not islet β cell, regeneration

Abstract

It has been suggested that pancreatic acinar cells can serve as progenitors for pancreatic islets, a concept with substantial implications for therapeutic efforts to increase insulin-producing β cell mass in patients with diabetes. We report what we believe to be the first in vivo lineage tracing approach to determine the plasticity potential of pancreatic acinar cells. We developed an acinar cell-specific inducible Cre recombinase transgenic mouse, which, when mated with a reporter strain and pulsed with tamoxifen, resulted in permanent and specific labeling of acinar cells and their progeny. During various time periods of observation and using several models to provoke injury, we failed to observe any chase of the labeled cells into the endocrine compartment, indicating that acinar cells do not normally transdifferentiate into islet β cells in vivo in adult mice. In contrast, we observed a substantial role for replication of preexisting acinar cells in the regeneration of new acinar cells after partial pancreatectomy. These results indicate that mature acinar cells harbor a facultative acinar but not endocrine progenitor capacity.

Pancreas organogenesis: From bud to plexus to gland

“…In this case, transient dedifferentiation of acinar cells is followed by acinar regeneration with no contribution of acinar lineage to ductal and endocrine lineages. The same conclusion was obtained from studies using Ppx in combination with acinar-specific lineage tracing (Desai et al, 2007). In the latter setting, Elastase-CreER T2 -labeled acini were only capable of producing acinar cells, but not ductal and endocrine cells.…”

“…After about E14.5, acinar cells are mainly generated by the duplication of existing acinar cells, and endocrine progenitor birth in the trunk domain ends by the beginning of postnatal life (Zhou et al, 2007;Solar et al, 2009). Acinar cells and endocrine cells go through a maturation process lasting into postnatal life, and there is significant postnatal expansion of endocrine cell numbers, likely linked to self-replication (Desai et al, 2007;Finegood et al, 1995;Teta et al, 2007).…”

“…Studies on postnatal b-cell growth and proliferation have been reviewed extensively elsewhere and will not be covered in this review (reviewed in Ackermann and Gannon, 2007;Bonner-Weir et al, 2010). In order to compensate for body growth, acinar differentiation, maturation, and proliferation also continue after birth before gradually decreasing until weaning (Desai et al, 2007;Salpeter et al, 2010).…”

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

“…Currently, there is little evidence that any other cell type contributes to β cell neogenesis. Although some studies had suggested the potential role of Pdx1 in promoting β cell transdifferentiation from acinar tissue [83,[104][105][106], a recent elegant lineage tracing analysis suggests that such cells do not contribute to new β cells in models of regeneration in vivo [107].…”

La thérapie cellulaire du diabète

“…Ces limites ont réorienté les investigations vers des stratégies de différenciation in situ, sans recours à l'isolement et à la culture cellulaires. Au-delà de la controverse sur les capacités des cellules acinaires à produire spontanément de nouvelles cellules β lors de pancréatecto-mies ou autres lésions pancréatiques [42], il est admis que ces cellules sont capables de régénérer le pancréas exocrine [43]. Elles sont considérées à ce titre comme des progéniteurs facultatifs.…”