The Ectopic Expression of Pax4 in the Mouse Pancreas Converts Progenitor Cells into α and Subsequently β Cells

Abstract

We have previously reported that the loss of Arx and/or Pax4 gene activity leads to a shift in the fate of the different endocrine cell subtypes in the mouse pancreas, without affecting the total endocrine cell numbers. Here, we conditionally and ectopically express Pax4 using different cell-specific promoters and demonstrate that Pax4 forces endocrine precursor cells, as well as mature alpha cells, to adopt a beta cell destiny. This results in a glucagon deficiency that provokes a compensatory and continuous glucagon+ cell neogenesis requiring the re-expression of the proendocrine gene Ngn3. However, the newly formed alpha cells fail to correct the hypoglucagonemia since they subsequently acquire a beta cell phenotype upon Pax4 ectopic expression. Notably, this cycle of neogenesis and redifferentiation caused by ectopic expression of Pax4 in alpha cells is capable of restoring a functional beta cell mass and curing diabetes in animals that have been chemically depleted of beta cells.

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

“…Several recent reports demonstrate that forced expression of lineageinappropriate transcription factors causes islet cells to switch identity (Collombat et al, 2007;Collombat et al, 2009;Gao et al, 2014;Papizan et al, 2011;, which has been attributed to the similar chromatin states of alpha and beta cells (Bramswig et al, 2013). This establishes that beta cells can arise from nonbeta endocrine cells in the islet via direct transdifferentiation.…”

Pancreas organogenesis: From bud to plexus to gland

“…Furthermore, Pax4 and Arx induce, respectively, either an a-to-b or b-to-a conversion upon misexpression in terminally differentiated mature endocrine cell types (Colombo et al, 2007;Collombat et al, 2009). Thus, Pax4 and Arx are required for b and a-cell fate allocation, respectively.…”

“…In this latter situation, it was proposed that the extended neogenesis of a-cells from ducts, hypothesized as being induced by the lack of circulating glucagon, continues to pump conversionready cells (we hypothesize that they might not be mature, but more like pro-a-cells) into the islets, where their continual change into b-cells keeps the stimulus to produce yet more acells, a cycle that ultimately results in mega-islet formation. Even in the face of these remarkable giant islets, with their large insulin store, the mice develop diabetes; it is now being tested whether the hyperglycemia arises because of a severe acquired insulin resistance in the peripheral tissues (Collombat et al, 2009).…”

La thérapie cellulaire du diabète

“…Chez l'adulte, les cellules ductales sont quiescentes mais elles semblent contenir des progéni-teurs facultatifs qui, via réactivation de l'expression géniteurs communs (qui expriment la neurogénine 3 [NGN3]) et sont capables à l'état mature, de plasticité. Ce phénomène inattendu a été dévoilé par l'équipe de Patrick Collombat grâce à un modèle transgénique de souris surexprimant le facteur de transcription PAX4 (paired box 4), marqueur de cellules β, dans des cellules α productrices de glucagon [37,61] (➜). Une transition des cellules α -conditionnées par PAX4 -vers un phé-notype β a en effet été observée, permettant un réapprovisionnement en cellules insulino-sécrétantes suffisant pour assurer une normalisation de la glycémie de souris traitées par la streptozotocine (qui détruit les cellules β).…”