Phenotypic plasticity in the pancreas: new triggers, new players

Abstract

The pancreas has a very limited regenerative potential during homeostasis. Despite its quiescent nature, recent in vivo models suggest a certain degree of regeneration and cellular interconversion is possible within the adult pancreas. It has now become evident that cellular plasticity can be observed in essentially all cell types within the pancreas when provided with the right stress stimuli. In this review, we will focus on the latest findings uncovering phenotypic plasticity of different cell types in the pancreas, the molecular mechanisms behind such plasticity and how plasticity associated with pancreatic or non-pancreatic cells could be harnessed in the generation of new insulin-producing beta cells.

Figure 1

Pancreas scheme. (a)Schematic overview of the pancreatic compartments, consisting of exocrine and endocrine parts. The acinar and ductal cells compose the exocrine pancreas; the acinar cells secrete digestive enzymes that are channeled to the small intestine via the pancreatic ductal tree. The endocrine cells, confined to the islets of Langerhans, secrete glucose-regulating hormones into the bloodstream. (b)Development of the three terminally differentiated cell types found in the adult pancreas. Endocrine, ductal and acinar cells arise from the Pdx1+ embryonic progenitors during development. Transcription factors such as Ngn3 (endocrine cells), Ptf1/Cpa1 (acinar cells) and Hnf6 (ductal cells) are key in coordinating cell fate decisions during embryogeneis.

Figure 2

Pancreas plasticity in vivo: intra-islet, acinar and ductal plasticity. (a)Intra-islet cell plasticity. Experimental and pathologic conditions can lead to interconversion between islet cell types. Specifically, various studies have shown that Fltp1 expression partly drives heterogeneity within beta cells, overexpression of Pax4 induces alpha-to-beta-cell conversion and delta cells spontaneously transdifferentiate into beta cells following beta cell ablation. (b)Acinar cell plasticity. Inflammation and oncogenic stress can cause transdifferentiation of acinar cells towards ductal-like cells with progenitor abilities (acinar-to-ductal metaplasia). Furthermore, acinar to beta cell plasticity has been artificially induced by various strategies such as the adenoviral infection of acinar cells with the proendocrine factors Ngn3/Pdx1/MafA, in vivo. Acinar to alpha and delta cell fate conversion could be controlled by Ngn3 and MafA expression patterns. (c)Ductal cell plasticity. Pancreatic duct ligation was the first trigger to demonstracte the ductal to beta conversion. Diphtheria toxin-induced depletion of acinar and beta cells can drive beta cell mass regeneration from the surviving ductal cells. Also, TGFa overexpression and pancreatic ductal deletion of Fbw7 were shown to convert ductal cells to beta cells. Moreover, activation of Stat3 and Ngn3 in ductal cells induces endocrine lineage transdifferentiation. Pax4 overexpression in alpha cells has also shown ductal-to-beta cell plasticity.

Figure 3

Inter-organ plasticity: intestine, stomach, liver transdifferentiation to beta-like cells. Studies have shown that stomach-residing antral cells, when genetically modified to overexpress Ngn3, Pdx1 and MafA, can give rise to beta cells which are functionally similar to native beta cells. Intestinal cells can also transdifferentiate into beta-like cells upon FoxO1 deletion or Ngn3, Pdx, MafA overexpression. Ngn3, Pdx1 and MafA ectopic expression in liver and gallbladder can activate some degree of plasticity towards pancreatic lineage.

Figure 4

In vitro/ex vivo pancreatic cell plasticity. (a)In vitro culturing of acinar cells affects their phenotype, making them susceptible to fate change. Primary acinar cells de-differentiate ex vivo, exhibiting a ductal-like phenotype (Sox9+, Hnf1b+ and CK19+), mimicking insult-induced ADM observed in vivo. Acinar cells can transdifferentiate into beta cells by either being conditioned with EGF, leukemia inhibitory factor (LIF) or ciliary neurotrophic factor (CNTF) or by inducing overexpression of Ngn3, Pdx1, MafA and Pax4. (b) Many adult tissue-derived primary cells can be cultured in a 3D system, forming spheres termed organoids. Pancreas, stomach, intestine and gallbladder cells can be cultured long-term as organoids, retaining their native features, and forced to transdifferentiate into beta-like cells when forced to overexpress Ngn3, Pdx1 and MafA.