Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss

Abstract

Pancreatic insulin-producing β-cells have a long lifespan, such that in healthy conditions they replicate little during a lifetime. Nevertheless, they show increased self-duplication upon increased metabolic demand or after injury (i.e. β-cell loss). It is unknown if adult mammals can differentiate (regenerate) new β-cells after extreme, total β-cell loss, as in diabetes. This would imply differentiation from precursors or other heterologous (non β-cell) source. Here we show β-cell regeneration in a transgenic model of diphtheria toxin (DT)-induced acute selective near-total β-cell ablation. If given insulin, the mice survived and displayed β-cell mass augmentation with time. Lineage-tracing to label the glucagon-producing α-cells before β-cell ablation tracked large fractions of regenerated β-cells as deriving from α-cells, revealing a previously disregarded degree of pancreatic cell plasticity. Such inter-endocrine spontaneous adult cell conversion could be harnessed towards methods of producing β-cells for diabetes therapies, either in differentiation settings in vitro or in induced regeneration.

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

“…Transdifferentiation from alpha to beta cells without genetic perturbation of transcription factor expression was first described following near-complete beta cell ablation in mice (Thorel et al, 2010). The process is commonly presumed to be induced by insulin deficiency or pancreatic injury and remodeling (Chera et al, 2014;Habener and Stanojevic, 2012).…”

“…This establishes that beta cells can arise from nonbeta endocrine cells in the islet via direct transdifferentiation. Indeed, near-complete ablation of pre-existing beta cells is eventually followed by the restoration of beta cell mass via transdifferentiation of non-beta endocrine cells in mice (Chera et al, 2014;Thorel et al, 2010). These studies provided important proof of principle that insulin independence can be regained by transdifferentiation, but have also led to the notion 4 that it is triggered by severe beta cell ablation and the associated pancreas remodeling (Habener and Stanojevic, 2012).…”

The Hydra model: disclosing an apoptosis-driven generator of Wnt-based regeneration

“…Finally another way to regenerate a tissue or an organ is to use transdifferentiation of differentiated cells that traverse or not the cell cycle 74 . A recent report showed that adult mice efficiently regenerate their pancreatic β-islets after massive lineage-specific apoptosis by reprogramming their α-islets, proving the plasticity of these cells 75 . Here again the intensity of the apoptotic process seems to play a role but the signaling function of the apoptotic cells remains to be investigated.…”

Pancreas organogenesis: From bud to plexus to gland

“…Thorel et al (2010) selectively expressed the diphtheria toxin (DT) receptor and used DT administration to achieve near total b-cell destruction in mice. Cre-based lineage tracing was used to conclude that under $99% b-cell destruction, a-cells move through a bihormonal glucagon þ /insulin þ state on their way to generate authentic insulin þ b-cells (Thorel et al, 2010). It is notable that such a deep lesion is needed, because a-to-b cell conversion was not seen under $95% destruction.…”