Conversion of Adult Pancreatic α-cells to β-cells After Extreme β-cell Loss

Conversion of Adult Pancreatic α-cells to β-cells After Extreme β-cell Loss

Nature. Author manuscript; available in PMC

22. October 2010

We have observed that the adult pancreas has the ability of making β-cells from heterologous origins in a pathological situation whereby β-cells have been completely lost, or almost. Regeneration in RIP-DTR mice is weaker than in other mouse models of less severe β-cell destruction 16,27,28 probably because there is almost no β-cells left after DT treatment; but why β-cell replication is not increased after the massive injury remains unclear, and is in contrast with observations reported after partial β-cell loss 16,27,28. This fact alone reveals the biological significance of studying regeneration and tissue responses under various contexts, such as the degree of injury or the age of disease onset.

Expression of Pdx1 may be part of the α-cell conversion mechanism: ectopic Pdx1 activity, alone or combined with other factors, drives hepatocytes or acinar cells into insulin production 3,32,33. Pdx1 binds directly to insulin and glucagon promoters 34, thus inhibiting glucagon expression and inducing insulin transcription 35. Other β-cell factors may determine the α-to-β reprogramming, such as Nkx6.1, which may also contribute to glucagon gene inhibition and activation of β-cell-specific genes 36, or Pax4, which regulates the balance between α- and β-cells by antagonizing Arx in endocrine progenitors 37. In this respect, it was recently reported that expression of Pax4 in embryonic α-cells using the Glucagon-Cre transgenics 21 induces their conversion into β-cells 38. Because mature α- and β-cells share a number of transcription factors (such as Isl1 and Pax6) 39 and a common ancestor 21,39, the α-cell represents an appropriate candidate for reprogramming to β-cell phenotype. Moreover, α- and β-cells are functionally very close, with a similar machinery to metabolize glucose and secrete hormones 40 : both cell types express glucokinase and ATP-regulated K+-channels, suggesting that they differ in glucose transport but not in glucose utilization 41,42. Expression of GLUT2 in insulin-producing reprogrammed α-cells, in addition to Nkx6.1 and Pdx1, should allow them to secrete insulin upon glucose stimulation, like functional β-cells.

Previous models of β-cell injury do not report heterologous regeneration of β-cells, yet this was not explored with lineage tracing analyses 16,27,28. In these models, remaining β-cells were abundant (at least 20% of the initial β-cell mass), which suggests that β-cell loss must be near total for triggering heterologous β-cell formation. In this regard, milder β-cell ablation in RIP-DTR mice, by using hemizygous females (50% ablation) or in males treated with lower doses of DT (95-98% ablation), has a different outcome: in these situations, either there is no measurable regeneration (after 50% ablation; Supplementary Fig. 12), or induction of α-cell reprogramming is decreased, with a more important contribution of spared β-cells (not shown). The amount of β-cell loss thus determines whether there is regeneration (Supplementary Fig. 12) and, together with the type of injury, it influences the degree of cell plasticity and regenerative resources of the adult pancreas (Supplementary Fig. 12).

These observations raise issues with respect to cell plasticity and regenerative recovery from lesion: α-cells were never considered previously as a potential source of cells for β-cell therapy in diabetics. Our results argue that a deep lesion (total or near-total β-cell ablation, as in T1D) causes the release of some form of signal that allows prolonged and substantial β-cell regeneration. The presence of bihormonal cells (glucagon+/insulin+) long time after lesion induction is compatible with α-cell reprogramming not being limited by temporal restrictions, and thus with regeneration in aged individuals. Alternatively or in addition, persistence of glucagon staining in some reprogrammed α-cells may reflect impaired or inhibited glucagon granule exocytosis: in cells possessing multiple types of regulated secretory granules, exocytosis can be activated independently for each of them 43.

We found that the proportion of β-cells derived from reprogrammed α-cells is very variable among individuals having the same degree (>99%) of β-cell destruction: between 32% and 81% (Fig. 3k). This further stresses the adaptability of adult pancreas and reveals high versatility in response to injury. This plasticity is reminiscent of the various mechanisms of liver regeneration 44.

In long-term human T1D patients, occasional β-cells are found scattered in the pancreas, as well as circulating C-peptide, an indicator of proinsulin processing and insulin secretion 11,45,46. Also, complete β-cell function recovery has been reported in young T1D patients 47,48. Whether this is the consequence of a continuous regeneration of new β-cells, as we have seen in mice, or persistence of few β-cells, which would escape autoimmunity, is not known 45. Nevertheless, our observations in mice should encourage attempts of treatment by inducing and enhancing regeneration after controlling the autoimmune aggression.

Finally, these findings suggest that the production of new models for selective and total cell ablation could lead to discoveries regarding regeneration induction and cell plasticity in other organs, including pathological conditions such as dysplasia or cancer.



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