Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon+ α-cells

Abstract

The mechanisms restricting regeneration and maintaining cell identity following injury are poorly characterized in higher vertebrates. Upon β-cell loss, 1–2% of the glucagon-producing α-cells spontaneously engage in insulin production in mice. Here we explore the mechanisms inhibiting α-cell plasticity. We show that the adaptive α-cell identity changes are constrained by intra-islet Insulin- and Smoothened-mediated signaling, among others. The combination of β-cell loss, or insulin signaling inhibition, with Smoothened inactivation in α- or δ-cells, stimulates insulin production in more α-cells. These findings suggest that removing constitutive “brake signals” is crucial for neutralizing the refractoriness to adaptive cell-fate changes. It appears that cell identity maintenance is an active process mediated by repressive signals, released by neighbor cells, curbing an intrinsic trend of differentiated cells to change.

In vivo hyperglycaemia exposure elicits distinct period‐dependent effects on human pancreatic progenitor differentiation, conveyed by oxidative stress

“…In these mice, the DTR is specifically overexpressed on the surface of the β‐cells, under the control of the RIP. As previously described, upon diphtheria toxin (DT) administration, the β‐cell compartment is specifically ablated with extremely high and reproducible efficiency (97.88% in NSG RIP‐DTR, Figure B,C), similar to the one reported for SCID RIP‐DTR (97.8%) . Ablated animals developed hyperglycaemia and displayed lower weight compared to their normoglycaemic counterparts (Figure D,E).…”

“…The mice were given ad libitum access to water and standard diet RM1A (SDS). First group received three intraperitoneally (ip) DT (Sigma, cat.# D0564‐1MG) injections to induce diabetes as previously described . Blood glucose was monitored twice a week at 4‐5 pm with a Contour XT glucometer (Bayer) to confirm diabetes (blood glucose >300 mg/dL on 2 consecutive measurements).…”

Tissue repair brakes: A common paradigm in the biology of regeneration

“…Their identification as regeneration modulators through gene profiling analyses will be cumbersome. As mentioned above, we have found, for instance, that insulin and hedgehog signaling in pancreatic islets are such players …”

“…Hence, Hedgehog and Insulin signaling are, together with other pathways not yet identified, natural brakes making α-cells to preserve their identity. 102 By using a wide range of genetic tools, recent studies have revealed that α-to-β transdifferentiation can be artificially potentiated by the concomitant inhibition of the key α-cell-specific transcription factor Arx and the epigenetic modifier DNMT1. 103 This suggests that α-cells are epigenetically locked, and that these brakes can be released.…”

“…We found that local intra‐islet blockade of Insulin and Hedgehog signaling pathways leads to improved reprogramming efficiency. Hence, Hedgehog and Insulin signaling are, together with other pathways not yet identified, natural brakes making α‐cells to preserve their identity …”