Pancreatic delta cells could be a new source of beta cells in adult zebrafish

Diabetes occurs under insulin resistance/deficiency and when insulin-producing pancreatic
beta-cell mass is dramatically reduced. Besides therapeutic strategies to preserve beta-cell
mass and function and improve insulin treatments, beta-cell replacement constitutes a
promising alternative to replenish the pancreas with functional beta-cells. Several observations
of pancreatic cell plasticity has led to the hope that triggering beta-cell regeneration within the
pancreas could be harnessed in future therapies. Notably, endocrine alpha- and delta-cells
have been shown in mouse to convert or transdifferentiate into beta-cell after massive
destruction in adult and juvenile, respectively [1] [2].
Due to its potent regenerative capabilities, zebrafish, unlike mammals, is a model of choice to
dissect the cellular and molecular mechanisms underlying beta-cell regeneration. Using a
chemogenetic model to induce selective destruction of beta-cells, we recently showed that
adult zebrafish duct cells display characteristics of embryonic pancreatic progenitors and that
they can give rise to beta-cells in physiological and induced diabetic condition [3].
In this study we pretend to search new sources of beta cell regeneration and understand the
underlying molecular and cellular basis in zebrafish. Indeed, recent observations in our
laboratory reveal the appearance of bi-hormonal Somatostatin/Insulin (Sst/ Ins) cells during
beta-cell regeneration in adult zebrafish. This suggests 1) other cellular origins of the
regenerated beta-cells, ie the endocrine delta-cells that express somatostatin (Sst) or 2) that
regenerated beta-cells display different features as compared to the original ones. To assess
both possibilities, we analyzed these bi-hormonal cells at different time points during
regeneration and at different ages. Here, we show the appearance of bi-hormonal cells (Sst/
Ins) after beta-cell ablation in embryos and larvae in the regeneration stage, similar to those
observed in adult fish. Transcriptomic analyses from adult zebrafish further show that at least
some regenerated beta cells have poly-hormonal characteristics corresponding to other
pancreatic and non-pancreatic endocrine cells. We are currently investigating whether these
features affect the function of the regenerated beta-cells and if delta-cells give rise to new betacells in zebrafish by lineage tracing studies.