Dept. Genetic Medicin & Development - CMU - UNIGE
We study the mechanisms of cell fate allocation and maintenance in the pancreas, both during ontogeny and, more specifically, during pancreas regeneration in the diabetic adult. In particular, we are interested in understanding the origin of insulin-producing beta-cells. These studies are performed through the generation of transgenic mice and using human pancreatic islets.
We pioneered the study of mouse pancreas development and performed the first in vivo cell lineage tracing analysis in mouse embryos using the Cre/loxP system (Herrera, 2000). We found that, contrary to the model prevailing at the time, insulin-producing cells in the pancreas do not derive from early progenitors that express the glucagon gene.
Later we showed that embryonic pancreatic Neurogenin3-expressing cells, which are the precursors to all islet endocrine cell types, are multipotent at the cell population level but, at the single cell level, on the contrary, they are strictly unipotent (Desgraz & Herrera, 2009).
In the field of regenerative biology, we have discovered that the adult pancreas retains the ability to generate new insulin-producing cells after a total beta-cell loss, and that this process reveals a high degree of cell plasticity, since the majority of the regenerated insulin-producing cells are derived from adult islet non-beta-cells that have spontaneously reprogrammed to producing insulin and other beta-cell-specific factors in this extreme situation of beta-cell loss (Thorel et al, 2010; Chera et al, 2014; Cigliola et al, 2016). We have partially uncovered the signals involved in islet non-beta-cell plasticity (Cigliola et al, 2018). More recently, we provided a proof of principle for the plasticity of human islet non-beta-cells, through the generation of glucose-sensing insulin-secreting human alpha-cells (Furuyama et al, 2019).
The micrographs represent a pseudoislet of glucose-sensing insulin-producing human alpha-cells transplanted underneath the kidney capsule of a diabetic mouse. The cells are lineage-traced (GFP+); insulin staining appears in red, and glucagon is blue