The origins and ID of pancreatic endocrine cells

Date:
April 19, 2022
Source:
Universite' de Gene`ve
Summary:
Scientists show that endocrine stem cells in the pancreas disappear
after birth, and detail the genetic identity of the different
types of pancreatic hormone-producing cells.



FULL STORY ==========================================================================
The pancreas is a key metabolic regulator. When pancreatic beta cells
cease producing enough insulin, blood sugar levels rise dangerously --
a phenomenon known as hyperglycemia -- thus triggering diabetes. After discovering that other mature pancreatic cells can adapt and partly
compensate for the lack of insulin, a team from the University of Geneva (UNIGE) demonstrates that the stem cells from which beta cells are
derived are only present during embryonic development. This discovery
puts an end to a long-standing controversy about the hypothetical
existence of adult pancreatic stem cells that would give rise to newly differentiated hormone-producing cells after birth. The scientists
also succeeded in precisely defining the 'identity card' of pancreatic endocrine cells, which is a promising tool for the production of
replacement insulin-secreting cells. These results can be read in Cell ReportsandNature Communications.


========================================================================== Diabetes is a common metabolic disease. It is characterised by a
persistent hyperglycemia that occurs when pancreatic cells responsible
for the production of insulin -- the beta cells -- are destroyed or
are no longer able to produce this regulatory hormone in sufficient
quantities. Since 2010, studies performed by the team of Pedro Herrera,
a professor in the Department of Genetic Medicine and Development and
in the Diabetes Centre at the UNIGE Faculty of Medicine, as well as at
the Geneva Institute of Genetics and Genomics (iGE3), reveal that the
other pancreatic endocrine cells -- namely alpha, delta and gamma cells,
which produce other hormones useful for the metabolic balance -- can
"learn" to produce insulin when beta cells are absent or defective. This phenomenon, observed in mice and humans, demonstrates the plasticity of pancreatic cells and paves the way to new therapeutic strategies.

The short life of pancreatic endocrine stem cells In two recent
publications, Pedro Herrera's team reports new advances in the knowledge
of the mechanisms of pancreatic cell formation, and in the gene expression profile defining the identity of each of the different islet endocrine
cell types. The first research, published and featured in the cover of
Cell Reports, demonstrates that pancreatic endocrine cells all derive
from undifferentiated progenitor cells that emerge exclusively during
embryonic development, but not after birth.

"Until now, some scientists thought that intra-pancreatic stem cells
persist throughout life,"explains Pedro Herrera. Marta Perez-Frances,
a researcher in Pedro Herrera's team and first author of this study,
adds: "Our work shows that this is not the case. Indeed, all pancreatic hormone-producing cells that emerge after birth originate from the
division of existing differentiated cells that were generated during
embryonic and fetal life from undifferentiated progenitor cells."
To decipher this mechanism, the scientists generated mouse models in
which the different types of pancreatic endocrine cells were genetically
tagged with a fluorescent tracer at different developmental stages in
order to track them down after birth. The cells were traced up to the
age of ten months, when mice are old.

A detailed ID card In a second article, published in Nature
Communications, Pedro Herrera's team focus on the gene expression profile
of pancreatic endocrine cells. "Precisely defining the 'identity card'
of these cells now helps us to design a tool aiming at engineering
cell replacement therapies to treat diabetes. Such therapies could for
instance consist of in vitro manufacturing of insulin- producing cells,
or in stimulating pancreatic regeneration by exploiting the plasticity
of the non-beta cells that we have discovered," explains Le'on van Gurp,
first author and post-doctoral fellow in the lab of Pedro Herrera.

The generation of surrogate cells with stable functional identities is
crucial for the development of cell-based therapies to treat degenerative diseases.

However, their generation requires reliable tools to accurately assess
cell identities. To this aim, the researchers performed an extensive meta-analysis of single-cell transcriptomics, i.e. the analysis of
the genes expressed by individual endocrine cells isolated from human pancreatic islets (these cells are grouped in small "clusters" within
the pancreas). The identification of robustly expressed gene-sets allow
the precise definition of the genetic signature of each endocrine cell
type of the pancreas.

"Our work has no immediate clinical translation. Yet, by deciphering in
detail the mechanisms governing the construction of cellular identities,
it paves the way for developing innovative therapeutic approaches for
treating diabetes and other pathologies linked to the loss of any given
cell type,"concludes Pedro Herrera.

The gene lists that the authors have generated can be downloaded from the Molecular Signatures Database (https://www.gsea-msigdb.org/gsea/msigdb)
or through the web application scPancMeta (https://rapps.hirnetwork.org/ scPancMeta)

========================================================================== Story Source: Materials provided by Universite'_de_Gene`ve. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Le'on van Gurp, Leon Fodoulian, Daniel Oropeza, Kenichiro Furuyama,
Eva
Bru-Tari, Anh Nguyet Vu, John S. Kaddis, Iva'n Rodri'guez,
Fabrizio Thorel, Pedro L. Herrera. Generation of human islet cell
type-specific identity genesets. Nature Communications, 2022; 13
(1) DOI: 10.1038/ s41467-022-29588-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220419092324.htm

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