Pedro Herrera obtient un master en biologie de l’université Complutense de Madrid en 1985. En 1994, il obtient un doctorat ès sciences de l’université de Genève et devient, en 1996, chercheur indépendant au sein du département de morphologie de la Faculté de médecine, avec le soutien de la Juvenile Diabetes Research Foundation, puis du FNS. Il est nommé maître d’enseignement et de recherche en 2000, professeur adjoint au sein du Département de médecine génétique et développement en 2009, puis professeur ordinaire en décembre 2013. En produisant des souris transgéniques, il publie le premier traçage génétique de lignages cellulaires in vivo chez un embryon de mammifère. Ses travaux, dans les domaines du développement embryonnaire et la régénération, portent sur l’origine des cellules à insuline et visent à développer des traitements innovants du diabète.

Research aims

Prof. Herrera's group studies the genetic regulation of pancreas development and, more extensively, of pancreas regeneration after injury. To address the biological questions related to the regeneration of insulin-producing beta-cells in diabetic situations, they use human pancreatic islets obtained from deceased donors. In parallel, they produce and use different lines of transgenic mice, which are powerful genetic tools to study the natural history of the human disease.

Main achievements of previous work

From the beginning of his scientific career Pedro Herrera investigated the embryonic origin of the different lineages of cells in the pancreas. As part of his thesis work he performed the first published experiments of selective ablation of cells in vivo, to study the formation of the different pancreatic endocrine cell types in developing mouse embryos (Herrera et al, 1994). This work was truly innovative from an experimental perspective. Soon thereafter, already as an independent young investigator, he pioneered again the field of mouse developmental biology by performing the first series of in vivo cell lineage tracing analyses in mammalian embryos using, in an innovative way, the genetic Cre/loxP system (Herrera, 2000; a single- authored paper). In short, he reported how to irreversibly “tag” any specific type of cell in a mouse embryo, in order to follow its progeny in the adult. This procedure has become ever since the standard approach to study the lineages of cells, from embryo to adult. In the mouse genetics field, the Cre/loxP was initially devised to “inactivate” genes in a cell-type-specific fashion; what he did instead is to selectively “activate” a gene that he called “reporter”, in order to label cells in mouse tissues. The seminal paper of year 2000 was considered as bringing “ground-breaking discoveries” with “elegant experiments” (see, for instance, the essay signed by Douglas Melton “The Molecular Biography of the Cell”, Cell 120, 729-31, 2005).

These studies revealed that all pancreatic cell types emerge from a common endodermal progenitor cell, and that insulin- and glucagon-producing cells represent two separate lineages sharing a common endocrine precursor cell. In his laboratory, they recently reported that all adult pancreatic endocrine cells emerge as fetal hormone-expressing cells (Pérez Francés et al, 2022).

Continuing in the field of pancreas development and cell fate allocation, Pedro Herrera showed the existence of developmental “competence windows” for cell signalling pathways during pancreatic growth (Strom et al, 2007), and demonstrated that pancreatic endocrine precursor cells are multipotent as a population but, at the cellular level, each single precursor cell is strictly unipotent, i.e., it gives rise to only one endocrine cell type (Desgraz & Herrera, 2009). His laboratory also found that pancreatic acinar cells convert into adipocytes during ageing and in certain pathologies (Bonal et al, 2009). This work shed new light on the origin of adipose tissue during ageing, and more broadly, on adult cell plasticity.

In the field of regenerative biology, observations made in Pedro Herrera’s laboratory and reported in three studies published in the journal Nature (2010, 2014 and 2019), and one in Nature Cell Biology (2018), have led to an entirely innovative breakthrough in the approach to develop new cell replacement therapies for diabetes. Indeed, they discovered that the adult pancreas retains the ability to generate new insulin-producing cells after the near total loss of native insulin-producing beta cells, a situation leading to diabetes. This unexpected finding revealed a high degree of cellular plasticity in adult organs: nearly all the reconstituted insulin-producing cells were indeed adult specialised mature islet non-beta cells, namely glucagon-producing alpha-cells (Thorel et al, 2010), somatostatin-producing delta-cells (Chera et al, 2014; Cigliola et al, 2016), and pancreatic polypeptide-producing gamma-cells (Pérez-Francés et al, 2021), which had spontaneously reprogrammed to produce insulin.

They showed that the reprogramming signals driving the “cell conversion” involve the close environment of the cells, namely the pancreatic “islets”, rather than the global systemic or physiological conditions in the body. Insulin itself, emanating from local neighbour beta-cells, blocks this capacity of functional change in the non-beta-cells, independently and autonomously for each individual pancreatic islet (Cigliola et al, 2018).

Biology textbooks teach us that fully differentiated cell types remain fixed in the identity they have acquired upon differentiation. More recently, by inducing non-insulin-producing human islet alpha- and gamma-cells, whether from diabetic or healthy donors, to modify their function to produce insulin in a regulated and sustainable way, the work by Pedro Herrera has revealed that the adaptive capacity of our cells is much greater than previously believed (Furuyama et al, 2019).