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PL Herrera Biography


Dr. PL Herrera works at University of Geneva Medical School (Switzerland), where he is now a full professor in the department of genetic medicine and development, the president of the university’s Animal Ethics Committee, and the director of the university’s Transgenic Core Facility.

Dr. Herrera completed his bachelor’s and master’s degrees in biology at Complutense University, in Madrid, and his doctorate degree from University of Geneva, in January 1994, under the guidance of Dr. Jean-Dominique Vassalli. In 1996, he became an independent investigator at the Faculty of Medicine of Geneva after obtaining his first regular research grant award from JDRF. Dr. Herrera has been recognized as a leader in diabetes and pancreatic research, and has been a recipient of several honors and awards, including the Denber-Pinard Prize for his graduate work on developing a genetic system to study the origins of beta cells, and more recently the Gerold & Kayla Grodsky Award for his regeneration studies. He is member of several international scientific committees and the Beta Cell Biology Consortium, which was established by the National Institutes of Health to facilitate the understanding of pancreatic islet development and function.


1994 –> Faculty of Medicine, University of Geneva: Denber-Pinard Prize

2003 & 2008 –> JDRF: Mary Jane Kugel Award

2011 –> Gerold & Kayla Grodsky Basic Research Scientist Award

Pedro investigates pancreas development, cell lineage allocation during pancreatic ontogeny, and adult pancreas regeneration using different transgenic mouse models, most of them developed in his own laboratory.

He pioneered the study of mouse pancreas development and carried out the first in vivo ablation of different pancreatic endocrine cell types during his thesis (Herrera et al, 1991; Herrera et al, 1994). Later, he performed the first in vivo cell lineage tracing analysis using the Cre/loxP system(Herrera, 2000).

Subsequently, he described the existence of competence windows for beta-catenin signaling in exocrine cells during pancreatic growth (Strom et al., 2007), and has found that adult acinar cells transdifferentiate to adipocytes during the process of ageing and in certain pathological conditions(Bonal et al., 2009); this seeds new light on the origin of adipose tissue during degeneration associated with ageing, and on adult cell plasticity.

More recently, he showed that pancreatic Neurogenin3-expressing cells, which during embryonic development are the precursors to all islet endocrine cell types as a population, are not multipotent progenitors in vivo, as believed, but on the contrary these cells are strictly unipotent at the single cell level (Desgraz & Herrera, 2009).

In the field of regenerative biology, he has found that the adult pancreas retains the ability of making new β-cells after their total loss (interestingly, total or near-total β-cell loss is the condition of patients with Type 1 diabetes mellitus). β-cell regeneration in adult mice involves a high degree of cell plasticity, since most of the regenerated insulin-producing cells, in this situation of extreme β-cell damage, are indeed adult α-cells that have spontaneously reprogrammed to producing insulin and other β-cell-specific factors (Thorel et al, 2010).

Establishment of cell fate allocation during pancreatic embryonic differentiation and postnatally, as well as maintenance and reprogramming of cell destiny in adult pancreas thus represent the main research areas in his laboratory.

Scientific Achievements – Pedro L. Herrera

Our laboratory has been working for many years in the field of pancreas ontogeny. This has allowed us to contribute to the elucidation of islet cell development, through the application of highly innovative and powerful genetic approaches to study the cell lineages of the endocrine pancreas.

My Ph.D. work focused on two different aspects of the biology of the islets of Langerhans: the pathogeny of Type 1 Diabetes, and the development of the endocrine pancreas. This second area of research was further pursued during my subsequent scientific career. During my thesis, we performed the first systematic analysis of the timing of expression of the islet hormone genes, and of the appearance of the corresponding endocrine cell types, during murine embryogenesis (1). This was one of the first studies to use RT-PCR to determine patterns of gene expression. We showed that pancreatic polypeptide (PP) mRNA is present in very early pancreatic buds, and that PP-family peptides co-localize during development with the other pancreatic hormones. This suggested a role, until then unsuspected, for PP-expressing cells in islet ontogeny.

We also provided evidence for a role of diffusible factors in pancreas morphogenesis. We observed that TGFβ1 inhibits the development of acinar tissue without decreasing the amount of endocrine cells (2). We also observed this phenomenon in vivo, in transgenic mice over-expressing TGFβ1 specifically in islets (3). Later studies made by others confirmed that TGFβ family members produced by the notochord modulate pancreas differentiation during development.

We approached the first in vivo analysis of the insulin-producing β-cell lineage through the selective ablation of specific islet cell types in transgenic mice. We used the diphtheria toxin A subunit coding region (DTA) under the control of insulin, glucagon or PP promoters, in order to eliminate insulin-, glucagon- or PP-expressing cells, respectively (4). Whether glucagon-expressing α-cells are the progenitors to β-cells had been until then a long-standing debate, but largely accepted. Contrary to the common view, we demonstrated that α-cells are not precursors of adult β-cells. We also showed that PP gene expression could be a hallmark of the β-cell differentiation pathway, since ablation of PP-expressing cells also resulted in β- and somatostatin-producing δ-cells destruction.

After obtaining the Ph.D. degree, we pursued these cell lineage analyses using a novel, more subtle and sophisticated approach, i.e. the labeling of progenitor cells through the expression of Cre recombinase in doubly transgenic mice (5). We performed the first lineage-tracing analysis during development in vivo using the Cre/loxP system. This method allows for discriminating between paracrine (horizontal) relationship and ontogenetic (cell lineage, vertical) connection. Indeed, cell lineages can be studied only by irreversibly (i.e. genetically) labeling cells and, therefore, their descendants. With this new tool at hand, we have been able to establish so far that:

1) Adult glucagon- and insulin-producing cells derive from embryonic precursors that have never transcribed insulin or glucagon, respectively; in other words: β-cells do not derive from glucagon-expressing precursors during embryonic development, as was believed at the time.

2) β-cell progenitors, but not α-cell progenitors, transcribe the PP gene.

3) Although adult α-cells do not express Pdx1 (pancreatic-duodenal homeobox-1), they derive from Pdx1+ progenitors, as do all other pancreatic cell types.

4) All islet endocrine cell types derive from progenitors expressing Ngn3 (neurogenin3) (6). Together, these studies were the first to clearly demonstrate that glucagon and insulin cell lineages arise independently during ontogeny, from a common precursor expressing successively Pdx1 and Ngn3.

5) Expression of the neural stem cell marker Nestin is not a feature of islet endocrine progenitors, contrary to what was proposed (7).

6) Increased β-catenin signaling in the developing pancreas leads to pancreatomegaly; this is strictly mediated by increased c-Myc expression in exocrine cells only, and is not tumorigenic per se, contrary to what happens in organs such as the liver or intestine (8).

7) Loss of c-Myc activity in pancreatic progenitor cells leads to a progressive transdifferentiation of adult acinar cells into adipocytes (9).

8) Using an innovative approach to perform in vivo clonal analyses in mice (Ngn3-Cre; MADM mice), we studied the differentiation potential of the common islet endocrine precursor cells (Ngn3+). As a population, Ngn3+ cells are multipotent. With the in vivo clonal analysis we showed that, at the single cell level, Ngn3+ cells are not multipotent progenitors, but instead represent a heterogeneous population of committed unipotent precursors (10).

9) The adult pancreas can reconstitute enough new β-cells to recover from diabetes after a total β-cell loss (RIP-DTR mice). This has revealed an unexpected degree is islet cell plasticity: most regenerated insulin-producing cells are indeed reprogrammed α-cells (11,12).

During the past years we have generated a number of costly and valuable research tools (reporter transgenic strains, tracer strains, targeted islet cell ablation models…), and we are now using them to tackle the problem of β-cell formation in the adult pancreas. Our experiments could ultimately contribute to develop novel therapeutic strategies to treat diabetes.


1 Herrera, P. L. et al. Embryogenesis of the murine endocrine pancreas; early expression of pancreatic polypeptide gene. Development 113, 1257-1265 (1991).

2 Sanvito, F. et al. TGF-beta 1 influences the relative development of the exocrine and endocrine pancreas in vitro. Development 120, 3451-3462 (1994).

3 Sanvito, F. et al. TGF-beta 1 overexpression in murine pancreas induces chronic pancreatitis and, together with TNF-alpha, triggers insulin-dependent diabetes. Biochemical and biophysical research communications 217, 1279-1286 (1995).

4 Herrera, P. L. et al. Ablation of islet endocrine cells by targeted expression of hormone-promoter-driven toxigenes. Proceedings of the National Academy of Sciences of the United States of America 91, 12999-13003 (1994).

5 Herrera, P. L. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 127, 2317-2322 (2000).

6 Herrera, P. L., Nepote, V. & Delacour, A. Pancreatic cell lineage analyses in mice. Endocrine 19, 267-278 (2002).

7 Delacour, A., Nepote, V., Trumpp, A. & Herrera, P. L. Nestin expression in pancreatic exocrine cell lineages. Mechanisms of development 121, 3-14 (2004).

8 Strom, A. et al. Unique mechanisms of growth regulation and tumor suppression upon Apc inactivation in the pancreas. Development 134, 2719-2725 (2007).

9 Bonal, C. et al. Pancreatic inactivation of c-Myc decreases acinar mass and transdifferentiates acinar cells into adipocytes in mice. Gastroenterology 136, 309-319 e309, doi:10.1053/j.gastro.2008.10.015 (2009).

10 Desgraz, R. & Herrera, P. L. Pancreatic neurogenin 3-expressing cells are unipotent islet precursors. Development 136, 3567-3574, doi:10.1242/dev.039214 (2009).

11 Thorel, F. et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464, 1149-1154, doi:10.1038/nature08894 (2010).

12 Thorel, F. et al. Normal glucagon signaling and beta-cell function after near-total alpha-cell ablation in adult mice. Diabetes 60, 2872-2882, doi:10.2337/db11-0876 (2011).


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