Menin and alpha-cell plasticity: identification of cellular and molecular bases of a-cell transdifferentiation into insulin-expressing cells triggered by Men1 inactivation – ABC-Trans

The proposed scientific program is designed to characterise in detail the conversion of transdifferentiating cells into insulin-secreting cells. It is carried out through three steps with the use of different methods : (1) Detailed analyses of the transdifferentiation procedure; (2) Determination of the endocrine nature of transdifferentiated cells ; (3) Identification of factors essential for the transdifferentiation, with the use of global and candidate-gene approaches.

Precise evaluation of the progress of alpha cell transdifferentiation ; Generation and characterisation of a novel murine model where alpha cells are marked by YFP ; Enrichment of transdifferentiating and transdifferentiated cells with success ; Detection within transdifferentiating cells the expression of beta cell factors; Advancement in establishing un novel cellular model of alpha cell transdifferentiation.

1) Conception of novel strategies of cell therapy for treating diabetes: it would be possible to induce the transdifferentiation of alpha-cells into beta-cells, permitting thus the generation of new cells secreting insulin. 2) Knowledge of the mechanisms controlling the populations of islet-cells: allowing to better understanding the biology of these cells and the interaction among different populations, crucial for the control of their cell proliferation and regeneration.

Zeinab Hamze, et al., Menin activates MafA transcription factor expression in islet ß-cells. Soumis au
journal Diabetes.
Remy BONNAVION et al., MAFA is expressed in a large subset of normal adult human pancreatic alpha-cells. En préparation avancée.
These two works, entirely integrated in the frame of the current research program, were aimed at identifying candidate genes involved in the control of alpha and beta cell plasticity. They are, therefore, of great help for the realisation of the program.

Recent breakthroughs in regenerative medicine have demonstrated that some adult cells that had previously been considered to be terminally differentiated may still maintain their potential to transdifferentiate into other types of differentiated cell. Interestingly, the work recently carried out in our group strongly suggests that cell transdifferentiation may also play an important but hitherto unknown role in tumorigenesis. Moreover, the work also indicates that the predisposition gene to Multiple Endocrine Neoplasia type 1, MEN1, known as a tumor suppressor of endocrine cells, is an important factor controlling the plasticity of the pancreatic a-cells. In fact, by the generation and characterization of a-cell-specific Men1 knockout mice, we found that the phenotype observed in the mutant mice reflects one of the most important features of islet-tumors described in humans, the multi-hormonality. The data obtained from our analyses indicate that MEN1 ablation specifically in a-cells led primarily to increased a-cell proliferation. By unknown mechanisms, these cells then transdifferentiated into cells secreting insulin.

This mouse model will, therefore, allow a better understanding of the biology of a-cells and the control of their proliferation and plasticity. More importantly, our unexpected findings may open the way to convert a-cells into ß-cells by modulating Men1 expression and that of its downstream targets. Further studying the control of a-cell plasticity by the MEN1 gene and the mechanisms involved will be of vital interest for developing novel strategies for treatment of metabolic diseases affecting islet-cells, such as diabetes.

The mechanisms involved in the a-cell transdifferentiation triggered by Men1 inactivation are so far totally unknown. The current research program we propose will focus on the identification of the cellular and molecular bases of the transdifferentiation related to MEN1 inactivation, by conducting a thorough characterization and analyses of our a-cell-specific Men1 mutant mouse model. The entire procedure of this newly uncovered transdifferentiation of a-cells into insulin-secreting cells will be detailed. The endocrine capacity of transdifferentiated insulin-secreting cells will be evaluated. The cellular and molecular mechanisms involved in the occurrence of the procedure will be fully studied in order to find the factors responsible for or participating in the a-cell transdifferentiation.

We have been working in the field of MEN1 since more than 12 years. Using the establishment and characterisation of mutant mouse models right from the beginning of gene functional study, our expertise in analysing mouse endocrine tumours has recently been extended to the endocrine developmental field. We believe that, based on the exploration of our mouse models and with our expertise, we will be able to advance substantially the proposal and achieve the goal.

The realisation of the proposal will be supported by our local and national collaborations. Dr. Jean-Yves SCOZEC‘s and Dr. Martine CORDIER-BUSSAT’s research groups (designated as Partner 2 and 3) have relevant expertise respectively in characterising lesions in the digestive tubes and in studying pancreatic endocrine factors using the pancreatic endocrine cellular models where MEN1 expression can be modulated. Dr. Jorg TOST (partner 4) is a specialist in high through-put gene expression and methylome study. These collaborations should be of great help for the current proposal.

We believe that the research program proposed here is a prerequisite to better understand the impact of this cell procedure both in the tumorigenesis of islet-cells and in ß-cell generation. Its realisation should help us to gain relevant clues for the clinical applications of the transdifferentiation, especially for the conception of new strategies for treating diabetes with cell-replacement therapy.