Cell Plasticity and Regeneration by Cell Type Interconversion

Thematic panel ©HERRERA/UNIGE

Diabetes Mellitus is characterised by the dysfunction or loss of insulin-producing beta-cells, yet current therapies do not address the underlying failure of beta-cell mass. Efforts to replace or regenerate these cells are central to developing durable treatments, particularly for Type 1 Diabetes, where autoimmune destruction leads to near-complete beta-cell loss.

Prof. Pedro Herrera’s research group investigates how the adult pancreas responds to such extreme beta-cell depletion. In a series of landmark studies published in the journals Nature (2010, 2014 and 2019), Nature Cell Biology (2018) and Nature Communications (2021), the laboratory has discovered that, after near-total-beta-cell loss, the adult pancreas can spontaneously regenerate insulin-producing cells in mice.

This regeneration occurs through a surprising mechanism: functional interconversion. After near-total beta-cell loss, other mature endocrine cells in the pancreatic islet (non-beta cells, i.e. alpha-, delta- and gamma-cells) reprogram themselves to produce insulin. This phenomenon of functional interconversion had never been documented in mammals before. Importantly, the laboratory has also demonstrated that this process is not restricted to animal models: similar plasticity has been observed in human pancreatic islets. These findings not only challenge the long-standing belief that differentiated cells are irreversibly fixed in identity but also offer a promising basis for developing innovative therapies for diabetes and other degenerative diseases.

RESEARCH AIMS

The Herrera laboratory aims to decipher the mechanisms that allow mature pancreatic cells to convert into insulin-producing cells. Their work focuses on understanding how insulin production can be acquired by neighbouring islet cells following beta-cell loss.  By combining advanced genetic mouse models with human pancreatic islets from deceased donors, the group investigates the molecular and cellular pathways that drive the complex process of functional interconversion. The transgenic mice are genetically engineered to allow for the selective ablation or tagging of specific cell types, enabling precise analysis of cellular regeneration and plasticity across different ages and conditions.

Key objectives include:

• Identifying the gene regulatory networks that enable or restrict cellular plasticity in alpha-, delta-, and gamma-cells.
• Characterising the signalling environments that trigger or modulate cell-type interconversion.
• Exploring how age, disease state, or different cues influence regenerative potential.

Ultimately, the lab seeks to translate these insights into new regenerative strategies that reactivate the body’s own ability to replenish insulin-producing cells, laying the foundation for innovative therapies for diabetes.

Graphical Abstract ©HERRERA/UNIGE

CORE EXPERTISE

The Herrera lab bridges multiple fields – developmental and cell biology, regenerative medicine, diabetes research, cellular reprogramming and transgenesis – to dissect how cell identity and plasticity are regulated in the pancreas.

The cell lineages of the islets of Langerhans are studied in mice bearing several transgenes simultaneously. Using the Cre / loxP system, we tag endocrine progenitor cells in vivo, either in embryos or adults. We can irreversibly mark precursor or hormone-producing cells through site-specific recombination mediated by Cre recombinase. Reporter gene expression is therefore dependent upon Cre activity in particular cell types.

Cell fate decisions in early pancreatic primordia are taken through cell-autonomous and cell-nonautonomous signals. We analyse the role of different effectors of signalling pathways in different conditional transgenic mice.

The regeneration potential of adult pancreata is studied by applying targeted cell ablation strategies to selectively eliminate defined pancreatic cell types in adult mice. These controlled injury models allow the study of beta-cell regeneration dynamics and were pivotal in demonstrating functional interconversion of non-beta endocrine cells into insulin-producing cells.

Complementing their in vivo work, the lab has developed a platform to isolate and purify human islet cell types, particularly alpha-cells, from islet donors. When combined with techniques such as ectopic gene expression via viral vectors, pharmacological manipulation, and gene knockdown, this approach enables the study of cell plasticity and reprogramming in primary human cells, adding critical translational value to their discoveries.

SELECTED PUBLICATIONS

• PEREZ FRANCES, Marta et al. Pancreatic Ppy-expressing γ-cells display mixed phenotypic traits and the adaptive plasticity to engage insulin production. In: Nature Communications, 2021, vol. 12, n° 1, p. 4458. doi: 10.1038/s41467-021-24788-0
• FURUYAMA, Kenichiro et al. Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells. In: Nature, 2019, vol. 567, n° 7746, p. 43–48. doi: 10.1038/s41586-019-0942-8
• CIGLIOLA, Valentina et al. Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon+ α-cells. In: Nature Cell Biology, 2018, vol. 20, n° 11, p. 1267–1277. doi: 10.1038/s41556-018-0216-y
• CHERA, Simona et al. Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers. In: Nature, 2014, vol. 514, n° 7523, p. 503–507. doi: 10.1038/nature13633
• THOREL, Fabrizio et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. In: Nature, 2010, vol. 464, n° 7292, p. 1149–1154. doi: 10.1038/nature08894

Research