Ibec Seminar. Santiago A. Rodríguez-Seguí
Epigenomic Control of Pancreatic β-Cell Development and Fate: Toward Engineering a Vascularized Organoid-on-Chip Platform
Santiago A. Rodríguez-Seguí1,2
1 Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-UBA-CONICET), Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina.
2 Departamento de Fisiología, Biología Molecular y Celular, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria, Buenos Aires, Argentina.
The human genome encodes the instructions for the vast cellular differentiation required for embryonic development and adult homeostasis. Some developmental programs are reactivated during regeneration upon tissue damage. Decoding this regulatory logic demands integrated approaches: the development of suitable human tissue models, genomic characterization of transcriptional and epigenetic programs, and experimental validation. State-of-the-art bioengineering technologies — including microfluidic and biomaterial platforms that recapitulate tissue microenvironments — are enabling insights into human biology that would otherwise be difficult to achieve.
Diabetes is associated with malfunction of pancreatic β-cells. Our work, based on pioneering ChIP-seq and scRNA-seq studies in human and mouse pancreatic samples — adult islets, embryonic pancreas, and iPSC-derived progenitors — has identified regulatory mechanisms controlling β-cell development and fate. We mapped the enhancer landscape of human islets, uncovered enhancer mutations causing pancreatic agenesis, and demonstrated that TEAD and YAP regulate key enhancers during pancreatic development. More recently, we showed that glucocorticoid receptor activation modulates early differentiation in pancreatic progenitors, and that HNF1B mutations disrupt this process in iPSC-derived models. From the regenerative angle, we reported that the peptide INGAP-PP signals to multiple islet cell types, including β-cells and endothelial cells, suggesting that its effects depend on multicellular crosstalk poorly captured by conventional culture.
Building on this foundation, we are now developing a vascularized pancreatic endocrine organoid-on-chip platform that recapitulates the β-cell vascular niche. This platform, developed in collaboration with the University of Barcelona and IBEC, integrates human β-cells, endothelial cells, and stromal cells in a perfusable microfluidic device. It will enable epigenomic dissection of how vascular niche signals modulate the enhancer landscape underlying β-cell fate in a controlled human microenvironment. Our long-term vision is to translate this mechanistic understanding into precision medicine approaches for diabetes.
Santiago Rodríguez Seguí is a Principal Investigator at the Institute for Physiology, Molecular Biology, and Neurosciences (IFIBYNE), affiliated with the National Scientific and Technical Research Council of Argentina (CONICET) and the University of Buenos Aires. He holds a degree in Bioengineering from the University of Entre Ríos, Argentina, and a PhD in Biomedicine from the University of Barcelona, Spain.
His research focuses on pancreatic beta cell development and regeneration. He has authored more than 20 publications, with significant contributions to the field published in high-impact journals such as Nature Genetics, Nature Cell Biology, and Development. His work has been recognized with awards from the National Academy of Medicine of Argentina and the Honorable Senate of the Argentine Nation.
