We are fascinated by the inherent plasticity of seemingly differentiated pancreatic cells and the molecular cues behind cell fate changes. Our previous work uncovered a latent capacity for regeneration in the pancreas, which could be harnessed to replace crucial insulin-producing cells lost to disease. Our main goal in the Sancho lab is to decipher the fundamental regulatory networks involved in pancreatic cell fate decisions using adult and iPSCs derived organoids, and to apply this knowledge to new strategies in regenerative medicine for diabetes.
Previous Lab Members
- Ana Maria Cujba: PhD student at the Sancho Lab from 2017-2021. Currently doing a PostDoc in Sarah Teichmann Lab at the Sanger Institute (Cambridge).
- Alexandra Goncalves: Research Assistant at the Sancho Lab from 2017-2019. Currently doing a A*Star PhD (University of Manchester / Skin Research Institute of Singapore)
People
PhD Student
PhD Student
PhD Student
PhD Student
Postdoctoral Research Associate
Group Leader / Reader
Projects
Novel molecular mechanisms regulating cell fate decisions of iPSC and adult derived pancreatic progenitors
Diabetes mellitus is a metabolic disorder characterised by hyperglycaemia following a loss of insulin-producing beta cells in the pancreas. Unfortunately, the pancreas is a low turnover organ with limited regenerative capacity. Therefore, we focus upon identifying the molecular mechanisms by which other pancreatic cell types can be converted into beta-like cells in order to restore glycaemic control. To address this question, we combine 3D cell culture, scRNAseq technologies and computational modelling in order to understand the molecular regulation of cell fate changes. These results will elucidate the fundamental biology of iPSC and adult progenitors plasticity and provide clues for how to unlock the regenerative capacity of pancreas progenitors for future therapies for diabetes.
Post-translational regulation of pancreas proendocrine factors
In the pancreas, proendocrine factors (NGN3, PDX1) expression is necessary to allow the activation of genes that further determine an endocrine fate from a progenitor state giving rise, among other types, to insulin producing cells. While its role is well established, little is known about the post-translational regulation of the proendocrine factors. Previous studies have shown that post translational modifications targeting NGN3/PDX1 for degradation have an important role in determining how these factors can affect endocrine cell production. We are exploring novel mechanisms identified for NGN3 and PDX1 degradation. Understanding and harnessing this machinery can represent a potential tool to improve beta cells production in vitro.
Modelling diabetes using induced pluripotent stem cells (iPSCs
In order to understand the molecular mechanism behind some specific types of monogenic diabetes (MODY) we use patient derived iPSCs to model beta cell differentiation in vitro. By using this approach, we have uncovered new roles of HNF1a mutations in MODY3. We used human induced pluripotent stem cells (iPSCs) derived from patients with MODY3 banked through the Human Induced Pluripotent Stem Cells Initiative (HiPSCi) and CRISPR/Cas9 technology to engineer HNF1α iPSC mutant lines and differentiated towards pancreatic fate in-vitro. In addition, we developed and characterized a novel expandable 3D-organoid system for iPSCs derived the pancreas progenitors, useful for studying MODY3 in-vitro. We conducted RNAseq and exome sequencing analysis to understand the mechanism through which the HNF1α mutation causes MODY3. Using these technologies, we discovered a novel function of HNF1a that could be responsible for the phenotype observed in MODY3 patients.
Publications
Awards
- Medical Research Council UKRMP2/JDRF (MR/T015470/1) - PEG-based hydrogels for iPSCs-derived regenerative therapies for diabetes. (2020-2023)
- Medical Research Council – New Investigator Research Grant (MR/S000011/1). Regulation of pancreas organoid plasticity: new strategies for diabetes. (2019-2022)
- King’s Together Seed Fund - Metal Fingerprints in Normal Cell States & Disease. (2019-2020)
- Wellcome Trust. Seed Award. Uncovering the molecular and cellular heterogeneity of pancreatic ductal cells. (2017-2019)
- NIHR-BRC, Cluster 1 contingency fund call. Modelling diabetes using induced Pluripotent Stem Cells (iPSCs). (2017-2018)
Activities
Engagement
Fully aware of the importance of dissemination of research and promotion of KCL and KHP outside the academic environment we have organized/participated numerous public engagement activities with charities (Diabetes UK and JDRF), patients (JP Morgan diabetes group, Cancer Survivors day -Guys), art studios (CSCRM-Art event), Students outside KCL (TU Dresden, Kent). Since January 2020 we are actively using social media (Twitter) to share our achievements and thoughts in the Sancho Lab (@Labsancho) with a wider community.
Sancho Lab - Our Research
Sancho Lab - Our Research
In the Sancho Lab, we are fascinated by the fundamentals of how the cells in the pancreas become what they are and how we can harness this information to direct their fate to cell types we want
People
PhD Student
PhD Student
PhD Student
PhD Student
Postdoctoral Research Associate
Group Leader / Reader
Projects
Novel molecular mechanisms regulating cell fate decisions of iPSC and adult derived pancreatic progenitors
Diabetes mellitus is a metabolic disorder characterised by hyperglycaemia following a loss of insulin-producing beta cells in the pancreas. Unfortunately, the pancreas is a low turnover organ with limited regenerative capacity. Therefore, we focus upon identifying the molecular mechanisms by which other pancreatic cell types can be converted into beta-like cells in order to restore glycaemic control. To address this question, we combine 3D cell culture, scRNAseq technologies and computational modelling in order to understand the molecular regulation of cell fate changes. These results will elucidate the fundamental biology of iPSC and adult progenitors plasticity and provide clues for how to unlock the regenerative capacity of pancreas progenitors for future therapies for diabetes.
Post-translational regulation of pancreas proendocrine factors
In the pancreas, proendocrine factors (NGN3, PDX1) expression is necessary to allow the activation of genes that further determine an endocrine fate from a progenitor state giving rise, among other types, to insulin producing cells. While its role is well established, little is known about the post-translational regulation of the proendocrine factors. Previous studies have shown that post translational modifications targeting NGN3/PDX1 for degradation have an important role in determining how these factors can affect endocrine cell production. We are exploring novel mechanisms identified for NGN3 and PDX1 degradation. Understanding and harnessing this machinery can represent a potential tool to improve beta cells production in vitro.
Modelling diabetes using induced pluripotent stem cells (iPSCs
In order to understand the molecular mechanism behind some specific types of monogenic diabetes (MODY) we use patient derived iPSCs to model beta cell differentiation in vitro. By using this approach, we have uncovered new roles of HNF1a mutations in MODY3. We used human induced pluripotent stem cells (iPSCs) derived from patients with MODY3 banked through the Human Induced Pluripotent Stem Cells Initiative (HiPSCi) and CRISPR/Cas9 technology to engineer HNF1α iPSC mutant lines and differentiated towards pancreatic fate in-vitro. In addition, we developed and characterized a novel expandable 3D-organoid system for iPSCs derived the pancreas progenitors, useful for studying MODY3 in-vitro. We conducted RNAseq and exome sequencing analysis to understand the mechanism through which the HNF1α mutation causes MODY3. Using these technologies, we discovered a novel function of HNF1a that could be responsible for the phenotype observed in MODY3 patients.
Publications
Awards
- Medical Research Council UKRMP2/JDRF (MR/T015470/1) - PEG-based hydrogels for iPSCs-derived regenerative therapies for diabetes. (2020-2023)
- Medical Research Council – New Investigator Research Grant (MR/S000011/1). Regulation of pancreas organoid plasticity: new strategies for diabetes. (2019-2022)
- King’s Together Seed Fund - Metal Fingerprints in Normal Cell States & Disease. (2019-2020)
- Wellcome Trust. Seed Award. Uncovering the molecular and cellular heterogeneity of pancreatic ductal cells. (2017-2019)
- NIHR-BRC, Cluster 1 contingency fund call. Modelling diabetes using induced Pluripotent Stem Cells (iPSCs). (2017-2018)
Activities
Engagement
Fully aware of the importance of dissemination of research and promotion of KCL and KHP outside the academic environment we have organized/participated numerous public engagement activities with charities (Diabetes UK and JDRF), patients (JP Morgan diabetes group, Cancer Survivors day -Guys), art studios (CSCRM-Art event), Students outside KCL (TU Dresden, Kent). Since January 2020 we are actively using social media (Twitter) to share our achievements and thoughts in the Sancho Lab (@Labsancho) with a wider community.
Sancho Lab - Our Research
Sancho Lab - Our Research
In the Sancho Lab, we are fascinated by the fundamentals of how the cells in the pancreas become what they are and how we can harness this information to direct their fate to cell types we want
Group lead
Group Leader / Reader