Paraish S. Misra, MD PhD

Excited to share our new paper in Nat Comms on how human stem cell-derived pancreatic progenitors choose between islet and enterochromaffin (EC)-like fates - and how we can steer that choice! A story in a few tweets… Full paper 👉 doi.org/10.1038/s414...

14/14 This project was a long, shared labour of love. Huge gratitude to the brilliant team who carried it forward, and to our friends in the Pavlinkova lab, whose elegant in vivo ISL1-CKO experiments were key to revealing the pancreatic EC story.

Excited to share our new paper in Nat Comms on how human stem cell-derived pancreatic progenitors choose between islet and enterochromaffin (EC)-like fates - and how we can steer that choice! A story in a few tweets… Full paper 👉 doi.org/10.1038/s414...

12/14 To probe mechanism, we compared endocrine specification under beta vs EC patterning. Most markers behaved similarly, but NGN3 stood out: it was transient with beta and persisted with EC patterning. ISL1-KO murine pancreatic EC-like cells also showed sustained Neurog3 expression.

Excited to share our new paper in Nat Comms on how human stem cell-derived pancreatic progenitors choose between islet and enterochromaffin (EC)-like fates - and how we can steer that choice! A story in a few tweets… Full paper 👉 doi.org/10.1038/s414...

10/14 We then re-explored the importance of early progenitor patterning. We generated PDX1+ progenitors with different NKX6-1 expression levels (low, medium, or high NKX6-1), and exposed each to endocrine patterning protocols we designed to favour beta-, alpha-, or EC-like cells.

Excited to share our new paper in Nat Comms on how human stem cell-derived pancreatic progenitors choose between islet and enterochromaffin (EC)-like fates - and how we can steer that choice! A story in a few tweets… Full paper 👉 doi.org/10.1038/s414...

8/14 In the gut, EC fate is blocked by ISL1. We thus studied a mouse where ISL1 is deleted after pancreatic specification occurs. These islets also developed abundant EC-like cells, revealing that pancreatic progenitors have latent EC-forming potential even in vivo.

Excited to share our new paper in Nat Comms on how human stem cell-derived pancreatic progenitors choose between islet and enterochromaffin (EC)-like fates - and how we can steer that choice! A story in a few tweets… Full paper 👉 doi.org/10.1038/s414...

6/14 Next, we thought that “better” pancreatic progenitors would suppress off-target fates. Refining early endoderm patterning gave us >90% PDX1+NKX6 1+ progenitors by day 13 - a seemingly pancreas-committed population.

Excited to share our new paper in Nat Comms on how human stem cell-derived pancreatic progenitors choose between islet and enterochromaffin (EC)-like fates - and how we can steer that choice! A story in a few tweets… Full paper 👉 doi.org/10.1038/s414...

4/14 We first improved the earliest step: helping pluripotent stem cells cleanly exit pluripotency and become definitive endoderm. To counteract high-density effects, we used a short Latrunculin A (LatA) pulse, which made primitive streak and endoderm formation more uniform.

Excited to share our new paper in Nat Comms on how human stem cell-derived pancreatic progenitors choose between islet and enterochromaffin (EC)-like fates - and how we can steer that choice! A story in a few tweets… Full paper 👉 doi.org/10.1038/s414...

2/14 For diabetes therapy, we want stem cell-derived islets packed with functional beta cells and predictable numbers of other endocrine cells, without off-target lineages. Yet many hPSC-islet protocols generate abundant EC-like cells for unclear reasons.