🥳 I am happy to share our latest manuscript published in @natcellbio.nature.com We use #Gastruloids to study #CellCompetition during early mammalian development and find not only that this is highly pronounced in our system but also tightly restricted in time. (1/12) www.nature.com/articles/s41...
Insights from derivation of human IPS #stemcell derived islet-like or off-target enterochromaffin (EC)-like cells in the pancreas #diabetes www.nature.com/articles/s41...
Grateful for funding from #CIHR-IRSC #UHNfoundation #HowardWebsterFoundation #BreakthroughT1D #KFoC #KRESCENT #UofT_DOM #CSTP #CST_transplant @cirtn.bsky.social @bbdc-uoft.bsky.social @czechacademy.bsky.social #CzechScienceFoundation
This work wouldn’t be possible without their support.
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.
13/14 Overall, we find that 1) EC-like cells can arise from well specified pancreatic progenitors, and 2) Tuning progenitor state plus endocrine patterning can be used to build “designer” hPSC-islets with defined endocrine mixes. There’s more in the paper, and much more yet to be discovered…
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.
11/14 High-NKX6-1 progenitors did what we expected: under beta patterning they formed beta enriched islet like clusters. Low-NKX6-1 progenitors made more alpha- and EC-like cells under those respective conditions. Surprisingly, with beta patterning, they generated the most delta-like cells.
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.
9/14 Back in our stem cell–derived islets, we dissected endocrine‑stage media. MEK and BMP inhibitors strongly biased endocrine progenitors toward EC‑like cells, especially together. In contrast, FGF2, Betacellulin, or BMP4 reduced EC‑like cells and boosted islet markers.
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.
7/14 But when we differentiated these progenitors into endocrine cells, EC-like cells still emerged at high frequency. Improving pancreatic identity alone was not enough to block the EC fate.
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.
5/14 This boosted downstream pancreatic progenitors and beta-like cells. Similar findings were recently reported by the Millman lab, showing that LatA can also improve endoderm and reduce EC-like cells in hPSC-islet differentiation.
Preprint 👉 doi.org/10.1101/2024...
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.
3/14 These cells express SLC18A1, a marker normally found in EC cells of the gut, not in islet cells. First highlighted in hPSC-islets by Douglas Melton’s group, they may alter graft behavior and add uncertainty for therapies.
Original report 👉 doi.org/10.1038/s415...
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.
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...
Hot off the press! This paper provides protocols for directed differentiation of hPSCs to different pancreatic islet-like endocrine cells as well as to enterochromaffin cells. Congratulations to the whole team! www.nature.com/articles/s41...
(🧵10/18) Works from Feb+March 2026🍀.
From Dr. M. Cristina Nostro:
“Efficient control of enterochromaffin versus islet differentiation from human pluripotent stem cell-derived pancreatic progenitors”
PMID 41851084
www.nature.com/articles/s41...
So excited to hear about Hypoimmune islet transplants from Sonja Schrepfer from Sana Biotechnology - without immunosuppression
Is this the future for cell therapy in diabetes?
@albertadiabetes.bsky.social celebrating the 25th anniversary of the Edmonton Protocol #25EP
Some chapters are harder to get out that others. This was like birthing an elephant. But it's great.
Channel your enthusiasm:
Chapter 19 part 1, Metabolic Acidosis
www.rosebook.club/episodes/202...
Pretty exciting! I wonder how long the effect will last…
Article In Press! Can gene therapy help prevent rejection? AAV-mediated PD-L1 delivery during cold storage was
associated with reduced acute rejection in a rat lung transplant model. www.amjtransplant.org/article/S160...
Well done! Congrats from the east 😎
🧬 Excited to share our latest study now In Press: In this study led by rising star @sarahcolpitts.bsky.social, we show that IL-10⁺ #ILC2s prevent rejection and improve islet graft survival and function in humanized mouse models. Read more: doi.org/10.1016/j.aj... #Immunology #ImmunoSky #CellTherapy
Interesting anecdote when a patient shows up with a ChatGPT differential diagnoses list 😏
www.ajkd.org/article/S027...
@ajkd.bsky.social
A greater understanding of hypoxia’s impact on stem cell-derived #islets offering a potential intervention for clinical applications #T1D @natcomms.nature.com www.nature.com/articles/s41...
ATC Research and Education Conference asset featuring keynote speakers June 5 and June 6, 2025.
📢 Register now! Annual Transplant Research and Education Conference
📅Thurs June 5, 2025 - Fri June 6, 2025
📍Toronto (Virtual option available)
More details and to register: bit.ly/ATCEduResDay
@uhn.ca @uhnresearch.ca @uoftmedicine.bsky.social
#education #transplant #research
Excited to enroll our first participant for testing an agent (tolimidone) we hope will promote beta cell regeneration, building on preclinical work from Dr Jean Buteau at @albertadiabetes.bsky.social. Supported by Alberta Diabetes Foundation & biodexa pharmaceuticals www.ualberta.ca/en/folio/202...