Jorge Ferrer

“Matters Arising”: Are new insulin-producing beta cells continuously being generated from duct progenitors in the adult pancreas? This question has huge implications for regenerative medicine

https://authors.elsevier.com/c/1gtA66tu0Cm4kh

https://www.sciencedirect.com/science/article/pii/S1934590923000747?dgcid=author

Thread below

Apr 7, 2023 at 8:57amWeb
Show threadJorge FerrerApr 7, 2023

1/
Gribben et al recently performed lineage tracing with existing pancreatic Cre lines and an efficient reporter allele, concluding that every week a substantial fraction of adult beta cells are formed from duct progenitors

https://www.sciencedirect.com/science/article/pii/S1934590921003404

Show threadJorge FerrerApr 7, 2023
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This idea used to be prevalent in the field, in part because beta cells are often located in ducts (and we now know duct and b cells have a common embryonic origin). But careful lineage tracing experiments from various groups countered that view
Show threadJorge FerrerApr 7, 2023

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For example, several studies marked beta cell DNA in vivo and found no dilution of the mark after many months. Others marked duct cells and observed that the mark was not acquired by new b-cells.

This showed that adult b-cells are formed from pre-existing b-cells

Show threadJorge FerrerApr 7, 2023
4/
A few recent papers, including this one from Pedro Herrera´s lab, used new genetic tools to set this in stone, leaving no room for a meaningful non-beta cell origin of beta-cells during postnatal life
https://pubmed.ncbi.nlm.nih.gov/35172145/
Adult pancreatic islet endocrine cells emerge as fetal hormone-expressing cells - PubMed

The precise developmental dynamics of the pancreatic islet endocrine cell types, and their interrelation, are unknown. Some authors claim the persistence of islet cell differentiation from precursor cells after birth ("neogenesis"). Here, using four conditional cell lineage tracing ("pulse-and-chase …

PubMed
Show threadJorge FerrerApr 7, 2023
5/ So how can all this be reconciled with the G. et al findings?
The main issue is that ngn3 and hnf1b Cre lines used by G. et al are not specific to duct cells or putative progenitors. Both directly mark islet somatostatin+ cells profusely, as well as a lower number of b cells
Show threadJorge FerrerApr 7, 2023
6/ Most somatostatin+ delta cells have thin elongated shapes (http://shorturl.at/otxRW)
G. et al did not simultaneously co-stain SMS, INS, reporter and nuclei. We show that if SMS+ reporter+ cells are surrounded by INS+ cells and only INS is stained, they appear to be INS+ cells
Show threadJorge FerrerApr 7, 2023
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We illustrate how this affects results by segregating G. et al´s image channels and recounting.
There is a response to our “matters arising” with new results and corrections, but no co-localizations to address this central problem... the Cre lines mark somatostatin cells
Show threadJorge FerrerApr 7, 2023

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Our conclusion is that this cannot be considered evidence that adult duct progenitors contribute to new beta cells in these conditions

Of course this is all based on mouse. New technologies, maybe single cell mutational analysis, may enable testing this in human

Show threadJorge FerrerApr 7, 2023
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This time its hard to say “we are excited to share a new publication” because this type of study is not particularly fun. But we felt it was very important for the field. We have respect for the authors though we disagree with that paper
Show threadJorge FerrerApr 7, 2023
Thanks to Yuval Dor (not in twitter, glad to co-lead with him), Judith Magenheim, Miguel A. Maestro, @JanelKopp, @NadavSharon3, Pedro Herrera, @TheMeltonLab, Charlie Murtaugh, Guoqiang Gu, @msanderlab
Show threadCorentin Cras-MéneurApr 7, 2023
@JorgeFerrer It might not be “fun”, but I think it’s an important question and had to be addressed. A lot of people forget that Are lines are not always as lineage-restrictive as they’d like them to be.