KatajistoLab

@natmetabolism.nature.com

Also read the research briefing on our latest paper in @natmetabolism.nature.com

New Type of Intestinal Stem Cell Discovered, Offering Hope for Enhanced Regeneration and Chemotherapy Recovery | HiLIFE – Helsinki Institute of Life Science | University of Helsinki A team of researchers from the University of Helsinki has discovered a previously unknown type of intestinal stem cell, which supports intestinal regeneration through its metabolically distinct mitoch...

Also read the news item by Uni Helsinki, descibing possible future application of the findings during chemothrapy-induced damage www.helsinki.fi/en/hilife-he... 8/8 @helsinki-biotech.bsky.social

Congratulations to Simon @simonsterson.bsky.social, for fantastic persistence during the whole journey, and big thank you to all co-authors, @hienbui.bsky.social Arto Viitanen @hietakangaslab.bsky.social @pekka-katajisto.bsky.social and others @metastem.bsky.social @helsinki.fi 7/8

Our results demonstrate the existence of previously unknown asymmetric division and metabolic heterogeneity in the intestinal stem cell pool, which can’t be seen in the transcriptome. Further, we find that metabolic intervention can be used for replacement of specific defective cells. 6/8

aKG supplementation in vivo leads to renewal of Paneth cells, which in old animals reduces expression of the Wnt-antagonist Notum, and rescues recovery after 5-FU-induced damage to the level of young animals. 5/8

ISCs with old mitochondria have faster TCA-cycle turnover and higher amounts of aKG, which drives the bias towards the Paneth cell linage and increased Tet2-dependent 5-hydroxy methylation of cytosines in DNA. 4/8

These stem cells (ISC-mito-O) are better at forming organoids in vitro due to their ability to regenerate Paneth cells faster. 3/8

Using in vivo snap-tag labeling of mitochondrial age-classes, we found that the intestine contains a subset of stem cells that retain old mitochondria through asymmetric division. 2/8

Old mitochondria regulate niche renewal via α-ketoglutarate metabolism in stem cells - Nature Metabolism Andersson et al. show that intestinal stem cells enriched for old mitochondria are metabolically distinct and have enhanced ability to regenerate the epithelial niche.

Proudly presenting Simon’s @simonsterson.bsky.social‬ paper on asymmetric apportioning of old mitochondria biasing intestinal stem cells for the Paneth cell linage through aKG-dependent metabolism
@naturemetabolism.bsky.social www.nature.com/articles/s42... @helsinki.fi @metastem.bsky.social 🧵1/8

Thank you to the organizers of the fantastic meeting #CSMetabolites2025 Kivanc Birsoy @robzonculab.bsky.social and @cellpress.bsky.social editors Allyson Evans @kristabledsoe.bsky.social We had a fantastic time in Sitges, looking forward to this meeting happening again! @cellpressevents.bsky.social

Thank you Christian 😊

Congratulations Hien Bui who showed remarkable persistence in initiating, leading and finalizing the project. Thank you to everyone involved, especially second authors @simonsterson.bsky.social Agustin Sola Carvajal and all collaborators at @helsinki.fi i.fi @metastem.bsky.social and @ki.se. 9/9

In conclusion, we discovered a new role for peroxisomes in determination of cell fate of adult stem cells through their age-dependent segregation and spatially compartmentalized metabolism. The SNAP-PTS1 mouse will be a valuable tool for studying peroxisomal heterogeneity also in other tissues. 8/9

We found that sub-cellular compartmentalization of specific metabolic reactions determines cell fate as expression of G6PD specifically on the peroxisome membrane, but not in the cytosol or in the peroxisome matrix, boosted stemness through peroxisomal ether lipid synthesis. 7/9

To find the mechanism, we performed proteomics of old and young peroxisomes isolated by density centrifugation and single-organelle FACS and found the metabolic enzyme G6PD to be enriched on old peroxisomes. 6/9

Similarly, during in vivo ACD of epidermal stem cells, old peroxisomes were preferentially inherited by the daughter cell that remains attached to the basement membrane. 5/9

In in vitro ACD of basal mammary epithelial cells, daughter cells with old peroxisomes PO exhibited higher self-renewal and bi-potency than daughter cells with young peroxisomes PY, demonstrated by their ability to form organoids and create the luminal lineage to induce branching morphogenesis. 4/9

To study if this takes place in primary adult stem and progenitor cells, we generated a novel mouse model expressing the SNAP-PTS1 construct, allowing for temporal labelling of peroxisomes in vivo, and saw heterogeneity of peroxisome age in epithelial cells in the mammary gland and the skin. 3/9

Hien asked if peroxisomes are age-selectively apportioned in asymmetric cell divisions (ACD) as we previously showed for mitochondria (Katajisto et al Science 2015, Döhla et al NCB 2022). To our surprise, this time it was the old organelles that were inherited by the self-renewing daughter cell! 2/9

Glucose-6-phosphate-dehydrogenase on old peroxisomes maintains self-renewal of epithelial stem cells after asymmetric cell division - Nature Communications Peroxisomes are essential but their role in cell fate regulation remains understudied. Here, the authors reveal that young and old peroxisomes are not equally distributed in asymmetrically dividing st...

Happy to present Hien’s paper on age-selective apportioning of peroxisomes as a fate determinant in adult stem cells www.nature.com/articles/s41... @metastem.bsky.social @helsinki.fi @ki.se @helsinki-biotech.bsky.social out now in @natcomms.nature.com
A thread 🧵 1/9

Tomorrow, welcome!

Welcome to the Stem Cell Seminar April 23rd. Stem cell metabolism of both tissue and pluripotent stem cells on the menu with exiting presentations from @rafabolism.bsky.social and @rutorregrosa.bsky.social @stemmprogram.bsky.social @helsinki.fi @helsinki-biotech.bsky.social @fimm-uh.bsky.social

The @katajistolab.bsky.social modeled #epithelial regeneration using small intestinal scaffolds and identified #asporin is a mediator of fetal-like reprogramming.

Read the @cp-cellstemcell.bsky.social article: bit.ly/41LJbhn
Listen to the conversation: bit.ly/4kTt36a

Fetal-like reversion in the regenerating intestine is regulated by mesenchymal asporin Mesenchymal cells and the extracellular matrix (ECM) support epithelium during homeostasis and regeneration. However, the role of the mesenchyme in ep…

1/6 Proudly presenting Sharif’s @sharifiqbal.bsky.social paper on the role of Asporin in intestinal regeneration through TGF-B-dependent fetal-like reversion www.sciencedirect.com/science/arti... out in @cp-cellstemcell.bsky.social @pekka-katajisto.bsky.social @helsinki.fi @metastem.bsky.social 🧵

6/6 Biggest congratulations of course go to Sharif Iqbal @sharifiqbal.bsky.social who initiated, led and finished the study through extremely hard work and persistence. A real tour de force! 👏🥳

5/6 Huge thanks to all co-authors @simonsterson.bsky.social, Ernesta Nesta and others, and collaborators, including groups of @kimbakjensen.bsky.social, Menno Oudhoff @seollila.bsky.social and Kirsi Pietiläinen, Markku Varjosalo, Alessandro Ori, Michael Jeltsch and Ari Ristimäki

4/6 Interestingly, high Aspn levels in the old lead to persistently activated fetal-like state without resolution post-injury, resulting in reduced recovery. This stalled developmental reversion can be resolved by activating Wnt signaling in the old animals