Growth of the maternal intestine during reproduction

Tomotsune Ameku; Anna Laddach; Hannah Beckwith; Alexandra Milona; Loranzie S Rogers; Cornelia Schwayer; Emma Nye; Iain R Tough; Jean-Louis Thoumas; Umesh Kumar Gautam; Yi-Fang Wang; Shreya Jha; Alvaro Castano-Medina; Christopher Amourda; Patric M Vaelli; Sira Gevers; Elaine E Irvine; Leah Meyer; Ivan Andrew; Ka Lok Choi; Bhavik Patel; Alice J Francis; Chris Studd; Laurence Game; George Young; Kevin G Murphy; Bryn Owen; Dominic J Withers; Maria Rodriguez-Colman; Helen M Cox; Prisca Liberali; Martin Schwarzer; François Leulier; Vassilis Pachnis; Nicholas W Bellono; Irene Miguel-Aliaga

doi:10.1016/j.cell.2025.02.015

Growth of the maternal intestine during reproduction

Tomotsune Ameku, Anna Laddach, Hannah Beckwith, Alexandra Milona, Loranzie S Rogers, Cornelia Schwayer, Emma Nye, Iain R Tough, Jean-Louis Thoumas, Umesh Kumar Gautam, Yi-Fang Wang, Shreya Jha, Alvaro Castano-Medina, Christopher Amourda, Patric M Vaelli, Sira Gevers, Elaine E Irvine, Leah Meyer, Ivan Andrew, Ka Lok ChoiBhavik Patel, Alice J Francis, Chris Studd, Laurence Game, George Young, Kevin G Murphy, Bryn Owen, Dominic J Withers, Maria Rodriguez-Colman, Helen M Cox, Prisca Liberali, Martin Schwarzer, François Leulier, Vassilis Pachnis, Nicholas W Bellono, Irene Miguel-Aliaga^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The organs of many female animals are remodeled by reproduction. Using the mouse intestine, a striking and tractable model of organ resizing, we find that reproductive remodeling is anticipatory and distinct from diet- or microbiota-induced resizing. Reproductive remodeling involves partially irreversible elongation of the small intestine and fully reversible growth of its epithelial villi, associated with an expansion of isthmus progenitors and accelerated enterocyte migration. We identify induction of the SGLT3a transporter in a subset of enterocytes as an early reproductive hallmark. Electrophysiological and genetic interrogations indicate that SGLT3a does not sustain digestive functions or enterocyte health; rather, it detects protons and sodium to extrinsically support the expansion of adjacent Fgfbp1-positive isthmus progenitors, promoting villus growth. Our findings reveal unanticipated specificity to physiological organ remodeling. We suggest that organ- and state-specific growth programs could be leveraged to improve pregnancy outcomes or prevent maladaptive consequences of such growth.

Original language	English
Pages (from-to)	2738-2756.e22
Journal	Cell
Volume	188
Issue number	10
Early online date	19 Mar 2025
DOIs	https://doi.org/10.1016/j.cell.2025.02.015
Publication status	Published - 15 May 2025

Keywords

Fgfbp1
SGLT3a
adult organ remodeling
intestinal epithelium
isthmus progenitor
lactation
plasticity
pregnancy
reproduction
small intestine

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10.1016/j.cell.2025.02.015Licence: CC BY

PIIS0092867425002004Final published version, 25.5 MBLicence: CC BY

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Ameku, T., Laddach, A., Beckwith, H., Milona, A., Rogers, L. S., Schwayer, C., Nye, E., Tough, I. R., Thoumas, J.-L., Gautam, U. K., Wang, Y.-F., Jha, S., Castano-Medina, A., Amourda, C., Vaelli, P. M., Gevers, S., Irvine, E. E., Meyer, L., Andrew, I., ... Miguel-Aliaga, I. (2025). Growth of the maternal intestine during reproduction. Cell, 188(10), 2738-2756.e22. https://doi.org/10.1016/j.cell.2025.02.015

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abstract = "The organs of many female animals are remodeled by reproduction. Using the mouse intestine, a striking and tractable model of organ resizing, we find that reproductive remodeling is anticipatory and distinct from diet- or microbiota-induced resizing. Reproductive remodeling involves partially irreversible elongation of the small intestine and fully reversible growth of its epithelial villi, associated with an expansion of isthmus progenitors and accelerated enterocyte migration. We identify induction of the SGLT3a transporter in a subset of enterocytes as an early reproductive hallmark. Electrophysiological and genetic interrogations indicate that SGLT3a does not sustain digestive functions or enterocyte health; rather, it detects protons and sodium to extrinsically support the expansion of adjacent Fgfbp1-positive isthmus progenitors, promoting villus growth. Our findings reveal unanticipated specificity to physiological organ remodeling. We suggest that organ- and state-specific growth programs could be leveraged to improve pregnancy outcomes or prevent maladaptive consequences of such growth.",

keywords = "Fgfbp1, SGLT3a, adult organ remodeling, intestinal epithelium, isthmus progenitor, lactation, plasticity, pregnancy, reproduction, small intestine",

author = "Tomotsune Ameku and Anna Laddach and Hannah Beckwith and Alexandra Milona and Rogers, {Loranzie S} and Cornelia Schwayer and Emma Nye and Tough, {Iain R} and Jean-Louis Thoumas and Gautam, {Umesh Kumar} and Yi-Fang Wang and Shreya Jha and Alvaro Castano-Medina and Christopher Amourda and Vaelli, {Patric M} and Sira Gevers and Irvine, {Elaine E} and Leah Meyer and Ivan Andrew and Choi, {Ka Lok} and Bhavik Patel and Francis, {Alice J} and Chris Studd and Laurence Game and George Young and Murphy, {Kevin G} and Bryn Owen and Withers, {Dominic J} and Maria Rodriguez-Colman and Cox, {Helen M} and Prisca Liberali and Martin Schwarzer and Fran{\c c}ois Leulier and Vassilis Pachnis and Bellono, {Nicholas W} and Irene Miguel-Aliaga",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

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Ameku, T, Laddach, A, Beckwith, H, Milona, A, Rogers, LS, Schwayer, C, Nye, E, Tough, IR, Thoumas, J-L, Gautam, UK, Wang, Y-F, Jha, S, Castano-Medina, A, Amourda, C, Vaelli, PM, Gevers, S, Irvine, EE, Meyer, L, Andrew, I, Choi, KL, Patel, B, Francis, AJ, Studd, C, Game, L, Young, G, Murphy, KG, Owen, B, Withers, DJ, Rodriguez-Colman, M, Cox, HM, Liberali, P, Schwarzer, M, Leulier, F, Pachnis, V, Bellono, NW & Miguel-Aliaga, I 2025, 'Growth of the maternal intestine during reproduction', Cell, vol. 188, no. 10, pp. 2738-2756.e22. https://doi.org/10.1016/j.cell.2025.02.015

TY - JOUR

T1 - Growth of the maternal intestine during reproduction

AU - Ameku, Tomotsune

AU - Laddach, Anna

AU - Beckwith, Hannah

AU - Milona, Alexandra

AU - Rogers, Loranzie S

AU - Schwayer, Cornelia

AU - Nye, Emma

AU - Tough, Iain R

AU - Thoumas, Jean-Louis

AU - Gautam, Umesh Kumar

AU - Wang, Yi-Fang

AU - Jha, Shreya

AU - Castano-Medina, Alvaro

AU - Amourda, Christopher

AU - Vaelli, Patric M

AU - Gevers, Sira

AU - Irvine, Elaine E

AU - Meyer, Leah

AU - Andrew, Ivan

AU - Choi, Ka Lok

AU - Patel, Bhavik

AU - Francis, Alice J

AU - Studd, Chris

AU - Game, Laurence

AU - Young, George

AU - Murphy, Kevin G

AU - Owen, Bryn

AU - Withers, Dominic J

AU - Rodriguez-Colman, Maria

AU - Cox, Helen M

AU - Liberali, Prisca

AU - Schwarzer, Martin

AU - Leulier, François

AU - Pachnis, Vassilis

AU - Bellono, Nicholas W

AU - Miguel-Aliaga, Irene

PY - 2025/5/15

Y1 - 2025/5/15

N2 - The organs of many female animals are remodeled by reproduction. Using the mouse intestine, a striking and tractable model of organ resizing, we find that reproductive remodeling is anticipatory and distinct from diet- or microbiota-induced resizing. Reproductive remodeling involves partially irreversible elongation of the small intestine and fully reversible growth of its epithelial villi, associated with an expansion of isthmus progenitors and accelerated enterocyte migration. We identify induction of the SGLT3a transporter in a subset of enterocytes as an early reproductive hallmark. Electrophysiological and genetic interrogations indicate that SGLT3a does not sustain digestive functions or enterocyte health; rather, it detects protons and sodium to extrinsically support the expansion of adjacent Fgfbp1-positive isthmus progenitors, promoting villus growth. Our findings reveal unanticipated specificity to physiological organ remodeling. We suggest that organ- and state-specific growth programs could be leveraged to improve pregnancy outcomes or prevent maladaptive consequences of such growth.

AB - The organs of many female animals are remodeled by reproduction. Using the mouse intestine, a striking and tractable model of organ resizing, we find that reproductive remodeling is anticipatory and distinct from diet- or microbiota-induced resizing. Reproductive remodeling involves partially irreversible elongation of the small intestine and fully reversible growth of its epithelial villi, associated with an expansion of isthmus progenitors and accelerated enterocyte migration. We identify induction of the SGLT3a transporter in a subset of enterocytes as an early reproductive hallmark. Electrophysiological and genetic interrogations indicate that SGLT3a does not sustain digestive functions or enterocyte health; rather, it detects protons and sodium to extrinsically support the expansion of adjacent Fgfbp1-positive isthmus progenitors, promoting villus growth. Our findings reveal unanticipated specificity to physiological organ remodeling. We suggest that organ- and state-specific growth programs could be leveraged to improve pregnancy outcomes or prevent maladaptive consequences of such growth.

KW - Fgfbp1

KW - SGLT3a

KW - adult organ remodeling

KW - intestinal epithelium

KW - isthmus progenitor

KW - lactation

KW - plasticity

KW - pregnancy

KW - reproduction

KW - small intestine

UR - http://www.scopus.com/inward/record.url?scp=105000528273&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2025.02.015

DO - 10.1016/j.cell.2025.02.015

M3 - Article

C2 - 40112802

SN - 0092-8674

VL - 188

SP - 2738-2756.e22

JO - Cell

JF - Cell

IS - 10

ER -

Growth of the maternal intestine during reproduction

Abstract

Keywords

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