Autophagy in PDGFRα+ mesenchymal cells is essential for intestinal stem cell survival

Yang Yang; Maria Gomez; Timothy Marsh; Laura Poillet-Perez; Akshada Sawant; Lei Chen; Noel R. Park; S. RaElle Jackson; Zhixian Hu; Noa Alon; Chen Liu; Jayanta Debnath; Jun Lin Guan; Shawn Davidson; Michael Verzi; Eileen White

doi:10.1073/pnas.2202016119

Autophagy in PDGFRα+ mesenchymal cells is essential for intestinal stem cell survival

Yang Yang, Maria Gomez, Timothy Marsh, Laura Poillet-Perez, Akshada Sawant, Lei Chen, Noel R. Park, S. RaElle Jackson, Zhixian Hu, Noa Alon, Chen Liu, Jayanta Debnath, Jun Lin Guan, Shawn Davidson, Michael Verzi, Eileen White^*

^*Corresponding author for this work

Medicine, Pulmonary Division

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

8 Scopus citations

Abstract

Autophagy defects are a risk factor for inflammatory bowel diseases (IBDs) through unknown mechanisms. Whole-body conditional deletion of autophagy-related gene (Atg) Atg7 in adult mice (Atg7^Δ/^Δ) causes tissue damage and death within 3 mo due to neurodegeneration without substantial effect on intestine. In contrast, we report here that whole-body conditional deletion of other essential Atg genes Atg5 or Fip200/Atg17 in adult mice (Atg5^Δ/^Δ or Fip200^Δ/^Δ) caused death within 5 d due to rapid autophagy inhibition, elimination of ileum stem cells, and loss of barrier function. Atg5^Δ/^Δ mice lost PDGFRα+ mesenchymal cells (PMCs) and Wnt signaling essential for stem cell renewal, which were partially rescued by exogenous Wnt. Matrix-assisted laser desorption ionization coupled to mass spectrometry imaging (MALDI-MSI) of Atg5^Δ/^Δ ileum revealed depletion of aspartate and nucleotides, consistent with metabolic insufficiency underlying PMC loss. The difference in the autophagy gene knockout phenotypes is likely due to distinct kinetics of autophagy loss, as deletion of Atg5 more gradually extended lifespan phenocopying deletion of Atg7 or Atg12. Thus, autophagy is required for PMC metabolism and ileum stem cell and mammalian survival. Failure to maintain PMCs through autophagy may therefore contribute to IBD.

Original language	English (US)
Article number	e2202016119
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	119
Issue number	21
DOIs	https://doi.org/10.1073/pnas.2202016119
State	Published - May 24 2022

Keywords

IBD
autophagy
intestine
metabolism
stem cells

ASJC Scopus subject areas

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10.1073/pnas.2202016119

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Yang, Y., Gomez, M., Marsh, T., Poillet-Perez, L., Sawant, A., Chen, L., Park, N. R., RaElle Jackson, S., Hu, Z., Alon, N., Liu, C., Debnath, J., Guan, J. L., Davidson, S., Verzi, M., & White, E. (2022). Autophagy in PDGFRα+ mesenchymal cells is essential for intestinal stem cell survival. Proceedings of the National Academy of Sciences of the United States of America, 119(21), Article e2202016119. https://doi.org/10.1073/pnas.2202016119

@article{4435965d09e745e482f9bf7bf10f3508,

title = "Autophagy in PDGFRα+ mesenchymal cells is essential for intestinal stem cell survival",

abstract = "Autophagy defects are a risk factor for inflammatory bowel diseases (IBDs) through unknown mechanisms. Whole-body conditional deletion of autophagy-related gene (Atg) Atg7 in adult mice (Atg7Δ/Δ) causes tissue damage and death within 3 mo due to neurodegeneration without substantial effect on intestine. In contrast, we report here that whole-body conditional deletion of other essential Atg genes Atg5 or Fip200/Atg17 in adult mice (Atg5Δ/Δ or Fip200Δ/Δ) caused death within 5 d due to rapid autophagy inhibition, elimination of ileum stem cells, and loss of barrier function. Atg5Δ/Δ mice lost PDGFRα+ mesenchymal cells (PMCs) and Wnt signaling essential for stem cell renewal, which were partially rescued by exogenous Wnt. Matrix-assisted laser desorption ionization coupled to mass spectrometry imaging (MALDI-MSI) of Atg5Δ/Δ ileum revealed depletion of aspartate and nucleotides, consistent with metabolic insufficiency underlying PMC loss. The difference in the autophagy gene knockout phenotypes is likely due to distinct kinetics of autophagy loss, as deletion of Atg5 more gradually extended lifespan phenocopying deletion of Atg7 or Atg12. Thus, autophagy is required for PMC metabolism and ileum stem cell and mammalian survival. Failure to maintain PMCs through autophagy may therefore contribute to IBD.",

keywords = "IBD, autophagy, intestine, metabolism, stem cells",

author = "Yang Yang and Maria Gomez and Timothy Marsh and Laura Poillet-Perez and Akshada Sawant and Lei Chen and Park, {Noel R.} and {RaElle Jackson}, S. and Zhixian Hu and Noa Alon and Chen Liu and Jayanta Debnath and Guan, {Jun Lin} and Shawn Davidson and Michael Verzi and Eileen White",

note = "Funding Information: ACKNOWLEDGMENTS This work was supported by NIH Grants R01 CA130893, CA188096, and CA163591 and the Ludwig Princeton Branch of the Ludwig Institute for Cancer Research at Princeton University (to E.W.) and NIH F31 Fellowship F31CA217015 (to T.M.). Services, results, and/or products in support of the research project were generated by the Rutgers Cancer Institute of New Jersey Biospecimen Repository and Histopathology Service Shared Resource, supported, in part, with funding from National Cancer Institute (NCI) Cancer Center Support Grant (CCSG) P30CA072720-5919. Similarly, the Metabo-lomics Shared Research received support from NCI CCSG P30CA072720-5923. S.D. was supported by a New Investigator Award (NCI CCSG P30CA072720-5931). M.G. was supported by NCI T32 Grant CA257957. We also thank Dr. Shalev Itzkovitz (Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel) for contributing the single-cell RNA-sequencing data. Publisher Copyright: Copyright {\textcopyright} 2022 the Author(s).",

year = "2022",

month = may,

day = "24",

doi = "10.1073/pnas.2202016119",

language = "English (US)",

volume = "119",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "21",

}

Yang, Y, Gomez, M, Marsh, T, Poillet-Perez, L, Sawant, A, Chen, L, Park, NR, RaElle Jackson, S, Hu, Z, Alon, N, Liu, C, Debnath, J, Guan, JL, Davidson, S, Verzi, M & White, E 2022, 'Autophagy in PDGFRα+ mesenchymal cells is essential for intestinal stem cell survival', Proceedings of the National Academy of Sciences of the United States of America, vol. 119, no. 21, e2202016119. https://doi.org/10.1073/pnas.2202016119

TY - JOUR

T1 - Autophagy in PDGFRα+ mesenchymal cells is essential for intestinal stem cell survival

AU - Yang, Yang

AU - Gomez, Maria

AU - Marsh, Timothy

AU - Poillet-Perez, Laura

AU - Sawant, Akshada

AU - Chen, Lei

AU - Park, Noel R.

AU - RaElle Jackson, S.

AU - Hu, Zhixian

AU - Alon, Noa

AU - Liu, Chen

AU - Debnath, Jayanta

AU - Guan, Jun Lin

AU - Davidson, Shawn

AU - Verzi, Michael

AU - White, Eileen

N1 - Funding Information: ACKNOWLEDGMENTS This work was supported by NIH Grants R01 CA130893, CA188096, and CA163591 and the Ludwig Princeton Branch of the Ludwig Institute for Cancer Research at Princeton University (to E.W.) and NIH F31 Fellowship F31CA217015 (to T.M.). Services, results, and/or products in support of the research project were generated by the Rutgers Cancer Institute of New Jersey Biospecimen Repository and Histopathology Service Shared Resource, supported, in part, with funding from National Cancer Institute (NCI) Cancer Center Support Grant (CCSG) P30CA072720-5919. Similarly, the Metabo-lomics Shared Research received support from NCI CCSG P30CA072720-5923. S.D. was supported by a New Investigator Award (NCI CCSG P30CA072720-5931). M.G. was supported by NCI T32 Grant CA257957. We also thank Dr. Shalev Itzkovitz (Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel) for contributing the single-cell RNA-sequencing data. Publisher Copyright: Copyright © 2022 the Author(s).

PY - 2022/5/24

Y1 - 2022/5/24

N2 - Autophagy defects are a risk factor for inflammatory bowel diseases (IBDs) through unknown mechanisms. Whole-body conditional deletion of autophagy-related gene (Atg) Atg7 in adult mice (Atg7Δ/Δ) causes tissue damage and death within 3 mo due to neurodegeneration without substantial effect on intestine. In contrast, we report here that whole-body conditional deletion of other essential Atg genes Atg5 or Fip200/Atg17 in adult mice (Atg5Δ/Δ or Fip200Δ/Δ) caused death within 5 d due to rapid autophagy inhibition, elimination of ileum stem cells, and loss of barrier function. Atg5Δ/Δ mice lost PDGFRα+ mesenchymal cells (PMCs) and Wnt signaling essential for stem cell renewal, which were partially rescued by exogenous Wnt. Matrix-assisted laser desorption ionization coupled to mass spectrometry imaging (MALDI-MSI) of Atg5Δ/Δ ileum revealed depletion of aspartate and nucleotides, consistent with metabolic insufficiency underlying PMC loss. The difference in the autophagy gene knockout phenotypes is likely due to distinct kinetics of autophagy loss, as deletion of Atg5 more gradually extended lifespan phenocopying deletion of Atg7 or Atg12. Thus, autophagy is required for PMC metabolism and ileum stem cell and mammalian survival. Failure to maintain PMCs through autophagy may therefore contribute to IBD.

AB - Autophagy defects are a risk factor for inflammatory bowel diseases (IBDs) through unknown mechanisms. Whole-body conditional deletion of autophagy-related gene (Atg) Atg7 in adult mice (Atg7Δ/Δ) causes tissue damage and death within 3 mo due to neurodegeneration without substantial effect on intestine. In contrast, we report here that whole-body conditional deletion of other essential Atg genes Atg5 or Fip200/Atg17 in adult mice (Atg5Δ/Δ or Fip200Δ/Δ) caused death within 5 d due to rapid autophagy inhibition, elimination of ileum stem cells, and loss of barrier function. Atg5Δ/Δ mice lost PDGFRα+ mesenchymal cells (PMCs) and Wnt signaling essential for stem cell renewal, which were partially rescued by exogenous Wnt. Matrix-assisted laser desorption ionization coupled to mass spectrometry imaging (MALDI-MSI) of Atg5Δ/Δ ileum revealed depletion of aspartate and nucleotides, consistent with metabolic insufficiency underlying PMC loss. The difference in the autophagy gene knockout phenotypes is likely due to distinct kinetics of autophagy loss, as deletion of Atg5 more gradually extended lifespan phenocopying deletion of Atg7 or Atg12. Thus, autophagy is required for PMC metabolism and ileum stem cell and mammalian survival. Failure to maintain PMCs through autophagy may therefore contribute to IBD.

KW - IBD

KW - autophagy

KW - intestine

KW - metabolism

KW - stem cells

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UR - http://www.scopus.com/inward/citedby.url?scp=85130004794&partnerID=8YFLogxK

U2 - 10.1073/pnas.2202016119

DO - 10.1073/pnas.2202016119

M3 - Article

C2 - 35537042

AN - SCOPUS:85130004794

SN - 0027-8424

VL - 119

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 21

M1 - e2202016119

ER -

Autophagy in PDGFRα+ mesenchymal cells is essential for intestinal stem cell survival

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Keywords

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