Autophagy in PDGFRα+ mesenchymal cells is essential for intestinal stem cell survival-Reference-Cited by-同舟云学术

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

Published:2022-05-10 Issue:21 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Yang Yang¹^ORCID,Gomez Maria¹²,Marsh Timothy³,Poillet-Perez Laura¹,Sawant Akshada¹,Chen Lei⁴,Park Noel R.⁵,Jackson S. RaElle⁵,Hu Zhixian¹²,Alon Noa¹⁶,Liu Chen⁷,Debnath Jayanta³,Guan Jun-Lin⁸,Davidson Shawn⁹,Verzi Michael⁴^ORCID,White Eileen¹²⁶¹⁰^ORCID

Affiliation:

1. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903

2. Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544

3. Department of Pathology, University of California, San Francisco, CA 94143

4. Department of Genetics, Rutgers University, Piscataway, NJ, 08854

5. Department of Molecular Biology, Princeton University, Princeton, NJ 08544

6. School of Art Sciences, Rutgers University, New Brunswick, NJ 08901

7. Department of Pathology and Laboratory Medicine, Robert Wood Johnson University Hospital, New Brunswick, NJ 08903

8. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267

9. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544

10. Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854

Abstract

Significance Autophagy defects are a risk factor for inflammatory bowel diseases (IBDs), but the mechanism remains unknown. We show here that conditional whole-body deletion of Atg5 or Fip200 , but not Atg7 , is lethal due to loss of ileum stem cells and barrier function likely caused by different kinetics of autophagy loss, which was rescued by slow deletion. Specific autophagy loss in PDGFRα+ mesenchymal cells (PMCs) resulted in loss of Wnt signaling responsible for failed stem cell renewal. We also observed depletion of aspartate and nucleotides throughout the ileum. Our results illustrate that autophagy is required for PMC metabolism and survival necessary to sustain intestinal stem cells and mouse survival, and failure to maintain PMCs through autophagy contributes to IBD.

Funder

HHS | NIH | National Cancer Institute

Ludwig Institute for Cancer Research

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2202016119

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