Intestinal stem cell aging signature reveals a reprogramming strategy to enhance regenerative potential

Christian M Nefzger; Thierry Jardé; Akanksha Srivastava; Jan Schroeder; Fernando J Rossello; Katja Horvay; Mirsada Prasko; Jacob M Paynter; Joseph Chen; Chen-Fang Weng; Yu B Y Sun; Xiaodong Liu; Eva Chan; Nikita Deshpande; Xiaoli Chen; Y Jinhua Li; Jahnvi Pflueger; Rebekah M Engel; Anja S Knaupp; Kirill Tsyganov; Susan K Nilsson; Ryan Lister; Owen J L Rackham; Helen E Abud; Jose M Polo

doi:10.1038/s41536-022-00226-7

Intestinal stem cell aging signature reveals a reprogramming strategy to enhance regenerative potential

NPJ Regen Med. 2022 Jun 16;7(1):31. doi: 10.1038/s41536-022-00226-7.

Authors

Christian M Nefzger^#^{1

2

3

4}, Thierry Jardé^#^{1

3

5}, Akanksha Srivastava⁶, Jan Schroeder^{1

2

3}, Fernando J Rossello^{1

2

3}, Katja Horvay^{1

3

5}, Mirsada Prasko^{1

3

5}, Jacob M Paynter^{1

2

3}, Joseph Chen^{1

2

3}, Chen-Fang Weng^{1

3

5}, Yu B Y Sun^{1

3}, Xiaodong Liu^{1

2

3}, Eva Chan^{1

3

5}, Nikita Deshpande⁴, Xiaoli Chen⁴, Y Jinhua Li^{1

3}, Jahnvi Pflueger^{6

7}, Rebekah M Engel^{1

3

8}, Anja S Knaupp^{1

2

3}, Kirill Tsyganov⁹, Susan K Nilsson^{2

10}, Ryan Lister^{6

7}, Owen J L Rackham¹¹, Helen E Abud^{12

13

14}, Jose M Polo^{15

16

17

18

19}

Affiliations

¹ Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.
² Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia.
³ Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
⁴ Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia.
⁵ Cancer Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
⁶ Australian Research Council Centre of Excellence in Plant Energy Biology, School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia.
⁷ Harry Perkins Institute of Medical Research, Nedlands, WA, Australia.
⁸ Cabrini Monash University Department of Surgery, Cabrini Hospital, Malvern, VIC, Australia.
⁹ Monash Bioinformatics Platform, Monash University, Clayton, VIC, Australia.
¹⁰ Biomedical Manufacturing CSIRO, Clayton, VIC, Australia.
¹¹ Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore, Singapore.
¹² Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia. [email protected].
¹³ Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. [email protected].
¹⁴ Cancer Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. [email protected].
¹⁵ Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia. [email protected].
¹⁶ Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia. [email protected].
¹⁷ Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. [email protected].
¹⁸ Adelaide Centre for Epigenetics, The University of Adelaide, Adelaide, SA, Australia. [email protected].
¹⁹ The South Australian Immunogenomics Cancer Institute, The University of Adelaide, Adelaide, SA, Australia. [email protected].

^# Contributed equally.

Abstract

The impact of aging on intestinal stem cells (ISCs) has not been fully elucidated. In this study, we identified widespread epigenetic and transcriptional alterations in old ISCs. Using a reprogramming algorithm, we identified a set of key transcription factors (Egr1, Irf1, FosB) that drives molecular and functional differences between old and young states. Overall, by dissecting the molecular signature of aged ISCs, our study identified transcription factors that enhance the regenerative capacity of ISCs.

Abstract

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