Induction of muscle-regenerative multipotent stem cells from human adipocytes by PDGF-AB and 5-azacytidine

Avani Yeola; Shruthi Subramanian; Rema A Oliver; Christine A Lucas; Julie A I Thoms; Feng Yan; Jake Olivier; Diego Chacon; Melinda L Tursky; Pallavi Srivastava; Jason R Potas; Tzongtyng Hung; Carl Power; Philip Hardy; David D Ma; Kristopher A Kilian; Joshua McCarroll; Maria Kavallaris; Luke B Hesson; Dominik Beck; David J Curtis; Jason W H Wong; Edna C Hardeman; William R Walsh; Ralph Mobbs; Vashe Chandrakanthan; John E Pimanda

doi:10.1126/sciadv.abd1929

Induction of muscle-regenerative multipotent stem cells from human adipocytes by PDGF-AB and 5-azacytidine

Sci Adv. 2021 Jan 13;7(3):eabd1929. doi: 10.1126/sciadv.abd1929. Print 2021 Jan.

Authors

Avani Yeola^{1

2}, Shruthi Subramanian^{1

3}, Rema A Oliver⁴, Christine A Lucas⁵, Julie A I Thoms^{1

2}, Feng Yan⁶, Jake Olivier⁷, Diego Chacon⁸, Melinda L Tursky⁹, Pallavi Srivastava¹⁰, Jason R Potas¹¹, Tzongtyng Hung¹², Carl Power¹², Philip Hardy¹³, David D Ma⁹, Kristopher A Kilian¹⁰, Joshua McCarroll¹⁴, Maria Kavallaris^{14

15

16}, Luke B Hesson^{3

17}, Dominik Beck⁸, David J Curtis^{6

18}, Jason W H Wong¹⁹, Edna C Hardeman⁵, William R Walsh⁴, Ralph Mobbs^{4

20}, Vashe Chandrakanthan^{21

2}, John E Pimanda^{21

2

3

22}

Affiliations

¹ Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia.
² School of Medical Sciences, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
³ Prince of Wales Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
⁴ Surgical and Orthopaedic Research Laboratories, Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia.
⁵ Cellular and Genetic Medicine Unit, School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia.
⁶ Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC, Australia.
⁷ School of Mathematics and Statistics, UNSW Sydney, Sydney, NSW 2052, Australia.
⁸ School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW 2007, Australia.
⁹ St. Vincent's Centre for Applied Medical Research, St Vincent's Hospital Sydney and St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia.
¹⁰ School of Material Sciences and Engineering, School of Chemistry, Australian Centre for Nanomedicine, UNSW Sydney, Sydney, NSW 2052, Australia.
¹¹ Translational Neuroscience Facility, School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia.
¹² Biological Resources Imaging Laboratory, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW 2052, Australia.
¹³ Cyto Labs, Bentley, WA 6102, Australia.
¹⁴ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, Sydney, NSW, Australia.
¹⁵ ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for Nanomedicine, UNSW Sydney, Sydney, NSW 2052, Australia.
¹⁶ School of Women's and Children's Health, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
¹⁷ Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
¹⁸ Department of Clinical Haematology, Alfred Health, Melbourne, VIC, Australia.
¹⁹ School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region.
²⁰ Department of Neurosurgery, Prince of Wales Hospital, Randwick, NSW 2031, Australia.
²¹ Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia. v.chandrakanthan@unsw.edu.au jpimanda@unsw.edu.au.
²² Department of Haematology, Prince of Wales Hospital, Randwick, NSW 2031, Australia.

Abstract

Terminally differentiated murine osteocytes and adipocytes can be reprogrammed using platelet-derived growth factor-AB and 5-azacytidine into multipotent stem cells with stromal cell characteristics. We have now optimized culture conditions to reprogram human adipocytes into induced multipotent stem (iMS) cells and characterized their molecular and functional properties. Although the basal transcriptomes of adipocyte-derived iMS cells and adipose tissue-derived mesenchymal stem cells were similar, there were changes in histone modifications and CpG methylation at cis-regulatory regions consistent with an epigenetic landscape that was primed for tissue development and differentiation. In a non-specific tissue injury xenograft model, iMS cells contributed directly to muscle, bone, cartilage, and blood vessels, with no evidence of teratogenic potential. In a cardiotoxin muscle injury model, iMS cells contributed specifically to satellite cells and myofibers without ectopic tissue formation. Together, human adipocyte-derived iMS cells regenerate tissues in a context-dependent manner without ectopic or neoplastic growth.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes
Adipose Tissue
Animals
Azacitidine* / pharmacology
Cell Differentiation
Cells, Cultured
Humans
Mice
Multipotent Stem Cells
Muscles
Platelet-Derived Growth Factor*

Substances

Platelet-Derived Growth Factor
platelet-derived growth factor AB
Azacitidine