Pdgf-ab and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells

Vashe Chandrakanthan*, Avani Yeola, Jair C. Kwan, Rema A. Oliver, Qiao Qiao, Young Chan Kang, Peter Zarzour, Dominik Beck, Lies Boelen, Ashwin Unnikrishnan, Jeanette E. Villanueva, Andrea C. Nunez, Kathy Knezevic, Cintia Palu, Rabab Nasrallah, Michael Carnell, Alex Macmillan, Renee Whan, Yan Yu, Philip Hardy & 12 others Shane T. Grey, Amadeus Gladbach, Fabien Delerue, Lars Ittner, Ralph Mobbs, Carl R. Walkley, Louise E. Purton, Robyn L. Ward, Jason W.H. Wong, Luke B. Hesson, William Walsh, John E. Pimanda

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Current approaches in tissue engineering are geared toward generating tissue-specific stem cells. Given the complexity and heterogeneity of tissues, this approach has its limitations. An alternate approach is to induce terminally differentiated cells to dedifferentiate into multipotent proliferative cells with the capacity to regenerate all components of a damaged tissue, a phenomenon used by salamanders to regenerate limbs. 5-Azacytidine (AZA) is a nucleoside analog that is used to treat preleukemic and leukemic blood disorders. AZA is also known to induce cell plasticity. We hypothesized that AZA-induced cell plasticity occurs via a transient multipotent cell state and that concomitant exposure to a receptive growth factor might result in the expansion of a plastic and proliferative population of cells. To this end, we treated lineagecommitted cells with AZA and screened a number of different growth factors with known activity in mesenchyme-derived tissues. Here, we report that transient treatment with AZA in combination with platelet-derived growth factor-AB converts primary somatic cells into tissue-regenerative multipotent stem (iMS) cells. iMS cells possess a distinct transcriptome, are immunosuppressive, and demonstrate long-term self-renewal, serial clonogenicity, and multigerm layer differentiation potential. Importantly, unlike mesenchymal stem cells, iMS cells contribute directly to in vivo tissue regeneration in a context-dependent manner and, unlike embryonic or pluripotent stem cells, do not form teratomas. Taken together, this vector-free method of generating iMS cells from primary terminally differentiated cells has significant scope for application in tissue regeneration.

Original languageEnglish
Pages (from-to)E2306-E2315
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number16
DOIs
Publication statusPublished - 19 Apr 2016
Externally publishedYes

Keywords

  • 5-Azacytidine
  • Cell reprogramming
  • Multipotent stem cells
  • Platelet-derived growth factor-AB
  • Tissue regeneration

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