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PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells


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 lineage-committed 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.

Type Journal
Authors Chandrakanthan, V.; Yeola, A.; Kwan, J. C.; Oliver, R. A.; Qiao, Q.; Kang, Y. C.; Zarzour, P.; Beck, D.; Boelen, L.; Unnikrishnan, A.; Villanueva, J. E.; Nunez, A. C.; Knezevic, K.; Palu, C.; Nasrallah, R.; Carnell, M.; Macmillan, A.; Whan, R.; Yu, Y.; Hardy, P.; Grey, S. T.; Gladbach, A.; Delerue, F.; Ittner, L.; Mobbs, R.; Walkley, C. R.; Purton, L. E.; Ward, R. L.; Wong, J. W.; Hesson, L. B.; Walsh, W.; Pimanda, J. E.;
Responsible Garvan Author Prof Shane Grey
Published Date 2016-04-19
Published Volume 113
Published Issue 16
Published Pages 2306-2315
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version