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

Chandrakanthan, V; Yeola, A; Kwan, JC; Oliver, RA; Qiao, Q; Kang, YC; Zarzour, P; Beck, D; Boelen, L; Unnikrishnan, A; Villanueva, JE; Nunez, AC; Knezevic, K; Palu, C; Nasrallah, R; Carnell, M; Macmillan, A; Whan, R; Yu, Y; Hardy, P; Grey, ST; Gladbach, A; Delerue, F; Ittner, L; Mobbs, R; Walkley, CR; Purton, LE; Ward, RL; Wong, JWH; Hesson, LB; Walsh, W; Pimanda, JE

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

Chandrakanthan, V Yeola, A Kwan, JC Oliver, RA Qiao, Q Kang, YC Zarzour, P Beck, D Boelen, L Unnikrishnan, A Villanueva, JE Nunez, AC Knezevic, K Palu, C Nasrallah, R Carnell, M Macmillan, A Whan, R Yu, Y Hardy, P Grey, ST Gladbach, A Delerue, F Ittner, L Mobbs, R Walkley, CR Purton, LE Ward, RL Wong, JWH Hesson, LB Walsh, W Pimanda, JE

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Publication Type:: Journal Article
Citation:: Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 (16), pp. E2306 - E2315
Issue Date:: 2016-04-19

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Field	Value	Language
dc.contributor.author	Chandrakanthan, V	en_US
dc.contributor.author	Yeola, A	en_US
dc.contributor.author	Kwan, JC	en_US
dc.contributor.author	Oliver, RA	en_US
dc.contributor.author	Qiao, Q	en_US
dc.contributor.author	Kang, YC	en_US
dc.contributor.author	Zarzour, P	en_US
dc.contributor.author	Beck, D	en_US
dc.contributor.author	Boelen, L	en_US
dc.contributor.author	Unnikrishnan, A	en_US
dc.contributor.author	Villanueva, JE	en_US
dc.contributor.author	Nunez, AC	en_US
dc.contributor.author	Knezevic, K	en_US
dc.contributor.author	Palu, C	en_US
dc.contributor.author	Nasrallah, R	en_US
dc.contributor.author	Carnell, M	en_US
dc.contributor.author	Macmillan, A	en_US
dc.contributor.author	Whan, R	en_US
dc.contributor.author	Yu, Y	en_US
dc.contributor.author	Hardy, P	en_US
dc.contributor.author	Grey, ST	en_US
dc.contributor.author	Gladbach, A	en_US
dc.contributor.author	Delerue, F	en_US
dc.contributor.author	Ittner, L	en_US
dc.contributor.author	Mobbs, R	en_US
dc.contributor.author	Walkley, CR	en_US
dc.contributor.author	Purton, LE	en_US
dc.contributor.author	Ward, RL	en_US
dc.contributor.author	Wong, JWH	en_US
dc.contributor.author	Hesson, LB	en_US
dc.contributor.author	Walsh, W	en_US
dc.contributor.author	Pimanda, JE	en_US
dc.date.issued	2016-04-19	en_US
dc.identifier.citation	Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 (16), pp. E2306 - E2315	en_US
dc.identifier.issn	0027-8424	en_US
dc.identifier.uri	http://hdl.handle.net/10453/122735
dc.description.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.	en_US
dc.relation.ispartof	Proceedings of the National Academy of Sciences of the United States of America	en_US
dc.relation.isbasedon	10.1073/pnas.1518244113	en_US
dc.subject.mesh	Cells, Cultured	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Transgenic	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Azacitidine	en_US
dc.subject.mesh	Platelet-Derived Growth Factor	en_US
dc.subject.mesh	Organ Specificity	en_US
dc.subject.mesh	Induced Pluripotent Stem Cells	en_US
dc.subject.mesh	Mesenchymal Stromal Cells	en_US
dc.subject.mesh	Cellular Reprogramming	en_US
dc.subject.mesh	Mesenchymal Stem Cells	en_US
dc.title	Pdgf-ab and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells	en_US
dc.type	Journal Article
utslib.citation.volume	16	en_US
utslib.citation.volume	113	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Software
pubs.organisational-group	/University of Technology Sydney/Strength - AAI - Advanced Analytics Institute Research Centre
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.issue	16	en_US
pubs.publication-status	Published	en_US
pubs.volume	113	en_US

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/122735