title: PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells.
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 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.
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia; jpimanda@unsw.edu.au v.chandrakanthan@unsw.edu.au.
authors.forename: Vashe
authors.initials: V
authors.lastname: Chandrakanthan
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Avani
authors.initials: A
authors.lastname: Yeola
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Jair C
authors.initials: JC
authors.lastname: Kwan
authors.affiliation: The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia; Surgical and Orthopaedic Research Laboratories, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Rema A
authors.initials: RA
authors.lastname: Oliver
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Qiao
authors.initials: Q
authors.lastname: Qiao
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Young Chan
authors.initials: YC
authors.lastname: Kang
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Peter
authors.initials: P
authors.lastname: Zarzour
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Dominik
authors.initials: D
authors.lastname: Beck
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Lies
authors.initials: L
authors.lastname: Boelen
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Ashwin
authors.initials: A
authors.lastname: Unnikrishnan
authors.affiliation: Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia;
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Villanueva
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Nunez
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Kathy
authors.initials: K
authors.lastname: Knezevic
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Cintia
authors.initials: C
authors.lastname: Palu
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Rabab
authors.initials: R
authors.lastname: Nasrallah
authors.affiliation: Mark Wainwright Analytical Centre, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Michael
authors.initials: M
authors.lastname: Carnell
authors.affiliation: Mark Wainwright Analytical Centre, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Alex
authors.initials: A
authors.lastname: Macmillan
authors.affiliation: Mark Wainwright Analytical Centre, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Renee
authors.initials: R
authors.lastname: Whan
authors.affiliation: The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia; Surgical and Orthopaedic Research Laboratories, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Cyto Labs Pty. Ltd. Australia, School of Medicine and Pharmacology, University of Western Australia, Fremantle, WA 6102, Australia;
authors.forename: Philip
authors.initials: P
authors.lastname: Hardy
authors.affiliation: Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia;
authors.forename: Shane T
authors.initials: ST
authors.lastname: Grey
authors.affiliation: Dementia Research Unit, Department of Anatomy, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia;
authors.forename: Amadeus
authors.initials: A
authors.lastname: Gladbach
authors.affiliation: Dementia Research Unit, Department of Anatomy, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia;
authors.forename: Fabien
authors.initials: F
authors.lastname: Delerue
authors.affiliation: Dementia Research Unit, Department of Anatomy, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia; Neuroscience Research Australia, Sydney, NSW 2031, Australia;
authors.forename: Lars
authors.initials: L
authors.lastname: Ittner
authors.affiliation: Department of Neurosurgery, The Prince of Wales Hospital, Sydney, NSW 2032, Australia;
authors.forename: Ralph
authors.initials: R
authors.lastname: Mobbs
authors.affiliation: St. Vincent's Institute of Medical Research, The University of Melbourne, Fitzroy, VIC 3065, Australia; The Department of Medicine, The University of Melbourne, Melbourne, VIC 3010, Australia;
authors.forename: Carl R
authors.initials: CR
authors.lastname: Walkley
authors.affiliation: St. Vincent's Institute of Medical Research, The University of Melbourne, Fitzroy, VIC 3065, Australia; The Department of Medicine, The University of Melbourne, Melbourne, VIC 3010, Australia;
authors.forename: Louise E
authors.initials: LE
authors.lastname: Purton
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Ward
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Jason W H
authors.initials: JW
authors.lastname: Wong
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: Luke B
authors.initials: LB
authors.lastname: Hesson
authors.affiliation: The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia; Surgical and Orthopaedic Research Laboratories, UNSW Australia, Sydney, NSW 2052, Australia;
authors.forename: William
authors.initials: W
authors.lastname: Walsh
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales (UNSW) Australia, Sydney, NSW 2052, Australia; The Prince of Wales Clinical School, UNSW Australia, Sydney, NSW 2052, Australia; Department of Haematology, The Prince of Wales Hospital, Sydney, NSW 2032, Australia jpimanda@unsw.edu.au v.chandrakanthan@unsw.edu.au.
authors.forename: John E
authors.initials: JE
authors.lastname: Pimanda
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000494:pharmacology*; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*
chemical_list: D010982:Platelet-Derived Growth Factor; C095477:platelet-derived growth factor AB; D001374:Azacitidine
keywords: 5-Azacytidine; cell reprogramming; multipotent stem cells; platelet-derived growth factor-AB; tissue regeneration