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Genomic Instability in Induced Stem Cells Cell Death and Differentiation (2011) 18, 745–753 & 2011 Macmillan Publishers Limited All rights reserved 1350-9047/11 www.nature.com/cdd Genomic instability in induced stem cells CE Pasi1,8, A Dereli-O¨ z2,8, S Negrini2,8, M Friedli3, G Fragola1,4, A Lombardo5, G Van Houwe2, L Naldini5, S Casola4, G Testa1, D Trono3, PG Pelicci*,1,6 and TD Halazonetis*,2,7 The ability to reprogram adult cells into stem cells has raised hopes for novel therapies for many human diseases. Typical stem cell reprogramming protocols involve expression of a small number of genes in differentiated somatic cells with the c-Myc and Klf4 proto-oncogenes typically included in this mix. We have previously shown that expression of oncogenes leads to DNA replication stress and genomic instability, explaining the high frequency of p53 mutations in human cancers. Consequently, we wondered whether stem cell reprogramming also leads to genomic instability. To test this hypothesis, we examined stem cells induced by a variety of protocols. The first protocol, developed specifically for this study, reprogrammed primary mouse mammary cells into mammary stem cells by expressing c-Myc. Two other previously established protocols reprogrammed mouse embryo fibroblasts into induced pluripotent stem cells by expressing either three genes, Oct4, Sox2 and Klf4, or four genes, OSK plus c-Myc. Comparative genomic hybridization analysis of stem cells derived by these protocols revealed the presence of genomic deletions and amplifications, whose signature was suggestive of oncogene-induced DNA replication stress. The genomic aberrations were to a significant degree dependent on c-Myc expression and their presence could explain why p53 inactivation facilitates stem cell reprogramming. Cell Death and Differentiation (2011) 18, 745–753; doi:10.1038/cdd.2011.9; published online 11 February 2011 Recent studies have demonstrated that it is possible to suggested that the absence of p53 enhances reprogramming, reprogram somatic cells into pluripotent stem cells by because it enhances cell proliferation.15 However, p53 is a expressing a specific combination of transcription factors.1–5 DNA damage response gene,16 raising the possibility that The typical mix of transcription factors used for this purpose reprogramming is accompanied by DNA damage and includes the oncogenes c-Myc and Klf4. Interestingly, genomic instability. Consistent with this interpretation, iPS oncogenes have the potential to induce genomic instability,6 cells generated from mouse embryo fibroblasts (MEFs) which raises the possibility that induced pluripotent stem (iPS) lacking p53 function, form malignant tumors when injected cells have aberrant genomes. in donor mice.17 Given the excitement in the stem cell field by the ability to In this study, we examined directly the genomes of induced transform adult differentiated cells into pluripotent stem cells, stem cells by array-based comparative genomic hybridization it is not surprising that research has focused mainly on (cGH) analysis. Using three different experimental systems, methods that enhance reprogramming efficiency, with less we report genomic aberrations in induced stem cells. These attention been paid to the genomic status of the generated iPS aberrations were associated with oncogene-induced DNA cells.7–9 However, the presence of genomic aberrations in iPS replication stress. cells could be one of the reasons why the efficiency with which these cells produce live mice in tetraploid complementation assays is very low.10 Results The possibility that aberrant genomes are prevalent in iPS cells became more likely after the demonstration that Genomic instability in induced mammary stem cells. As p53 inactivation facilitates reprogramming.11–14 One study a first step in exploring whether stem cell reprogramming is 1Department of Experimental Oncology at the IFOM-IEO Campus, Istituto Europeo di Oncologia, Milan, Italy; 2Department of Molecular Biology, University of Geneva, Geneva, Switzerland; 3School of Life Sciences, Ecole Polytechnique Fe´de´rale de Lausanne, Lausanne, Switzerland; 4IFOM, FIRC Institute of Molecular Oncology Foundation, Milan, Italy; 5San Raffaele Telethon Institute for Gene Therapy, Vita Salute San Raffaele University, Milan, Italy; 6Dipartimento di Medicina, Chirurgia ed Odontoiatria, Universita degli Studi di Milano, Milan, Italy and 7Department of Biochemistry, University of Geneva, Geneva, Switzerland *Corresponding authors: PG Pelicci, Istituto Europeo di Oncologia (IEO), Department of Experimental Oncology at the IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy. Tel: þ 39 02 5748 9831; Fax: þ 39 02 5748 9851; E-mail: [email protected] or TD Halazonetis, Department of Molecular Biology, University of Geneva, quai Ernest-Ansermet 30, 1205 Geneva, Switzerland. Tel: þ 41 22 379 6112; Fax: þ 41 22 379 68 68; E-mail: [email protected] 8These authors contributed equally to this work. Keywords: induced pluripotent stem cells; genomic instability; c-Myc Abbreviations: iPS, induced pluripotent stem; OSK, Oct4, Sox2, Klf4; OSKC, Oct4, Sox2, Klf4, c-Myc ; TAM, 4-hydroxytamoxifen; MEF, mouse embryo fibroblast; CFS, common fragile site; cGH, comparative genomic hybridization; CNC, copy number change; Rora, retinoic acid receptor-related orphan receptor A; Pde4D, phosphodiesterase 4D; Ptprg, protein tyrosine phosphatase receptor type G; Fhit, fragile histidine triad; Jarid2, jumonji AT rich interactive domain 2; Dtnbp1, dystrobrevin-binding protein 1; Odz3, odd Oz/ten-m homolog 3; Cdh13, cadherin 13; Fto, fat mass and obesity associated; Dock3, dedicator of cytokinesis 3; Cadm2, cell adhesion molecule 2; Lsamp, limbic system-associated membrane protein; Naaladl2, N-acetylated alpha-linked acidic dipeptidase-like 2; Erc2, ELKS–RAB6-interacting/CAST family member 2 Received 10.1.11; revised 13.1.11; accepted 13.1.11; Edited by G Melino; published online 11.2.11 Genomic instability in induced stem cells CE Pasi et al 746 accompanied by genomic instability, we developed a protocol ability to form mammospheres and repopulate a cleared for inducing mammary stem cells. The protocol involves mouse fat pad (Figure 1). expressing c-Myc, one of the four original stem cell Having established that c-Myc can reprogram mammary reprogramming genes, in mouse mammary cells and progenitor cells into stem cells, we repeated these experi- examining whether these cells acquire stem cell properties, ments bypassing the PKH26-sorting step. Control virus- such as the ability to form mammospheres in vitro and to infected mammospheres prepared from wild-type mice could repopulate cleared mouse fat pads.18 be maintained only for a few passages in tissue culture, We first attempted to reprogram nearly homogeneous suggesting exhaustion of the stem cell population. In contrast, populations of mammary progenitor cells. These cells, chosen mammospheres infected with the virus-expressing MycER because they lack stem cell properties, were obtained using a could be easily expanded with no signs of crisis or stem cell previously described PKH26-based label-retaining protocol.19 exhaustion and could also repopulate a cleared mouse fat pad Briefly, primary mammary cells were pulse-labeled with the (Figure 2). lipophilic, fluorescent-dye PKH26 and then cultured as The reprogramming of mammary progenitor cells into mammospheres for two passages. At this time, PKH26-high mammary stem cells described above was performed in the cells (about 0.3% of all cells, representing stem cells) and absence of 4-hydroxytamoxifen (TAM). When TAM was added PKH26-negative cells (about 30% of all cells, representing to the media, nuclear MycER protein levels increased (Supple- progenitor cells) were isolated by flow sorting.19 The PKH26- mentary Figure 1a) and the MycER-expressing mammosphere negative cells were then infected with a control lentivirus or a cultures were exhausted within one passage (Figure 2a). This lentivirus-expressing MycER, a c-Myc protein containing a was associated with phosphorylation and stabilization of p53, modified estrogen receptor hormone-binding domain at its expression of p53 target genes and apoptosis (Supplementary C-terminus.20 Five thousand infected cells were cultured Figure 1b), suggesting that high levels of MycER protein under non-adherent conditions to generate mammospheres, induced a p53-dependent DNA damage response.16,21–23 which were then passaged on a weekly basis. The control- Consistent with this scenario, MycER-expressing mammo- infected progenitor cells formed mammospheres with very low spheres prepared from p53À/À mice could be expanded in the efficiency even at the first passage and both the mammo- presence of TAM (Figure 2a). During stem cell reprogramming, sphere number and the cumulative cell number declined to MycER levels were lower and apparently insufficient to induce practically zero within a few passages (Figures 1a–c). In an overt DNA damage response (Supplementary Figure 1b), contrast, the MycER-expressing progenitor cells were repro- but whether they were low enough to prevent induction of grammed into mammary stem cells, as ascertained by their genomic instability was not clear. 103 106 MycER MycER 102 105 101 104 100 103 Empty Cell Number -1 2 10 Vector 10 Empty Vector Mammosphere Number 10-2 101 142 3 5 1 2 3 4 5 Passage Number Passage Number Passage #1 Passage #2 MycER Empty Vector Figure 1 Reprogramming of progenitor mammary cells to stem cells by MycER. (a and b) PKH26-negative cells, which are devoid of stem cells,
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