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• W2783702177 abstract "•We generated MEFS lacking two essential mediators of apoptosis, BAK and BAX•Loss of BAK and BAX significantly enhances MEF reprogramming in the presence of MYC•Thus, mitochondrial apoptosis limits reprogramming of MEFs in the presence of MYC•The integrity of the genome is not reduced in reprogrammed MEFs lacking BAK and BAX Despite intensive efforts to optimize the process, reprogramming differentiated cells to induced pluripotent stem cells (iPSCs) remains inefficient. The most common combination of transcription factors employed comprises OCT4, KLF4, SOX2, and MYC (OKSM). If MYC is omitted (OKS), reprogramming efficiency is reduced further. Cells must overcome several obstacles to reach the pluripotent state, one of which is apoptosis. To directly determine how extensively apoptosis limits reprogramming, we exploited mouse embryonic fibroblasts (MEFs) lacking the two essential mediators of apoptosis, BAK and BAX. Our results show that reprogramming is enhanced in MEFs deficient in BAK and BAX, but only when MYC is part of the reprogramming cocktail. Thus, the propensity for Myc overexpression to elicit apoptosis creates a significant roadblock to reprogramming under OKSM conditions. Our results suggest that blocking apoptosis during reprogramming may enhance the derivation of iPSCs for research and therapeutic purposes. Despite intensive efforts to optimize the process, reprogramming differentiated cells to induced pluripotent stem cells (iPSCs) remains inefficient. The most common combination of transcription factors employed comprises OCT4, KLF4, SOX2, and MYC (OKSM). If MYC is omitted (OKS), reprogramming efficiency is reduced further. Cells must overcome several obstacles to reach the pluripotent state, one of which is apoptosis. To directly determine how extensively apoptosis limits reprogramming, we exploited mouse embryonic fibroblasts (MEFs) lacking the two essential mediators of apoptosis, BAK and BAX. Our results show that reprogramming is enhanced in MEFs deficient in BAK and BAX, but only when MYC is part of the reprogramming cocktail. Thus, the propensity for Myc overexpression to elicit apoptosis creates a significant roadblock to reprogramming under OKSM conditions. Our results suggest that blocking apoptosis during reprogramming may enhance the derivation of iPSCs for research and therapeutic purposes. Reprogramming somatic cells to a pluripotent state can be achieved through ectopic expression of pluripotency transcription factors (Takahashi and Yamanaka, 2006Takahashi K. Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (18864) Google Scholar). The resulting induced pluripotent stem cells (iPSCs) hold immense promise as tools for research and regenerative therapy. To harness their full potential, studies have scrutinized the molecular mechanisms underpinning reprogramming, and sought to identify factors able to improve this inherently inefficient process (Esteban et al., 2010Esteban M.A. Wang T. Qin B. Yang J. Qin D. Cai J. Li W. Weng Z. Chen J. Ni S. et al.Vitamin C enhances the generation of mouse and human induced pluripotent stem cells.Cell Stem Cell. 2010; 6: 71-79Abstract Full Text Full Text PDF PubMed Scopus (789) Google Scholar, Onder et al., 2012Onder T.T. Kara N. Cherry A. Sinha A.U. Zhu N. Bernt K.M. Cahan P. Marcarci B.O. Unternaehrer J. Gupta P.B. et al.Chromatin-modifying enzymes as modulators of reprogramming.Nature. 2012; 483: 598-602Crossref PubMed Scopus (499) Google Scholar). One well-characterized means of enhancing reprogramming is to inhibit the activity of TP53/TRP53 (hereafter, p53) (Hong et al., 2009Hong H. Takahashi K. Ichisaka T. Aoi T. Kanagawa O. Nakagawa M. Okita K. Yamanaka S. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway.Nature. 2009; 460: 1132-1135Crossref PubMed Scopus (1062) Google Scholar, Kawamura et al., 2009Kawamura T. Suzuki J. Wang Y.V. Menendez S. Morera L.B. Raya A. Wahl G.M. Izpisua Belmonte J.C. Linking the p53 tumour suppressor pathway to somatic cell reprogramming.Nature. 2009; 460: 1140-1144Crossref PubMed Scopus (892) Google Scholar, Marion et al., 2009Marion R.M. Strati K. Li H. Murga M. Blanco R. Ortega S. Fernandez-Capetillo O. Serrano M. Blasco M.A. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity.Nature. 2009; 460: 1149-1153Crossref PubMed Scopus (842) Google Scholar, Utikal et al., 2009Utikal J. Polo J.M. Stadtfeld M. Maherali N. Kulalert W. Walsh R.M. Khalil A. Rheinwald J.G. Hochedlinger K. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells.Nature. 2009; 460: 1145-1148Crossref PubMed Scopus (695) Google Scholar). The improved reprogramming efficiency of p53-deficient cells has been attributed to the ability of p53 to trigger senescence and apoptosis. While senescence has been confirmed as a major reprogramming barrier (Banito et al., 2009Banito A. Rashid S.T. Acosta J.C. Li S. Pereira C.F. Geti I. Pinho S. Silva J.C. Azuara V. Walsh M. et al.Senescence impairs successful reprogramming to pluripotent stem cells.Genes Dev. 2009; 23: 2134-2139Crossref PubMed Scopus (488) Google Scholar, Kawamura et al., 2009Kawamura T. Suzuki J. Wang Y.V. Menendez S. Morera L.B. Raya A. Wahl G.M. Izpisua Belmonte J.C. Linking the p53 tumour suppressor pathway to somatic cell reprogramming.Nature. 2009; 460: 1140-1144Crossref PubMed Scopus (892) Google Scholar), the significance of mitochondrial apoptosis is less clear. Mitochondrial apoptosis is a conserved intrinsic cell death program controlled by interactions between diverse members of the BCL2 protein family, of which there are three functional classes: the pro-survival BCL2-like proteins, the pro-apoptotic BH3-only proteins, and the apoptosis effector proteins, BAK and BAX (Figure S1). In healthy cells, the BCL2-like survival proteins suppress mitochondrial apoptosis by restraining BAK and BAX. However, in response to various forms of cellular stress, including cytokine deprivation, DNA damage, and oncogene activation, BH3-only proteins are triggered to initiate apoptosis both by inhibiting BCL2-like proteins and by directly activating BAK and BAX. Once activated, BAK and BAX oligomerize on the outer mitochondrial membrane to drive its rupture (Czabotar et al., 2013Czabotar P.E. Westphal D. Dewson G. Ma S. Hockings C. Fairlie W.D. Lee E.F. Yao S. Robin A.Y. Smith B.J. et al.Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis.Cell. 2013; 152: 519-531Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar). The ensuing mitochondrial outer membrane permeabilization (MOMP) results in the efflux of pro-apoptogenic factors, including cytochrome c, to the cytosol. At this point, the cell is irreversibly committed to death, and a cascade of proteolytic caspases is activated that brings about the ordered demolition of cellular components. Deciphering the role of apoptosis in cellular processes can be complicated by the fact that each of the three classes of BCL2 family proteins comprises multiple family members, and that each of these proteins has a certain propensity to interact with and regulate the others (Chen et al., 2005Chen L. Willis S.N. Wei A. Smith B.J. Fletcher J.I. Hinds M.G. Colman P.M. Day C.L. Adams J.M. Huang D.C. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function.Mol. Cell. 2005; 17: 393-403Abstract Full Text Full Text PDF PubMed Scopus (1515) Google Scholar, Czabotar et al., 2014Czabotar P.E. Lessene G. Strasser A. Adams J.M. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy.Nat. Rev. Mol. Cell Biol. 2014; 15: 49-63Crossref PubMed Scopus (2141) Google Scholar, Willis et al., 2007Willis S.N. Fletcher J.I. Kaufmann T. van Delft M.F. Chen L. Czabotar P.E. Ierino H. Lee E.F. Fairlie W.D. Bouillet P. et al.Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak.Science. 2007; 315: 856-859Crossref PubMed Scopus (933) Google Scholar). As such, there is a large degree of functional overlap and redundancy within the family. Importantly for our studies, however, BAK and BAX are the only two BCL2 family members able to drive MOMP, and in their combined absence, the mitochondrial apoptosis pathway is completely abolished (Lindsten et al., 2000Lindsten T. Ross A.J. King A. Zong W.X. Rathmell J.C. Shiels H.A. Ulrich E. Waymire K.G. Mahar P. Frauwirth K. et al.The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues.Mol. Cell. 2000; 6: 1389-1399Abstract Full Text Full Text PDF PubMed Scopus (1191) Google Scholar). Thus far, attempts to resolve the role, if any, of mitochondrial apoptosis during reprogramming have primarily focused on upstream regulators, including BCL2, the archetypal pro-survival BCL2 family member, and PUMA, a p53-regulated BH3-only protein (Kawamura et al., 2009Kawamura T. Suzuki J. Wang Y.V. Menendez S. Morera L.B. Raya A. Wahl G.M. Izpisua Belmonte J.C. Linking the p53 tumour suppressor pathway to somatic cell reprogramming.Nature. 2009; 460: 1140-1144Crossref PubMed Scopus (892) Google Scholar, Lake et al., 2012Lake B.B. Fink J. Klemetsaune L. Fu X. Jeffers J.R. Zambetti G.P. Xu Y. Context-dependent enhancement of induced pluripotent stem cell reprogramming by silencing Puma.Stem Cells. 2012; 30: 888-897Crossref PubMed Scopus (25) Google Scholar, Li et al., 2013Li Y. Feng H. Gu H. Lewis D.W. Yuan Y. Zhang L. Yu H. Zhang P. Cheng H. Miao W. et al.The p53-PUMA axis suppresses iPSC generation.Nat. Commun. 2013; 4: 2174Crossref PubMed Scopus (53) Google Scholar). These studies have produced conflicting data, with two studies reporting significant enhancement of reprogramming efficiency when apoptosis was blocked, either through BCL2 overexpression or PUMA depletion (Kawamura et al., 2009Kawamura T. Suzuki J. Wang Y.V. Menendez S. Morera L.B. Raya A. Wahl G.M. Izpisua Belmonte J.C. Linking the p53 tumour suppressor pathway to somatic cell reprogramming.Nature. 2009; 460: 1140-1144Crossref PubMed Scopus (892) Google Scholar, Li et al., 2013Li Y. Feng H. Gu H. Lewis D.W. Yuan Y. Zhang L. Yu H. Zhang P. Cheng H. Miao W. et al.The p53-PUMA axis suppresses iPSC generation.Nat. Commun. 2013; 4: 2174Crossref PubMed Scopus (53) Google Scholar), and another reporting that PUMA depletion promoted reprogramming under OKS but not OKSM conditions (Lake et al., 2012Lake B.B. Fink J. Klemetsaune L. Fu X. Jeffers J.R. Zambetti G.P. Xu Y. Context-dependent enhancement of induced pluripotent stem cell reprogramming by silencing Puma.Stem Cells. 2012; 30: 888-897Crossref PubMed Scopus (25) Google Scholar). To directly evaluate the influence of apoptosis on the efficiency of reprogramming, we used mouse embryonic fibroblasts (MEFs) lacking both BAK and BAX. Such cells provide a definitive model system in which to study cellular processes in the absence of mitochondrial apoptosis (Lindsten et al., 2000Lindsten T. Ross A.J. King A. Zong W.X. Rathmell J.C. Shiels H.A. Ulrich E. Waymire K.G. Mahar P. Frauwirth K. et al.The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues.Mol. Cell. 2000; 6: 1389-1399Abstract Full Text Full Text PDF PubMed Scopus (1191) Google Scholar). Here, we report that Bak−/−;Bax−/− MEFs undergo reprogramming with markedly increased efficiency compared with their wild-type (WT) counterparts in OKSM, but not OKS conditions. Remarkably, they traverse this process without incurring significantly increased genomic instability. Our data conclusively demonstrate that mitochondrial apoptosis imposes a strong barrier to OKSM-mediated iPSC induction, and that this roadblock is MYC-dependent. While the overall efficiency of iPSC derivation is markedly improved with ectopic Myc expression, the heightened sensitivity to apoptosis curtails its full benefit in reprogramming. To examine the role of mitochondrial apoptosis in reprogramming, WT and Bak−/−;Bax−/− MEFs were transduced with lentiviral OKSM factors. After 18 days of reprogramming, Bak−/−;Bax−/− MEFs yielded alkaline phosphatase (AP)-positive colonies (Figure 1A) that were morphologically indistinguishable from those derived from WT MEFs (Figure S2A). Moreover, they displayed markedly improved reprogramming efficiency compared with WT MEFs, as measured by AP activity (Figure 1B) and verified by immunocytochemical staining of the pluripotency marker, NANOG (Figure S2B). Meanwhile, deficiency in either BAK or BAX alone did not significantly affect the yield of AP-positive colonies (Figures 1A and 1B). This is consistent with their functional redundancy in mediating MOMP, and proves that the increased reprogramming efficiency of Bak−/−;Bax−/− MEFs is attributable to attenuation of mitochondrial apoptosis. To further assess the pluripotency of colonies generated from Bak−/−;Bax−/− MEFs, we cultured them over at least five passages to confirm their self-renewal capacity, during which time they maintained a shiny, rounded morphology and expression of the pluripotency markers SSEA1, NANOG, and OCT4 (Figure 1C). These observations are consistent with those reported for embryonic stem cells deficient in BAK and BAX (Wang et al., 2015Wang E.S. Reyes N.A. Melton C. Huskey N.E. Momcilovic O. Goga A. Blelloch R. Oakes S.A. Fas-activated mitochondrial apoptosis culls stalled embryonic stem cells to promote differentiation.Curr. Biol. 2015; 25: 3110-3118Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). Next, to assess the differentiation capacity of Bak−/−;Bax−/− iPSCs, we generated embryoid bodies by the hanging drop method. Cells from three independent lines spontaneously differentiated into cells representative of all three germ layers (Figure 1D). Finally, we investigated the in vivo differentiation capacity of the Bak−/−;Bax−/− iPSC lines by injecting them subcutaneously into mice. The resulting teratomas contained tissues derived from all three germ layers (Figure 1E). Having observed that Bak−/−;Bax−/− MEFs reprogrammed more efficiently upon the expression of OKSM factors, we next tested whether this would also hold true when MEFs were reprogrammed without MYC, given its propensity to promote apoptosis. When MEFs were reprogrammed with only OKS, there was a striking decrease in iPSC formation compared with MEFs reprogrammed with OKSM (Figure 2A), consistent with previous reports (Nakagawa et al., 2008Nakagawa M. Koyanagi M. Tanabe K. Takahashi K. Ichisaka T. Aoi T. Okita K. Mochiduki Y. Takizawa N. Yamanaka S. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts.Nat. Biotechnol. 2008; 26: 101-106Crossref PubMed Scopus (2200) Google Scholar). However, there was no significant difference in reprogramming efficiencies between Bak−/−;Bax−/− and WT cultures (Figure 2A); this suggests that in the absence of ectopic MYC expression, apoptosis does not significantly limit reprogramming. Conversely, we hypothesize that ectopic MYC expression drives elevated levels of apoptosis that in turn limits the efficiency of OKSM reprogramming. To determine whether apoptosis was indeed elevated during OKSM relative to OKS reprogramming, we measured caspase-3/7 activity over the first 12 days of reprogramming using the Caspase-Glo 3/7 Assay System (Promega). To establish a reference for these assays, we induced apoptosis in 100% of MEFs by treating them with small molecule inhibitors of the pro-survival proteins, MCL1 (S63845; Kotschy et al., 2016Kotschy A. Szlavik Z. Murray J. Davidson J. Maragno A.L. Le Toumelin-Braizat G. Chanrion M. Kelly G.L. Gong J.N. Moujalled D.M. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models.Nature. 2016; 538: 477-482Crossref PubMed Scopus (654) Google Scholar) and BCLXL for 6 hr (A-1331,852; Leverson et al., 2015Leverson J.D. Phillips D.C. Mitten M.J. Boghaert E.R. Diaz D. Tahir S.K. Belmont L.D. Nimmer P. Xiao Y. Max Ma X. et al.Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy.Sci. Transl. Med. 2015; 7: 279ra40Crossref PubMed Scopus (363) Google Scholar). As expected, robust caspase-3/7 activity was elicited in WT but not Bak−/−;Bax−/− MEFs (Figure 2B). WT MEF cultures reprogrammed with OKSM exhibited elevated caspase-3/7 activity that peaked at approximately 10% of the level observed in the apoptotic reference sample (Figure 2C). Furthermore, caspase-3/7 activity was consistently higher in WT MEFs reprogrammed with OKSM compared with OKS throughout the duration of the experiment (Figure 2C). In contrast, we detected very low caspase-3/7 activity in reprogramming Bak−/−;Bax−/− MEFs (Figures 2B and 2C). These data are consistent with prior findings that ectopic MYC expression sensitizes cells to apoptosis (McMahon, 2014McMahon S.B. MYC and the control of apoptosis.Cold Spring Harb. Perspect. Med. 2014; 4: a014407Crossref PubMed Scopus (136) Google Scholar, Pelengaris et al., 2002Pelengaris S. Khan M. Evan G. c-MYC: more than just a matter of life and death.Nat. Rev. Cancer. 2002; 2: 764-776Crossref PubMed Scopus (918) Google Scholar) and lead us to conclude that mitochondrial apoptosis constitutes a major barrier to reprogramming when MYC is included as one of the pluripotency factors (Figure 2D). Thus, while MYC enhances overall reprogramming efficiency through reinforcing cell proliferation and growth, this is mitigated in part by an increase in BAK/BAX-mediated apoptosis. Previous studies have established p53 as a barrier to both OKSM and OKS-mediated reprogramming. While p53 drives a variety of cellular responses, it is primarily thought to hinder iPSC derivation by provoking senescence and apoptosis. Based on our observations that apoptosis was not a major barrier to OKS-mediated reprogramming (Figure 2A), we reasoned that deficiency of BAK and BAX would add little further advantage to p53-deficient cultures in OKS conditions. To test this, we introduced p53 mutations in primary MEFs using CRISPR/Cas9 targeting. Western blots confirmed that single-guide RNAs (sgRNAs) targeting either exon 4 or exon 5 of p53 were highly effective at ablating p53 expression (Figure 3A; Aubrey et al., 2015Aubrey B.J. Kelly G.L. Kueh A.J. Brennan M.S. O'Connor L. Milla L. Wilcox S. Tai L. Strasser A. Herold M.J. An inducible lentiviral guide RNA platform enables the identification of tumor-essential genes and tumor-promoting mutations in vivo.Cell Rep. 2015; 10: 1422-1432Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar). When reprogrammed with OKS, WT and Bak−/−;Bax−/− MEFs expressing Cas9 together with sgRNA targeting p53 both formed AP-positive iPSCs more efficiently than controls expressing only Cas9 (Figure 3B). However, we observed no significant difference between the reprogramming capacity of WT or Bak−/−;Bax−/− MEFs in the absence of p53 (Figure 3B). This confirms that when mitochondrial apoptosis is blocked in OKS conditions, other p53-driven responses, such as senescence, are likely to pose the primary reprogramming roadblocks. Apoptosis is sometimes regarded as a mechanism to safeguard genome integrity. A block in mitochondrial apoptosis might therefore have deleterious effects on genomic integrity during reprogramming. To investigate this, we examined DNA double-strand breaks and copy number alterations (CNAs) in several independent Bak−/−;Bax−/− iPSC lines that had been propagated for two or more passages. Using γH2AX as a marker, we quantified DNA double-strand breaks and found no significant difference between WT and Bak−/−;Bax−/− iPSC lines (Figures 4A and 4B ). Furthermore, using low pass whole genome sequencing, we observed no significant difference in the number of CNAs in iPSC clones derived from Bak−/–;Bax−/– MEFs compared with those derived from WT MEFs (Figures 4C, 4D, S3A, and S3B). Although this method is not sensitive enough to detect single-nucleotide aberrations that may occur during reprogramming, these results are consistent with reports that the process of reprogramming is not inherently mutagenic (Young et al., 2012Young M.A. Larson D.E. Sun C.W. George D.R. Ding L. Miller C.A. Lin L. Pawlik K.M. Chen K. Fan X. et al.Background mutations in parental cells account for most of the genetic heterogeneity of induced pluripotent stem cells.Cell Stem Cell. 2012; 10: 570-582Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar) and that embryonic stem cells lacking BAK and BAX maintain a normal karyotype (Wang et al., 2015Wang E.S. Reyes N.A. Melton C. Huskey N.E. Momcilovic O. Goga A. Blelloch R. Oakes S.A. Fas-activated mitochondrial apoptosis culls stalled embryonic stem cells to promote differentiation.Curr. Biol. 2015; 25: 3110-3118Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). In contrast, iPSC clones derived from p53-deficient MEFs exhibited a significantly higher number of CNAs compared with the Bak−/–;Bax−/– and WT groups (Figures 4C, 4D, and S3C). In summary, MEFs unable to execute mitochondrial apoptosis display enhanced reprogramming capacity with OKSM without notable changes in genome stability. Our observations lead us to conclude that MYC-driven BAK/BAX-mediated mitochondrial apoptosis presents a significant roadblock to OKSM reprogramming. While the overall effect of forced MYC expression favors reprogramming by regulating a broad range of biosynthetic processes required for enhanced cell growth and proliferation, including transcription, translation, and energy production (Nie et al., 2012Nie Z. Hu G. Wei G. Cui K. Yamane A. Resch W. Wang R. Green D.R. Tessarollo L. Casellas R. et al.c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells.Cell. 2012; 151: 68-79Abstract Full Text Full Text PDF PubMed Scopus (742) Google Scholar, Polo et al., 2012Polo J.M. Anderssen E. Walsh R.M. Schwarz B.A. Nefzger C.M. Lim S.M. Borkent M. Apostolou E. Alaei S. Cloutier J. et al.A molecular roadmap of reprogramming somatic cells into iPS cells.Cell. 2012; 151: 1617-1632Abstract Full Text Full Text PDF PubMed Scopus (622) Google Scholar, Sridharan et al., 2009Sridharan R. Tchieu J. Mason M.J. Yachechko R. Kuoy E. Horvath S. Zhou Q. Plath K. Role of the murine reprogramming factors in the induction of pluripotency.Cell. 2009; 136: 364-377Abstract Full Text Full Text PDF PubMed Scopus (524) Google Scholar), its propensity to sensitize cells to mitochondrial apoptosis partly mitigates these advantages (Figure 2D). In our hands, inhibiting apoptosis in Bak−/−;Bax−/− iPSCs does not compromise their capacity to differentiate into lineages derived from all three germ layers, both in vitro and in vivo, nor have an adverse effect on genome integrity." @default.
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• W2783702177 title "BAK/BAX-Mediated Apoptosis Is a Myc-Induced Roadblock to Reprogramming" @default.
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