Apoptotic Caspases Regulate Induction of iPSCs from Human Fibroblasts

Li, Fang; He, Zhiwei; Shen, Jingping; Huang, Qian; Li, Wenrong; Liu, Xinjian; He, Yonghong; Wolf, Frank de; Li, Chuan-Yuan

doi:10.1016/j.stem.2010.09.003

Cited by 99 publications

(83 citation statements)

References 68 publications

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“…Of note, both p70S6K and 4EBP1 are caspase substrates known to undergo cleavage during apoptosis. 17,18 Since GSK-3b inhibition is known to maintain the pluripotency of stem cells, 19 and caspases are implicated in iPSC generation, 2 we examined the blebbishields for expression of core stem-cell transcription factors. Blebbishields expressed Sox-2, Nanog, L-myc (but not c-Myc or N-myc) and hard-todetect low levels of Oct4, suggesting that the blebbishields possess stemness (Figure 2b; Supplementary Figures S2b and c).…”

Section: Resultsmentioning

confidence: 99%

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Blebbishields, the emergency program for cancer stem cells: sphere formation and tumorigenesis after apoptosis

et al. 2012

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Caspases mediate apoptosis and have also been implicated in stem-cell biology. How caspases are linked to stem-cell biology is not known. Here, we show that the apoptotic blebs of cancer cells fuse together to form novel structures called 'blebbishields'. Blebbishields form spheres by fusion. Both blebbishield formation and sphere formation involve active caspases and N-linked glycosylation. Sphere formation is enhanced by acidic pH and is counteracted by inhibitors of proton pump, caspases, and cholesterol. The blebbishields from VEGFR2 High cells are capable of enhanced sphere formation. Blebbishields express transiently downregulated stem-cell markers and the sphere-forming blebbishield-derived cells are tumorigenic. Our study demonstrates that the cancer stem cells can survive after apoptosis by blebbishield formation and subsequent sphere formation.

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Section: Resultsmentioning

confidence: 99%

“…1 Caspases have been implicated in the generation of iPSCs after transduction of iPSC inducing transcription factors. 2 It is not known whether iPSC generation is supported by the apoptotic or non-apoptotic functions of caspases. Hematopoietic stem cells (HSCs), iPSCs, and cancer stem cells (CSCs) share many characteristics in common.…”

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confidence: 99%

Blebbishields, the emergency program for cancer stem cells: sphere formation and tumorigenesis after apoptosis

et al. 2012

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“…Li et al documented the important finding of caspase involvement during reprogramming [49]. Two key apoptotic proteases, caspases 3 and 8, are activated following transduction of the reprogramming factors (c-Myc was excluded in their experiments because it is able to activate caspases and induce apoptosis).…”

Section: Apoptosis: Somatic Cell Reprogramming and The Role Of P53mentioning

confidence: 99%

Apoptosis: Reprogramming and the Fate of Mature Cells

2012

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Apoptosis is essential for embryogenesis, organ metamorphosis, and tissue homeostasis. In embryonic stem cells, self-renewal is balanced with proliferative potential, inhibition of differentiation, and prevention of senescence and apoptosis. Growing evidence supports the role of apoptosis in self-renewal, differentiation of pluripotent stem cells, and dedifferentiation (reprogramming) of somatic cells. In this paper we discuss the multiple roles of apoptosis in embryonic stem cells (ESCs) and reprogramming of differentiated cells to pluripotency. The role of caspases and p53 as key effectors in controlling the generation of iPSC is emphasized. Remarkably, the complication of apoptosis arising during reprogramming may provide insights into technical improvements for derivation of iPSC from senescent cells as a tool for modeling aging-related diseases.

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“…6 Apoptotic caspases have also been suggested to regulate B-lymphocyte proliferation, 7 HSC quiescence, 8 activation of microglia, 9 and the reprogramming of fibroblasts into iPS (induced pluripotent stem cells). 10 There are 2 pathways to apoptosis, the intrinsic and the extrinsic. Both ultimately converge on the apoptotic effector caspases, caspase-3 and caspase-7.…”

Section: Introductionmentioning

confidence: 99%

Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function

White

Schoenwaelder

Josefsson

et al. 2012

Blood

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Apoptotic caspases, including caspase-9, are thought to facilitate platelet shedding by megakaryocytes. They are known to be activated during platelet apoptosis, and have also been implicated in platelet hemostatic responses. However, the precise requirement for, and the regulation of, apoptotic caspases have never been defined in either megakaryocytes or platelets. To establish the role of caspases in platelet production and function, we generated mice lacking caspase-9 in their hematopoietic system. We demonstrate that both megakaryocytes and platelets possess a functional apoptotic caspase cascade downstream of Bcl-2 family-mediated mitochondrial damage. Caspase-9 is the initiator caspase, and its loss blocks effector caspase activation. Surprisingly, steady-state thrombopoiesis is unperturbed in the absence of caspase-9, indicating that the apoptotic caspase cascade is not required for platelet production. In platelets, loss of caspase-9 confers resistance to the BH3 mimetic ABT-737, blocking phospha- IntroductionApoptotic caspases are a family of aspartate-specific cysteinyl proteases that are activated during, and facilitate the execution of, programmed cell death. They cleave a range of cellular substrates, thereby causing the morphologic and biochemical signatures of apoptosis, such as DNA fragmentation, membrane blebbing, and phosphatidylserine (PS) externalization. In addition to their role in cell death, apoptotic caspases have been ascribed an increasing number of functions. These include critical roles in the differentiation of erythroid cells, 1 osteoblasts, 2 keratinocytes, 3 lens fiber cells, 4 skeletal muscle, 5 and embryonic stem (ES) cells. 6 Apoptotic caspases have also been suggested to regulate B-lymphocyte proliferation, 7 HSC quiescence, 8 activation of microglia, 9 and the reprogramming of fibroblasts into iPS (induced pluripotent stem cells). 10 There are 2 pathways to apoptosis, the intrinsic and the extrinsic. Both ultimately converge on the apoptotic effector caspases, caspase-3 and caspase-7. The intrinsic (or mitochondrial) apoptosis pathway is regulated by the interaction between Bcl-2 family proteins, which are divided into prosurvival and prodeath subsets. The critical mediators of the pathway are the prodeath proteins Bak and Bax, which, in viable cells are restrained by one or more of the 5 prosurvivals: Bcl-2, Bcl-x L , Mcl-1, Bcl-w, and A1. In response to apoptotic signals such as DNA damage or growth factor deprivation, a third group of Bcl-2 family members, the "BH3-only" proteins, trigger the activation of Bak and Bax. 11,12 Active Bak and Bax cause mitochondrial outer membrane permeabilization (MOMP), which allows apoptogenic factors, including cytochrome c, to enter the cytosol. 13 Cytochrome c interacts with the scaffolding protein Apaf-1. Subsequently, the initiator caspase, caspase-9, is recruited to the cytochrome c/Apaf-1 complex to form the apoptosome. 14 This leads to the activation of caspase-9 and triggering of the caspase cascade. The importance of the caspas...

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Apoptotic Caspases Regulate Induction of iPSCs from Human Fibroblasts

Cited by 99 publications

References 68 publications

Blebbishields, the emergency program for cancer stem cells: sphere formation and tumorigenesis after apoptosis

Blebbishields, the emergency program for cancer stem cells: sphere formation and tumorigenesis after apoptosis

Apoptosis: Reprogramming and the Fate of Mature Cells

Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function

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