Two Factor Reprogramming of Human Neural Stem Cells into Pluripotency

Hester, Mark E.; Song, SungWon; Miranda, Carlos J.; Eagle, Amy; Schwartz, Phillip H.; Kaspar, Brian K.

doi:10.1371/journal.pone.0007044

Cited by 63 publications

(42 citation statements)

References 32 publications

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“…It is wellestablished that hESC, unlike murine ESC, do not require LIF either for maintenance of pluripotency or for differentiation along the neuronal lineage [34][35][36][37][38], although the LIF receptor components are expressed in both hESC [34] and primate ESC [37]. In contrast, LIF affects the in vitro maintenance and differentiation of NP cells isolated from fetal as well as adult human sources [17,38,39].…”

Section: Discussionmentioning

confidence: 99%

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

et al. 2012

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Various growth factor cocktails have been used to proliferate and then differentiate human neural progenitor (NP) cells derived from embryonic stem cells (ESC) for in vitro and in vivo studies. However, the cytokine leukemia inhibitory factor (LIF) has been largely overlooked. Here, we demonstrate that LIF significantly enhanced in vitro survival and promoted differentiation of human ESC-derived NP cells. In NP cells, as well as NP-derived neurons, LIF reduced caspase-mediated apoptosis and reduced both spontaneous and H 2 O 2 -induced reactive oxygen species in culture. In vitro, NP cell proliferation and the yield of differentiated neurons were significantly higher in the presence of LIF. In NP cells, LIF enhanced cMyc phosphorylation, commonly associated with self-renewal/proliferation. Also, in differentiating NP cells LIF activated the phosphoinositide 3-kinase and signal transducer and activator of transcription 3 pathways, associated with cell survival and reduced apoptosis. When differentiated in LIF 1 media, neurite outgrowth and ERK1/2 phosphorylation were potentiated together with increased expression of gp130, a component of the LIF receptor complex. NP cells, pretreated in vitro with LIF, were effective in reducing infarct volume in a model of focal ischemic stroke but LIF did not lead to significantly improved initial NP cell survival over nontreated NP cells. Our results show that LIF signaling significantly promotes human NP cell proliferation, survival, and differentiation in vitro. Activated LIF signaling should be considered in cell culture expansion systems for future human NP cell-based therapeutic transplant studies.

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Section: Discussionmentioning

confidence: 99%

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

et al. 2012

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“…[2][3][4][5] Moreover, reprogramming by only two factors can be achieved, especially on less differentiated cells. [6][7][8][9][10] For mechanistic studies of reprogramming, mouse embryo fibroblasts (MEFs) are the most commonly used source of somatic cells. [10][11][12][13][14][15] These studies showed that reprogramming is largely a stochastic process that relies on multiple independent epigenetic events.…”

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confidence: 99%

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

Petrenko

Nemajerová

et al. 2013

Cell Death Differ

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Somatic cells can be converted into induced pluripotent stem cells (iPSCs) by forced expression of various combinations of transcription factors, but the molecular mechanisms of reprogramming are poorly understood. Specifically, evidence that the reprogramming process can take many distinct routes only begins to emerge. It is definitively established that p53 deficiency greatly enhances reprogramming, revealing p53's barrier function for induced pluripotency, but the role of its homologs p63 and p73 are unknown. Here we report that in stark contrast to p53, p73 has no role in reprogramming. However, p63 is an enabling (rather than a barrier) factor for Oct4, Sox2 and Klf4 (OSK) and Oct4 and Sox2 (OS), but not for Oct4 and Klf4 (OK) reprogramming of mouse embryonic fibroblasts. Specifically, p63 is essential during reprogramming for maximum efficiency, albeit not for the ability to reprogram per se, and is dispensable for maintaining stability and pluripotency of established iPSC colonies. DNp63, but not TAp63, is the principal isoform involved. Loss of p63 can affect reprogramming via several mechanisms such as reduced expression of mesenchymal-epithelial transition and pluripotency genes, hypoproliferation and loss of the most reprogrammable cell populations. During OSK and OS reprogramming, different mechanisms seem to be critical, such as regulation of epithelial and pluripotency genes in OSK reprogramming versus regulation of proliferation in OS reprogramming. Finally, our data reveal three different routes of reprogramming by OSK, OS or OK, based on their differential p63 requirements for iPSC efficiency and pluripotency marker expression. This supports the concept that many distinct routes of reprogramming exist.

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“…This implicates different levels of changes in DNA factor binding, transcription and chromatin state [103] . Since the discovery by Takahashi (known as OKMS) could reprogram mouse embryonic and adult fibroblasts into induced pluripotent stem cells (iPSCs) [104] , the field of reprogramming has considerably evolved and several studies have reported the use of sets of these transcription factors in various combinations to reprogram mouse and human somatic cells [105][106][107][108] . More recently, murine B lymphocytes, liver, stomach and pancreatic b-cells were showed to reprogram into iPSCs using the combination of factors OKMS [109][110][111] .…”

Section: Epigenetic Changes During Nscs Reprogramming To Induced Plurmentioning

confidence: 99%

Epigenetic regulation of stemness maintenance in the neurogenic niches

Montalbán-Loro

Domingo-Muelas

Bizy

et al. 2015

WJSC

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In the adult mouse brain, the subventricular zone lining the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus are two zones that contain neural stem cells (NSCs) with the capacity to give rise to neurons and glia during the entire life of the animal. Spatial and temporal regulation of gene expression in the NSCs population is established and maintained by the coordinated interaction between transcription factors and epigenetic regulators which control stem cell fate. Epigenetic mechanisms are heritable alterations in genome function that do not involve changes in DNA sequence itself but that modulate gene expression, acting as mediators between the environment and the genome. At the molecular level, those epigenetic mechanisms comprise chemical modifications of DNA such as methylation, hydroxymethylation and histone modifications needed for the maintenance of NSC identity. Genomic imprinting is another normal epigenetic process leading to parentalspecific expression of a gene, known to be implicated in the control of gene dosage in the neurogenic niches. The generation of induced pluripotent stem cells from NSCs by expression of defined transcription factors, provide key insights into fundamental principles of stem cell biology. Epigenetic modifications can also occur during reprogramming of NSCs to pluripotency and a better understanding of this process will help to elucidate the mechanisms required for stem cell maintenance. This review takes advantage of recent studies from the epigenetic field to report knowledge regarding the mechanisms of stemness maintenance of neural stem cells in the neurogenic niches.

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Two Factor Reprogramming of Human Neural Stem Cells into Pluripotency

Cited by 63 publications

References 32 publications

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

Epigenetic regulation of stemness maintenance in the neurogenic niches

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