mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert

This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2016.Contributed by Helen M. Blau, May 15, 2017 (sent for review April 3, 2017; reviewed by Douglas P. Millay and Fabio M. V. Rossi)Skeletal muscles harbor quiescent muscle-specific stem cells (MuSCs) capable of tissue regeneration throughout life. Muscle injury precipitates a complex inflammatory response in which a multiplicity of cell types, cytokines, and growth factors participate. Here we show that Prostaglandin E2 (PGE2) is an inflammatory cytokine that directly targets MuSCs via the EP4 receptor, leading to MuSC expansion. An acute treatment with PGE2 suffices to robustly augment muscle regeneration by either endogenous or transplanted MuSCs. Loss of PGE2 signaling by specific genetic ablation of the EP4 receptor in MuSCs impairs regeneration, leading to decreased muscle force. Inhibition of PGE2 production through nonsteroidal anti-inflammatory drug (NSAID) administration just after injury similarly hinders regeneration and compromises muscle strength. Mechanistically, the PGE2 EP4 interaction causes MuSC expansion by triggering a cAMP/phosphoCREB pathway that activates the proliferation-inducing transcription factor, Nurr1. Our findings reveal that loss of PGE2 signaling to MuSCs during recovery from injury impedes muscle repair and strength. Through such gain-or loss-of-function experiments, we found that PGE2 signaling acts as a rheostat for muscle stem-cell function. Decreased PGE2 signaling due to NSAIDs or increased PGE2 due to exogenous delivery dictates MuSC function, which determines the outcome of regeneration. The markedly enhanced and accelerated repair of damaged muscles following intramuscular delivery of PGE2 suggests a previously unrecognized indication for this therapeutic agent. muscle stem cells | PGE2 | regeneration | NSAIDs | strength

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“…The concomitant increase in the incidence of larger cell sizes observed after PGE2 treatment (Fig. 1K) supports its role in mitotic events (29).…”

Section: A Surge Of Pge2 In Damaged Muscle Tissues Accelerates Muscsupporting

confidence: 64%

Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength

Palla

Blake

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

184

169

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“…mTORC1 activity is necessary and sufficient for the transition of stem cells from a quiescent status to an active one (21). The present study found that the DNMT3A mutation contributed to hypomethylation in the gene body region of mTOR in Dnmt3a R878H/WT mice.…”

Section: Discussionsupporting

confidence: 54%

“…S6C). mTOR has been recently reported to play a role in adaptive transition of quiescent stem cells from G 0 to G Alert (21). Similarly, the percentage and number of both LSK and LRP cells significantly decreased in Dnmt3a R878H/WT mice treated with rapamycin ( Fig.…”

Section: Modulation Of Ezh2 By Cdk1 Leads To Changes Of H3k27 Trimethmentioning

confidence: 67%

Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement

Dai

Wang

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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DNMT3A is frequently mutated in acute myeloid leukemia (AML). To explore the features of human AML with the hotspot DNMT3A R882H mutation, we generated Dnmt3a R878H conditional knockin mice, which developed AML with enlarged Lin − Sca1 + cKit + cell compartments. The transcriptome and DNA methylation profiling of bulk leukemic cells and the single-cell RNA sequencing of leukemic stem/progenitor cells revealed significant changes in gene expression and epigenetic regulatory patterns that cause differentiation arrest and growth advantage. Consistent with leukemic cell accumulation in G 2 /M phase, CDK1 was up-regulated due to mTOR activation associated with DNA hypomethylation. Overexpressed CDK1-mediated EZH2 phosphorylation resulted in an abnormal trimethylation of H3K27 profile. The mTOR inhibitor rapamycin elicited a significant therapeutic response in Dnmt3a R878H/WT mice.have been identified in a subset of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL), with DNMT3A R882 being the hotspot (1-4). Clinical features of most AML cases with DNMT3A mutations include preferential involvement of a monocytic lineage (AML-M4 and -M5 subtypes), thrombocytosis, onset at a relatively old age, and poor prognosis (2, 5, 6). Careful genotypephenotype correlations suggest that patients manifest DNMT3A mutations in preleukemic hematopoietic stem cells (HSCs)/multipotent progenitors (MPPs), which exhibit a competitive advantage over normal HSCs. Because these mutations occur at a very early stage among genetic abnormalities, they are likely involved in the development of leukemia (7,8).Functionally, the DNMT3A R882 mutation might disrupt epigenetic regulation. This kind of DNMT3A mutation confers reduced methyltransferase activity and promotes the possibility of dominant-negative consequences compared with the wild-type (WT) allele (2, 9, 10). Moreover, the DNMT3A mutation causes aberrant DNA hypomethylation and up-regulates a series of target genes involved in AML pathogenesis (11-13).In vivo animal tests have shown that the Dnmt3a gene plays an essential role in hematopoiesis regulation. Dnmt3a −/− HSCs expand remarkably, but their differentiation is inhibited when Dnmt3a is conditionally inactivated in the murine hematopoietic system; this phenomenon is consistent with a preleukemic state (7). Moreover, all lethally irradiated mice transplanted with Dnmt3a-deleted HSCs died within 1 y and were diagnosed with a spectrum of malignancies similar to those observed in patients carrying DNMT3A mutations, including MDS, AML, primary myelofibrosis, and ALL, suggesting that Dnmt3a functions as a tumor suppressor (7). With a second hit of mutations in various genes such as N-RAS, C-KIT, or FLT3 in Dnmt3a −/− mice, Dnmt3a deletion induces leukemic transformation (14, 15). Although these results indicate a major role of Dnmt3a deletion in facilitating the development of leukemia, the in vivo roles of DNMT3A mutants in leukemogenesis still need to be addressed. In our previous work, b...

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“…41,44 c-Met is also involved in stem cell reprogramming and transitioning from a quiescent to an active self proliferating state. 45 Similarly, HIF2A is a hypoxia regulated transcription factor and effector of stem cell maintenance that drives GIC self-renewal, growth, and tumorigenicity, and its expression negatively correlates with glioma patient survival. 43 With respect to the regulation of differentiation processes, the miR-182-repressed transcriptome was enriched for a stem cell specific signature, mirrored phenotypically by reduced sphere size and expansion, and enhanced differentiation along neuronal and astroglial axes.…”

Section: Mir-182 Expression Influences Multiple Tumor Biological Propmentioning

confidence: 99%

miRNA-182 and the regulation of the glioblastoma phenotype - toward miRNA-based precision therapeutics

2015

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mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert

Cited by 661 publications

References 35 publications

Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength

Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength

Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement

miRNA-182 and the regulation of the glioblastoma phenotype - toward miRNA-based precision therapeutics

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