Stem Cells
- Sox2, a marker for stem‐like tumor cells in skin squamous cell carcinoma and hedgehog subgroup medulloblastoma
- 1Division of Pediatric Hematology‐Oncology, Duke University Medical Center, Durham, NC, USA
- 2Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA
- 3Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- 4Alvord Brain Tumor Center, University of Washington, Seattle, WA, USA
Heterogeneity within tumors is becoming increasingly recognized as an important cause of treatment failure in cancer. Two recent studies use fate‐mapping and limiting dilution transplantation assays to identify SRY (sex determining region Y)‐box 2 (Sox2) as cancer stem‐cell marker and driver of cancer stemness.
See also: RJ Vanner et al (July 2014),
S Boumahdi et al (July 2014) and
M Kool et al (March 2014)
The identification of Sox2 as cancer stem‐cell marker and driver of cancer stemness in distinct tumor types suggests that each tumor resembles the hierarchical organization of the tissue from which it arises.
- © 2014 The Authors
- MiR‐133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures
- Naoto Muraoka1,2,
- Hiroyuki Yamakawa1,2,
- Kazutaka Miyamoto1,2,
- Taketaro Sadahiro1,2,
- Tomohiko Umei1,
- Mari Isomi1,
- Hanae Nakashima1,
- Mizuha Akiyama1,
- Rie Wada1,
- Kohei Inagawa1,2,
- Takahiko Nishiyama1,2,
- Ruri Kaneda1,2,
- Toru Fukuda3,
- Shu Takeda3,
- Shugo Tohyama2,
- Hisayuki Hashimoto2,
- Yoshifumi Kawamura4,
- Naoki Goshima5,
- Ryo Aeba6,
- Hiroyuki Yamagishi7,
- Keiichi Fukuda2 and
- Masaki Ieda*,1,2,8
- 1Department of Clinical and Molecular Cardiovascular Research, Keio University School of Medicine, Shinjuku‐ku Tokyo, Japan
- 2Department of Cardiology, Keio University School of Medicine, Shinjuku‐ku Tokyo, Japan
- 3Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Bunkyo‐ku Tokyo, Japan
- 4Japan Biological Informatics Consortium (JBiC), Koto‐ku Tokyo, Japan
- 5Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Koto‐ku Tokyo, Japan
- 6Division of Cardiovascular Surgery, Keio University School of Medicine, Shinjuku‐ku Tokyo, Japan
- 7Department of Pediatrics, Keio University School of Medicine, Shinjuku‐ku Tokyo, Japan
- 8JST CREST, Shinjuku‐ku Tokyo, Japan
- ↵*Corresponding author. Tel: +81 3 5843 6702; Fax: +81 3 5363 3875; E‐mail: mieda{at}z8.keio.jp
Reprogramming of fibroblasts into cardiomyocytes is inefficient. Adding miR‐133a to the reprogramming cocktail increases the efficiency of the process in both mouse and human fibroblasts. Mechanistically, miR‐133a directly down‐regulates Snai1, a critical activator of the fibroblast transcriptional signature.
Synopsis
Reprogramming of fibroblasts into cardiomyocytes is inefficient. Adding miR‐133a to the reprogramming cocktail increases the efficiency of the process in both mouse and human fibroblasts. Mechanistically, miR‐133a directly down‐regulates Snai1, a critical activator of the fibroblast transcriptional signature.
MiR‐133 is induced by reprogramming factors during cardiac differentiation of fibroblasts.
Addition of miR‐133 to reprogramming factors strongly promotes cardiac differentiation from both mouse and human fibroblasts.
MiR‐133 directly represses Snai1, a master gene of epithelial‐to‐mesenchymal transition.
Snai1 suppression by miR‐133 silences fibroblast signatures and promotes direct cardiac differentiation in combination with the reprogramming factors.
The EMBO Journal (2014) 33: 1565–1581
- Received December 16, 2013.
- Revision received April 18, 2014.
- Accepted May 5, 2014.
- © 2014 The Authors
- ‘From blood to blood’: de‐differentiation of hematopoietic progenitors to stem cells
Recent studies have reported that fibroblasts or differentiated pluripotent cells can be reprogrammed with transcription factors (TFs) into cells with hematopoietic potential. A study published in Cell now suggests that committed blood precursors may provide a source for blood stem cell transplantation after reprogramming (Riddell et al, 2014). The authors report that a combination of eight TFs reprogram murine committed blood progenitors into long‐term engrafting and serially transplantable hematopoietic stem cells with a molecular signature similar to their endogenous counterparts.
See also: J Riddell et al (April 2014)
The reprogramming of committed blood progenitors offers a new route to generate long‐term engrafting, serially transplantable hematopoietic stem cells with future therapeutic potential.
- © 2014 The Authors
- NAD+ controls neural stem cell fate in the aging brain
Loss of the coenzyme NAD+, which is required for many energy‐dependent cellular processes, has emerged as a potentially unifying mechanism for age‐related conditions. A study in this issue of The EMBO Journal identifies a novel link between depletion of NAD+ and age‐associated loss of proliferating adult neural stem/progenitor cells in the murine brain (Stein & Imai, 2014). These data have important implications for how brain function might decline with age.
See also: LR Stein & S Imai (June 2014)
Age‐associated loss of NAD+ or Nampt, the rate‐limiting biosynthetic step for this coenzyme, accounts for the loss of neural stem/progenitor cells self‐renewal and differentiation.
- © 2014 The Authors
- Epithelial regeneration and cancer: news from the Src front
Src family kinases (SFKs) have long been implicated in tumorigenesis, but the exact requirement for individual kinase members, and their specific spatially and temporally defined roles in the maintenance of epithelial homeostasis remained unclear. A study by Cordero et al (2014) now combines the strengths of Drosophila and mouse models for intestinal epithelial regeneration to characterize the role of individual SFKs in epithelial stem cells, tissue regeneration, and tumorigenesis.
See also: JB Cordero et al (July 2014)
The experimental power of Drosophila and mouse models enables the functional dissection of distinct Src family kinase family members in the homeostasis of intestinal stem cells.
- © 2014 The Authors
- Wnt meets Warburg: another piece in the puzzle?
- Craig B Thompson (craig{at}mskcc.org) 1
One of the most common abnormalities of cancer cells is their predilection to engage in a high rate of glycolysis despite the continued availability of oxygen. First described by Otto Warburg, this phenomenon of aerobic glycolysis (or the Warburg effect) has recently been proposed to result from cancer‐associated alterations in signal transduction pathways. In this issue of The EMBO Journal, Pate et al provide further support for this hypothesis by demonstrating that Wnt signaling plays an important role in establishing aerobic glycolysis as a mechanism to support in vivo cancer cell proliferation.
See also: KT Pate et al (July 2014)
The discovery of PDK1 and the lactate transporter MCT‐1 as direct Wnt targets functionally links Wnt signaling to the aerobic switch and critical angiogenic responses in tumor cells and normal stem cells.
- © 2014 The Author
- Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging
- ↵*Corresponding author. Tel: +1 314 362 7228; Fax: +1 314 362 7058; E‐mail: imaishin{at}wustl.edu
NAD+ and the NAD+ biosynthetic enzyme Nampt decline in the aging hippocampus. Nampt ablation in adult neural stem cells in vivo reduces cell numbers, proliferation, and oligodendrogenesis. Decreases in the stem cell pool are reversed by enhancing hippocampal NAD+.
Synopsis
Levels of NAD+ and the NAD+ biosynthetic enzyme Nampt decline in the hippocampus during aging. Nampt ablation in adult neural stem/progenitor cells reduces self‐renewal, proliferation, and oligodendrogenesis. Age‐associated decreases in the stem cell pool are reversed by the administration of nicotinamide mononucleotide, a key NAD+ intermediate.
Nampt is expressed in adult neural/progenitor stem cells and is the main source of their NAD+ levels.
Loss of Nampt reduces proliferation by stalling progression of the neural stem/progenitor cell cycle at G0/G1.
The NAD+‐dependent sirtuins Sirt1 and Sirt2 redundantly mediate neural stem/progenitor cell fate decisions into oligodendrocytes.
Loss of Nampt reduces neural stem/progenitor cell‐derived oligodendrocyte regeneration after cuprizone‐induced demyelination.
The EMBO Journal (2014) 33: 1321–1340
- Received September 17, 2013.
- Revision received March 27, 2014.
- Accepted March 29, 2014.
- © 2014 The Authors
- MiR‐135b is a direct PAX6 target and specifies human neuroectoderm by inhibiting TGF‐β/BMP signaling
- Akshay Bhinge1,
- Jeremie Poschmann2,†,
- Seema C Namboori1,†,
- Xianfeng Tian1,†,
- Sharon Jia Hui Loh1,
- Anna Traczyk1,
- Shyam Prabhakar2 and
- Lawrence W Stanton*,1,3,4
- 1Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore City, Singapore
- 2Computational and Systems Biology, Genome Institute of Singapore, Singapore City, Singapore
- 3Department of Biological Sciences, National University of Singapore, Singapore City, Singapore
- 4School of Biological Sciences Nanyang Technological University, Singapore City, Singapore
- ↵*Corresponding author. Tel: +65 6478 8006; Fax: +65 6478 9051; E‐mail: stantonl{at}gis.a-star.edu.sg
-
↵† These authors contributed equally to this work.
A genome‐wide association study on the neural inducer Pax6 identifies miR‐135b as a novel Pax6 target that promotes neuroectoderm induction by antagonizing BMP and Activin/Nodal signals.
Synopsis
A genome‐wide association study on the neural inducer Pax6 identifies miR‐135b as a novel Pax6 target that promotes neuroectoderm (NE) induction by antagonizing BMP and Activin/Nodal signals.
Genome‐wide study to identify downstream targets of the master transcriptional regulator Pax6 in human NE;
Reports direct Pax6 localization to promoters of several TFs known to govern neural differentiation;
Reveals Pax6 regulation of microRNAs involved in neural specification;
Identifies Pax6 regulation of miR‐135b to inhibit TGF‐β and BMP signals and thus facilitate NE specification.
The EMBO Journal (2014) 33: 1271–1283
- Received October 22, 2013.
- Revision received April 3, 2014.
- Accepted April 3, 2014.
- © 2014 The Authors
- The ER under rapid fire
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease leading to selective death of upper and lower motoneurons. Clinically, the ALS syndrome is linked to pathogenic mutations in superoxide dismutase 1 (SOD1), though actual molecular mechanisms remain ill understood. Two papers recently published in Cell Stem Cell and Cell Reports employ syngenic, iPSC‐derived cell lines of one of the most severe SOD1 mutations to report mitochondrial and ER stress as causal for perturbed electrical activity in ALS neurons (Kiskinis et al, 2014; Wainger et al, 2014).
See also: E Kiskinis et al (April 2014) &
BJ Wainger et al (April 2014)
Combining the iPSC technology with genome‐editing/genome‐sequencing and cell‐biological tools offers intriguing novel insights into the molecular aberrations that cause fatal motoneuron death in ALS patients.
- © 2014 The Authors
- c‐Src drives intestinal regeneration and transformation
- Julia B Cordero15,
- Rachel A Ridgway1,
- Nicola Valeri2,
- Colin Nixon1,
- Margaret C Frame4,
- William J Muller3,
- Marcos Vidal1 and
- Owen J Sansom*,1
- 1The Beatson Institute for Cancer Research, Bearsden Glasgow, UK
- 2Institute of Cancer Research, Sutton London, UK
- 3Goodman Cancer Research Center McGill University, Montreal, QC, Canada
- 4Edinburgh Cancer Research Centre Institute of Genetics & Molecular Medicine University of Edinburgh, Edinburgh, UK
- 5Wolfson Wohl Cancer Research Centre Institute of Cancer Sciences University of Glasgow, Garscube Estate, Switchback Road, Bearsden Glasgow, UK
- ↵*Corresponding author: Tel: +44 141 330 3953; E‐mail: o.sansom{at}beatson.gla.ac.uk
These comprehensive, cross‐organismal experiments determine the evolutionary conservation and central position of Src family kinases in intestinal stem cell renewal, tumour formation and proliferative tissue regeneration.
Synopsis
These comprehensive, cross‐organismal experiments determine the evolutionary conservation and central position of Src family kinases in intestinal stem cell renewal, tumour formation and proliferative tissue regeneration.
Src is activated in stem/progenitor cells in response to damage and loss of Apc in the intestine.
Src is required for intestinal regeneration and Apc loss‐driven tumourigenesis.
Src family kinases are required for homeostatic self‐renewal of the intestinal epithelium.
Src requirement in intestine physiology and pathology is conserved from Drosophila to mammals.
The EMBO Journal (2014) 33: 1474–1491
- Received November 19, 2013.
- Revision received March 11, 2014.
- Accepted April 8, 2014.
- © 2014 The Authors. Published under the terms of the CC BY NC ND 4.0 license
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
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