Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells
From PNAS
By Stuart P. Atkinson
Tumour initiating stem cells (TISCs) are rare, highly malignant cells identified within diverse tumor types that share important similarities with embryonic stem cells (ESCs) (Clark and Fuller, Visvader and Lindeman and Clevers) including the mis-regulated expression of OCT4, SOX2, and NANOG (Chen et al and Kim et al). Studies have begun to give insight into the events behind TISC function, such as the loss of function of the type II TGF-β receptor and excessive activation of the IL-6 cytokine-signaling pathway, including the downstream effector STAT3 human hepatocellular carcinoma (HCC) (Baek et al and Tang et al). In a mouse model of HCC, isolation of highly tumourigenic CD133+/Nanog+ liver TISCs (Machida et al) on the basis of cell-surface receptors has suggested that identification of TISC-associated cell surface receptor expression and associated signal transduction pathways may be important for TISC function. Therefore researchers from the laboratories of Douglas Edmund Feldman and Keigo Machida at the University of Southern California sought to study this hypothesis and report that the leptin receptor (OB-R or Lepr), a transmembrane receptor for the adipocyte-derived peptide hormone leptin, is important for the tumourigenic nature of TISCs and also for the pluripotent nature of ESCs and induced pluripotent stem cells (iPSCs) (Feldman et al).
Skeletogenic phenotype of human Marfan ESCs faithfully phenocopied by patient-specific iPSCs
From PNAS
By Stuart P. Atkinson
Marfan syndrome (MFS) is a heritable dominant disorder caused by mutations in the FBN1 gene (Dietz et al and Pereira et al) affecting the skeletal, ocular and cardiovascular systems. FBN1 itself is an extracellular matrix (ECM) glycoprotein and although the molecular pathogenesis was originally thought to be due to resultant defects in the ECM, other results suggested that altered TGFβ signalling may be the main cause of pathogenic abnormalities in MFS (Dietz et al and Liu et al). Now, researchers from the laboratory of Michael Longlaker at the Standford University School of Medicine have succeeded in deriving FBN1 mutant human embryonic stem cells (hESCs) and also producing human induced pluripotent stem cells (hiPSCs) from FBN1 mutant fibroblasts (Quarto et al). Importantly, during this study of FBN1 mutations in hESCs, they also found that mutant hESCs and hiPSCs give rise to differentiated cells which demonstrate the same phenotype, demonstrating that iPSCs can provide complementary and powerful tools to gain further insights into human molecular pathogenesis.
New production method could fill major need for new sources of MSCs
Durham, NC – Stem cell scientists from the University of Queensland Centre for Clinical Research (UQCCR) in Australia have discovered a new method for producing mesenchymal stem/stromal cells (MSCs) from human iPSCs that substantially improves on current methods and speeds up conversion time. The research, published today in STEM CELLS Translational Medicine, reveals that treating iPSCs with the transforming growth factor-ß pathway inhibitor SB431542 leads to rapid and uniform MSC conversion of pluripotent stem cells without the need for embryoid body formation or feeder cell co-culture.
Study shows cardiac stem cells outperform bone marrow stem cells in treating heart attacks
Durham, NC – A new study by collaborating researchers at the University of Miami Miller School of Medicine and L’Institut du Thorax in Nantes, France, indicates that stem cells derived from cardiac tissue are far more effective in repairing damage caused by a heart attack than therapies using stem cells taken from bone marrow. The study, published today in STEM CELLS Translational Medicine, suggests that human fetal cardiac-derived c-kit+ stem cells (CSCs) can be 30 times more potent than bone marrow mesenchymal stem cells (MSCs) for treating a heart attack.
Interactions between cancer stem cells and their niche govern metastatic colonization
From Nature
By Stuart P. Atkinson
While metastatic tumour growth is the major cause of cancer mortality, this process is very inefficient for many cancers (Kouros-Mehr et al and Nguyen et al) and suggests that a barrier to implantation and growth exists to these few initiatory cancer cells mediated by the distant tissues in which they attempt to colonize. Further studies have demonstrated that metastases have prevalent target sites (Hess et al), again suggesting that normal tissue at the metastatic site may mediate colonisation. Now, researchers from the laboratory of Joerg Huelsken at the École Polytechnique Fédérale De Lausanne (EPFL), Switzerland have shown that cancer stem cells (CSCs), or tumour initiating stem cells (TISCs), are vitally important in metastatic growth but this is reliant on complex interactions between the CSCs and their metastatic niche (Malanchi and Santamaria-Martínez et al).
Rejuvenation of Regeneration in the Aging Central Nervous System
From Cell Stem Cell
By Stuart P. Atkinson
Oligodendrocytes precursor cells (OPCs) differentiate into oligodendrocytes with remyelination capabilities which, in the adult central nervous system (CNS), restores conduction, prevents axonal degradation and promotes functional recovery. Reduction in this capacity in aging (Sim et al) leads to demyelinated neurons and axonal degeneration, which is understood to be mediated in part by environmental signals (Hinks and Franklin). This suggests that exogenous factors may be able to reverse this age-associated decline in function, which has now been addressed in an article (Ruckh and Zhao et al) in Cell Stem Cell by researchers in the laboratory of Amy J. Wagers (Howard Hughes Medical Institute) and Robin J.M. Franklin (MRC Centre for Stem Cell Biology and Regenerative Medicine).
Generation of Chimeric Rhesus Monkeys
From Cell
By Stuart P. Atkinson
A recent research article in Cell from the laboratory of Shoukhrat Mitalipov at the Oregon National Primate Research Center at the Oregon Health & Science University has reported the generation of the first chimaeras from a non-human primate (Tachibana et al). In mouse, the ability to contribute to chimeric animals upon re-introduction into host embryos is the key feature of totipotent and pluripotent cells, and while chimaeric animals have been produced in other mammals (rats, rabbits, sheep and cattle) this had not been extended to non-human primates. Further as relatively little is known about human and non-human primate embryo development and lineage specification and how closely the mouse development reflects primates, research such as this promises to assess the usefulness of mouse models and mouse embryonic stem cells (mESCs) to human embryonic stem cell (hESC) biology
The Living Dead (of the iPSC world): Autopsy donor-derived iPSCs
From Neuroscience Letters
Commentary by Carla B. Mellough
In vitro disease modelling approaches largely involve the use of immortalised cell lines that have been genetically altered in order to induce a disease phenotype. While these systems provide valuable information, such models are unable to represent complex human disease aetiology and are therefore not always physiologically relevant. As induced pluripotent stem cells (iPSCs) retain the genetic profile of the somatic donor cell of origin, iPSCs represent an important additional option for disease modelling in vitro. This approach offers many advantages over previous methods, for example the non-invasive study of neurological or neurodegenerative conditions that are ordinarily impossible premortem, or certainly risk some cognitive or functional impairment if undertaken. Yet one major complication of this approach is that the effectiveness of iPSC disease models in vitro relies entirely upon the accuracy of the premortem diagnosis. In fact, most premortem diagnoses of neurological disease made from clinical criteria are not definite and can only be confirmed following postmortem histopathological analysis, so it would be advantageous if we could generate iPSC from post-mortem tissues. A study from Arizona, USA, by Hjelm et al.1 has demonstrated that iPSCs can indeed be generated from autopsy-derived fibroblasts. Creating iPSC lines from dead human tissues may be viewed by some as a little macabre, hence our reference to the 1974 film “The living dead” in the title, but in reality this development opens another avenue for iPSC-based disease modelling following a definite postmortem diagnosis.
