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A decade of transcription factor-mediated reprogramming to pluripotency
This year marks the tenth anniversary of the generation of induced pluripotent stem cells (iPSCs) by transcription factor-mediated somatic cell reprogramming. Takahashi and Yamanaka portray the path towards this ground-breaking discovery and discuss how, since then, research has focused on understanding the mechanisms underlying iPSC generation and on translating such advances to the clinic.
The past 10 years have seen great advances in our ability to manipulate cell fate, including the induction of pluripotency
in vitro
to generate induced pluripotent stem cells (iPSCs). This process proved to be remarkably simple from a technical perspective, only needing the host cell and a defined cocktail of transcription factors, with four factors — octamer-binding protein 3/4 (OCT3/4), SOX2, Krüppel-like factor 4 (KLF4) and MYC (collectively referred to as OSKM) — initially used. The mechanisms underlying transcription factor-mediated reprogramming are still poorly understood; however, several mechanistic insights have recently been obtained. Recent years have also brought significant progress in increasing the efficiency of this technique, making it more amenable to applications in the fields of regenerative medicine, disease modelling and drug discovery.
Journal Article
Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection
The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n = 122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression. Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed. Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants. Expression of 'exhaustion' or 'immune checkpoint' markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches.
Journal Article
The mobile connection : the cell phone's impact on society
Has the cell phone forever changed the way people communicate? The mobile phone is used for \"real time\" coordination while on the run, adolescents use it to manage their freedom, and teens \"text\" to each other day and night. The mobile phone is more than a simple technical innovation or social fad, more than just an intrusion on polite society. This book, based on world-wide research involving tens of thousands of interviews and contextual observations, looks into the impact of the phone on our daily lives. The mobile phone has fundamentally affected our accessibility, safety and security, coordination of social and business activities, and use of public places. Based on research conducted in dozens of countries, this insightful and entertaining book examines the once unexpected interaction between humans and cell phones, and between humans, period. The compelling discussion and projections about the future of the telephone should give designers everywhere a more informed practice and process, and provide researchers with new ideas to last years. *Rich Ling (an American working in Norway) is a prominent researcher, interviewed in the new technology article in the November 9 issue of the New York Times Magazine. *A particularly \"good read\", this book will be important to the designers, information designers, social psychologists, and others who will have an impact on the development of the new third generation of mobile telephones. *Carefully and wittily written by a senior research scientist at Telenor, Norway's largest telecommunications company, and developer of the first mobile telephone system that allowed for international roaming.
eBook
Programming self-organizing multicellular structures with synthetic cell-cell signaling
The ability to program the manufacture of biological structures may yield new biomaterials or synthetic tissues and organs. Toda et al. engineered mammalian “sender” and “receiver” cells with synthetic cell surface ligands and receptors that controlled gene regulatory circuits based on Notch signaling. Programming the cells to express cell adhesion molecules and other regulatory molecules enabled spontaneous formation of multilayered structures, like those that form during embryonic development. The three-layered structures even showed regeneration after injury. Science , this issue p. 156 A synthetically engineered signaling system programs cell-cell contact–dependent pattern formation. A common theme in the self-organization of multicellular tissues is the use of cell-cell signaling networks to induce morphological changes. We used the modular synNotch juxtacrine signaling platform to engineer artificial genetic programs in which specific cell-cell contacts induced changes in cadherin cell adhesion. Despite their simplicity, these minimal intercellular programs were sufficient to yield assemblies with hallmarks of natural developmental systems: robust self-organization into multidomain structures, well-choreographed sequential assembly, cell type divergence, symmetry breaking, and the capacity for regeneration upon injury. The ability of these networks to drive complex structure formation illustrates the power of interlinking cell signaling with cell sorting: Signal-induced spatial reorganization alters the local signals received by each cell, resulting in iterative cycles of cell fate branching. These results provide insights into the evolution of multicellularity and demonstrate the potential to engineer customized self-organizing tissues or materials.
Journal Article
Environmental cues regulate epigenetic reprogramming of airway-resident memory CD8+ T cells
Tissue-resident memory T cells (T
RM
cells) are critical for cellular immunity to respiratory pathogens and reside in both the airways and the interstitium. In the present study, we found that the airway environment drove transcriptional and epigenetic changes that specifically regulated the cytolytic functions of airway T
RM
cells and promoted apoptosis due to amino acid starvation and activation of the integrated stress response. Comparison of airway T
RM
cells and splenic effector-memory T cells transferred into the airways indicated that the environment was necessary to activate these pathways, but did not induce T
RM
cell lineage reprogramming. Importantly, activation of the integrated stress response was reversed in airway T
RM
cells placed in a nutrient-rich environment. Our data defined the genetic programs of distinct lung T
RM
cell populations and show that local environmental cues altered airway T
RM
cells to limit cytolytic function and promote cell death, which ultimately leads to fewer T
RM
cells in the lung.
Kohlmeier and colleagues showed that the airway environment drove transcriptional and epigenetic changes that regulated the cytolytic functions of airway T
RM
cells and promoted their apoptosis due to amino acid starvation and activation of the integrated stress response.
Journal Article