DIY anti-inflammatories

To hear biomedical researchers tell it, chronic inflammation is practically the root of all evil. Now, a team at Washington University School of Medicine has reported using CRISPR/Cas9 to engineer stem cells modified for autonomous regenerative therapy, or SMART cells, that could produce an anti-inflammatory cytokine in response to excess inflammation. So far, experiments with the cells have been conducted in cell culture, but the goal is to transplant them into arthritic joints and have them replace degenerated tissue while preventing further degeneration by secreting anti-inflammatory biologics as necessary. "Our results show that genome engineering can be used successfully to rewire endogenous cell circuits to allow for prescribed input/output relationships between inflammatory mediators and their antagonists, providing a foundation for cell-based drug delivery or cell-based vaccines via a rapidly responsive, autoregulated system," the authors wrote. "The customization of intrinsic cellular signaling pathways in stem cells, as demonstrated here, opens innovative possibilities for safer and more effective therapeutic approaches for a wide variety of diseases." Their work appeared in the April 27, 2017, issue of Stem Cell Reports.

Enrichment helps heal

Environmental enrichment, in which research animals are housed in groups and in an interesting environment rather than alone, improved survival in male mice with colon cancer by strengthening processes that are involved in wound healing. Scientists from the Huntsman Cancer Institute investigated why animals that live in an enriched environment are better able to fight off cancer. They showed that an enriched environment activated pathways involved in wound healing in mice with colon cancer, including nuclear hormone receptor (NHR) signaling pathways. That enabled the animals to better wall off the tumor from its surroundings. The authors concluded that "reactivation of the NHR pathways in wound repair following [enriched environment] has revealed potential therapeutic strategies for pharmaceutical interventions that mimic the beneficial effects of [enriched environment] in wound repair in colon tumors." Their work appeared in the April 25, 2017, online issue of Cell Reports.

RNA for diagnostics

Despite the vast progress made in DNA sequencing for the diagnosis of rare disorders, there's still plenty of room for improvement – to date, the success rate for diagnosis through DNA sequencing is below 50 percent. Researchers from the Broad Institute have shown that by RNA sequencing (RNA-seq), they could diagnose the genetic cause of muscle disorders in about a third of patients where genome sequencing had not provided a diagnosis, by comparing their sequenced RNA transcriptome to a reference panel of healthy individuals. "This work suggests that RNA-seq is a valuable component of the diagnostic toolkit for rare diseases and can aid in the identification of new pathogenic variants in known genes as well as new mechanisms for Mendelian disease," the authors wrote. The findings appeared in the April 19, 2017, issue of Science Translational Medicine.

How FTD causes OCD

Frontotemporal dementia (FTD) is an early onset dementia whose worst symptoms are neuropsychiatric, including withdrawal, disinhibition, loss of empathy and compulsive behaviors. Researchers at the Gladstone Institute have traced the molecular route from progranulin mutations, which are found in a significant fraction of FTD patients, to obsessive-compulsive disorder (OCD)-like behaviors. They showed that knocking out progranulin specifically in microglia, which are immune cells of the brain, led to compulsive grooming as well as excitability of neurons in a midbrain region associated with OCD development. Progranulin knockouts produced excessive amounts of the cytokine TNF-alpha, and counteracting that excess production reversed both the compulsive behaviors and the neuronal firing abnormalities in knockout animals. The authors concluded that in mice, "OCD behavior results partially from elevated levels of the cytokine TNF-alpha and aberrant activation of immune cells of the brain known as microglia. Our findings provide evidence that targeting innate immune pathways could be a new therapeutic strategy to treat FTD." The team's findings appeared in the April 24, 2017, issue of the Proceedings of the National Academy of Sciences.

Polyglutamine impairs autophagy

The polyQ diseases, most famously Huntington's disease, are characterized by longer-than-normal stretches of glutamine in proteins that lead to neurodegeneration. While part of the toxicity of the polyQ repeats results from protein aggregations, the proteins are also toxic when they are not aggregated. Researchers from the British Cambridge University have discovered one mechanism of soluble protein toxicity. They found that the polyQ domain of ataxin, which causes ataxia when it has an expanded glutamine stretch, interacted with the key autophagy protein beclin-1. Proteins with longer polyglutamine stretches displaced proteins with shorter ones in cell and mouse models of ataxia and Huntington's disease. "Our data thus describe a specific function for a wild-type polyQ tract that is abrogated by a competing longer polyQ mutation in a disease protein, and identify a deleterious function of such mutations distinct from their propensity to aggregate," the authors wrote. Their work appeared in the April 26, 2017, online issue of Nature.

Organoids: Brain . . .

Two groups described generating organoid systems of the developing brain. Organoid model systems, which have been developed for a number of organs, are more naturalistic in vitro systems than cell lines. Previously, researchers had generated an organoid that mimicked the connections found in the forebrain. In their new work, separate teams from Stanford University and Massachusetts General Hospital, respectively, developed organoids consisting of multiple cell types that connected to each other. The Massachusetts General Hospital group developed an organoid that included light-sensitive cells, offering the possibility of modeling sensory input into the brain. The Stanford researchers focused on the interplay between excitation and inhibition in the forebrain, an approach that may give insight into neurodevelopmental disorders where such signaling is out of balance. Both papers appeared in the April 26, 2017, online issue of Nature.

. . . And Breath

Researchers have developed lung bud organoids from stem cells, adding lungs to the organs for which a 3-D model culture exists. The team from Columbia University used human pluripotent stem cells to develop lung bud organoids, which contained several different cell types and developed into branching structures and alveolar cells. Gene expression analysis showed that the organoids reached the developmental stage of lungs in second trimester fetuses. The organoids recapitulated the response to infant lungs in models of both respiratory syncytial virus infection and a genetic form of pulmonary fibrosis, showing, the authors wrote, that their organoids "recapitulate lung development and may provide a useful tool to model lung disease." They published their findings in the April 24, 2017, issue of Nature Cell Biology.

Pluripotency pitfall

Through sequencing 140 lines of human pluripotent stem (hPS) cells, including more than two dozen lines prepared for potential clinical use, researchers from Harvard University have shown that five unrelated lines carried mutations in the tumor suppressor gene TP53. The mutations were the ones most frequently encountered in human cancers and were more likely to be in cell lines that had been cultured through more divisions, suggesting they conferred a growth advantage. A literature search of published RNA sequencing data from 117 hPS cell lines turned up another nine lines with TP53 mutations. The authors wrote, "As the acquisition and expansion of cancer-associated mutations in hPS cells may go unnoticed during most applications, we suggest that careful genetic characterization of hPS cells and their differentiated derivatives be carried out before clinical use," but also stressed that most of the lines they investigated were TP53 mutation-free and concluded that "regenerative medicine remains a viable and exciting goal that is more likely to succeed as potential pitfalls, like the one we report here, are identified and addressed." Their findings appeared in the April 27, 2017, issue of Nature.

Making more muscle

Aging muscles no longer regenerate muscle fibers because they permanently turn on the DNA damage response. Muscles, like other body parts, become less able to repair themselves as the body ages, going into a state of senescence. Researchers from Sanford Burnham Prebys Medical Discovery Institute and the Italian Institute of Translational Pharmacology looked into the molecular underpinnings of that inability. They found that the DNA damage response, which prevents cells from progressing through the cell division cycle, is permanently activated in aging muscle cells. Inhibiting the DNA damage response could re-start muscle cell division, but increase the risk that the resulting muscle fibers would have abnormalities, leading the authors to caution that the "finding raises concerns on the potential detrimental effects of anti-aging treatments aimed at reversing cellular senescence, as they might lead to the formation of genetically unstable myofibers with impaired functions." Their work appeared in the April 26, 2017, issue of Genes & Development.

Single-dose antimalarial

A new small molecule was able to block at least parts of all life cycle stages of the malaria parasite Plasmodium vivax in mice and primates. P. vivax has a complicated life cycle, complicating efforts to fight malaria, which is one of the major killers in the developing world. Previous work had shown that the parasite kinase phosphatidylinositol 4-kinase (PI4K) was a target that could interfere with all stages of the parasite's life cycle. Researchers from the South African University of Cape Town developed MMV-390048 and showed that the compound had the ability to block all stages of the malaria parasite in both humans and mosquitoes, with the exception of the late stage of human liver infection. "The ability of MMV-390048 to block all life cycle stages of the malaria parasite suggests that this compound should be further developed and may contribute to malaria control and eradication as part of a single-dose combination treatment," the authors wrote. Such single-dose treatment is a particularly desirable feature for drugs used in low-resource settings. The work appeared in the April 26, 2017, issue of Science Translational Medicine.