Thyroid hormone has role in fibrosis

Thyroid hormone (TH) activity was beneficial for resolving pulmonary fibrosis, or scarring of the lung, in mouse models of the disease, researchers from Yale University have reported. Pulmonary fibrosis can be the result of lung injury, but can also occur for unknown reasons, a condition known as idiopathic pulmonary fibrosis (IPF) that has been increasing in incidence and has a median survival time of three years from diagnosis. The team looked at changes in gene expression in lung epithelial cells of patients with IPF and showed that levels of a TH-activating enzyme were increased. The team then knocked out that enzyme in mice and showed that they had more severe pulmonary fibrosis in response to injury, indicating that TH activation was a protective response. Aerosolized TH reversed fibrosis in mice, through improving mitochondrial function. The authors concluded that "the antifibrotic properties of TH are associated with protection of alveolar epithelial cells and restoration of mitochondrial function and that TH may thus represent a potential therapy for pulmonary fibrosis." Their work appeared in the Dec. 4, 2017, online issue of Nature Medicine.

Engineered ovarian organoids an alternative to pills

Bioengineered ovarian organoids that recapitulated the interactions between different cell types could lead to safer alternatives to pharmacological hormone replacement. Loss of ovarian function, whether due to menopause or medical treatments, has negative health effects that can include sexual dysfunction, increased fat mass and decreased bone density. Pharmacological replacement of ovarian hormones comes with its own risks, though, most importantly an increased risk of gynecological cancers. Optimal levels of hormone replacement, however, might lead to benefits that outweigh the risks of hormone replacement. Researchers from Wake Forest University hypothesized that hormone levels might be optimized by cell-based treatment that could be susceptible to biological feedback from the hypothalamus-pituitary-ovary feedback control loop. They showed that treating rats with ovarian organoids that modeled the interaction of key ovarian cell types led to "stable secretion of hormones during 90 days of study. Further, we show these constructs with isogeneic cells to be effective in ameliorating adverse effects of hormone deficiency, including bone health, uterine health, and body composition in this rat model." The researchers reported their results in the Dec. 5, 2017, issue of Nature Communications.

In neurons, mutations start early, keep going

Two separate research groups have used single-cell analyses to gain new insights into mutation rates and patterns of neurons across the life span. One team, from the Mayo Clinic and Yale University, looked at brain cells from fetuses who died between 15 and 20 weeks of gestation, while researchers at Harvard Medical School looked at brains of both normal individuals ranging in age from 4 months to more than 80 years, and compared them to brains of individuals with early onset neurodegenerative disease. The scientists found that even fetuses had between 200 and 400 individual single-nucleotide variants (SNVs) per cell, and that the number of mutations increased linearly throughout life during normal aging. The mutations did show distinct patterns that were related to age, brain region and disease state. The researchers published their findings in back to back papers in the Dec. 7, 2017, online issue of Science.

CRISPR, in vivo

By using CRISPR/Cas9 to induce epigenetic gene activation, scientists at the Salk Institute for Biological Studies have improved the symptoms of type I diabetes, acute kidney injury and Duchenne muscular dystrophy. There are high hopes for CRISPR genome editing's clinical potential, but to date in vivo editing has been inefficient. Forms of the technology that induce double-stranded DNA breaks also have safety concerns associated with them. The team engineered CRISPR/Cas9 to activate target genes via actions of epigenetic regulators, obviating the need for double-stranded breaks, with sufficiently high efficiency to improve symptoms in mouse models of disease. "CRISPR/Cas9-mediated target gene activation can be achieved in vivo, leading to observable phenotypic changes and amelioration of disease symptoms. This establishes new avenues for developing targeted epigenetic therapies against human diseases," the authors wrote. They published their findings in the Dec. 7, 2017, issue of Cell.

Metabolism and HD

Huntington's disease (HD) neurons had impaired oxidative metabolism that could be rectified by treatment with peroxisome proliferator-activated receptor (PPAR)-delta agonists, suggesting a possible clinical strategy for HD and other neurodegenerative disorders. Neurons are energy hogs, and as a result, their mitochondria, which produce the cellular energy currency ATP, need to be in optimal working order to avoid problems. Researchers from the University of California at San Diego showed that treatment with the approved cancer drug bexarotene led to improved protein quality control, was neuroprotective in cellular and mouse models of HD, and improved motor function and survival in an HD mouse model. The authors concluded that "PPAR-delta activation may have therapeutic applications in HD and potentially other neurodegenerative diseases." They described their findings in the Dec. 6, 2017, issue of Science Translational Medicine.