Investigators Uncover Small Molecule to Engineer Intestinal Cell Types

Paneth cells (red) within a small intestinal organoid treated with Xpo1 inhibitor

Investigators at the Brigham and the Broad Institute have created specialized, tissue-like structures in the laboratory to model barrier tissues, such as the intestines, to identify new targets for treatment. Barrier tissues are exposed to substances from the outside world but serve as a layer of protection. Over the years, researchers have developed more sophisticated, three-dimensional models of epithelial barrier tissues, such as the intestine. These models are known as intestinal organoids. In a new study, investigators discovered a tissue-modifying molecule that can target intestinal stem cells and signal them to create Paneth cells, a rare but important cell type that can alter the gut microbiota. Previous studies have shown that Paneth cells are depleted in diseases such as inflammatory bowel disease and graft-versus-host disease. Replenishing these rare cells could represent a new therapeutic pathway. The team’s approach could also be used to identify molecules that could target other intestinal cell types.

“Our paper provides the first approach to engineering our barrier tissues like the intestine by targeting and activating stem cells in situ and causing new important cell types to form,” said co-lead author Benjamin Mead, PhD, of the Broad Institute. “This could be used to potentially treat a wide range of diseases by manipulating the cell composition of the intestine.”

“This approach has wide ranging implications and can be used to manipulate the cellular makeup of the intestine, including cells that can enhance barrier function, produce gut hormones, or that have key roles in coordinating insulin levels as well as food digestion and absorption,” said co-corresponding author Jeff Karp, PhD, Distinguished Chair in Clinical Anesthesiology, Perioperative and Pain Medicine. “This approach also enables a completely new strategy to manipulate gut microbiota and thus offer insights into the treatment of a wide range of diseases.”

Read more in Nature Biomedical Engineering.

Metabolomic Study Links Inhaled Cortical Steroid Treatment for Asthma to Adrenal Suppression

Inhaled cortical steroids (ICS) can help patients manage asthma symptoms, and recent updates to asthma treatment guidelines have expanded recommended, low-dose treatment. But concerns persist that ICS may reduce production of the steroid hormone cortisol in the body leading to adrenal suppression. While initial adrenal suppression symptoms are subtle, continued progression can lead to fatigue, headache, abdominal pain, vomiting and psychiatric symptoms.

Until now, studies of ICS and adrenal suppression have been limited and have produced conflicting findings.  To better understand the association between ICS and adrenal suppression, researchers from Brigham and Women’s Hospital and the University of Cambridge conducted the largest metabolomic study of asthma to date. By analyzing the blood plasma of 14,000 individuals from four independent study cohorts, the team identified 17 steroid metabolites that were reduced in individuals with asthma and found that, even among patients taking low-dose ICS, ICS usage was associated with reduced cortisol levels. The researchers also found significant associations between adrenal insufficiency symptoms, including fatigue and anemia, in asthma patients taking ICS treatment compared to those who were not.

“The use of ICS has been instrumental in reducing asthma exacerbations and improving overall quality of life. However, while their effectiveness should not be understated, our findings suggest that the risks of ICS usage must also be considered,” said co-senior author Jessica Lasky-Su, ScD, of the Channing Division of Network Medicine at the Brigham.

“Our work suggests that simple measures, such as regular cortisol monitoring and prescription of the lowest effective ICS dose, may help to mitigate the systemic side effects of ICS use,” said co-senior author Claudia Langenberg, MD, PhD, of the MRC Epidemiology Unit at the University of Cambridge, UK, and Berlin Institute of Health at Charité Universitätsmedizin, Germany.

Read more in Nature Medicine.

Study Explores How the Immune System Fine Tunes SARS-CoV-2 Vaccine Antibody Diversity and Affinity

After vaccination against COVID-19, follicular T cells must strike a fine balance to help optimize immunity, a new study in preclinical models finds. Investigators from the Brigham studied the roles of follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells after vaccination by perturbing these cell types in mice. They found that the two cell types helped to balance out antibody diversity and affinity, and deleting either type of cell altered the immune response after vaccine boosting. Additionally, the team found important differences in aged mice, which have altered Tfh and Tfr cells. The authors note that although this work was performed in preclinical models using a non-FDA approved vaccine formulation, the immunologic principals likely extend to current and future clinical vaccines.

“This work lays a foundation for new ways to enhance SARS-CoV-2 vaccine effectiveness by targeting specific cells of the immune system,” said corresponding author Peter Sage, PhD, of the Transplantation Research Center in the Brigham’s Renal Division. “This work uncovers how vaccine responses are altered in the elderly, providing a framework for new strategies to enhance vaccine effectiveness later in life.”

Read more in Cell Reports.

Adjuvant Compared to Early Salvage Therapy Post Prostatectomy in Men with pN1 Prostate Cancer and Decreased Risk of Mortality

Men with microscopic evidence of prostate cancer spreading to their pelvic lymph nodes (LNs) following the surgical resection of the prostate and pelvic lymph nodes (LN) are at a very high risk of dying from prostate cancer. Pelvic LN radiation therapy (RT) is a potentially curative treatment. However, no randomized clinical trials have been conducted in men with pN1 prostate cancer to evaluate whether survival is prolonged when giving pelvic LN RT when the post-operative prostate-specific antigen level is undetectable (i.e., adjuvant) versus the current standard of care, which involves waiting until the PSA becomes detectable (i.e., early salvage). Researchers at the Brigham sought to understand whether adjuvant, compared to early salvage, RT could reduce mortality. The team studied a cohort of 17,913 men, median age of 64 years, and consecutively treated between 1995 and 2017 with radical prostatectomy and pelvic LN assessment and then followed for possible treatment with adjuvant RT or early salvage RT. The authors found that adjuvant compared to early salvage RT in men with pelvic node positive prostate cancer was associated with a decreased risk of death, and this reduction increased by 8 percent for each additional positive pelvic LN found at surgery.

“The lack of randomized trial data and the high risk of death from prostate cancer in this patient population compelled us to conduct this study and explore the findings,” said senior author Anthony D’Amico, MD, PhD, of the Department of Radiation Oncology.  “We are excited for men with node positive prostate cancer because our results have the potential to change practice and lengthen their survival.”

Read more in the Journal of Clinical Oncology.

microRNA Reprograms Smooth Muscle Cells into Endothelial Cells

microRNAs (miRNA), non-coding RNA molecules, have emerged as powerful regulators of cellular processes including proliferation, differentiation, and function. Targeting miRNAs allows for cellular reprogramming and is thought to be a promising regenerative therapy for vascular disease states associated with endothelial injury or dysfunction. Researchers at the Brigham sought to understand if differentiating vascular smooth muscle cells into endothelial cells (ECs) using a miRNA cassette would be a promising, novel regenerative strategy for endothelial repair. Using a miRNA cassette composed of miR—142-3p and miR-145-3p inhibitors and miR-146A-5p and miR-181B-5p mimics, researchers created induced endothelial cells (iECs) that exhibited a remarkable similarity to native ECs. Furthermore, in a murine hindlimb ischemia model, the iECs were able to restore blood flow more quickly than conventional ECs. This work contributes to a growing body of evidence supporting the possibility of regenerating endothelial populations from pre-existing mural cells and creating a scalable source of ECs for disease states associated with ischemic injury.

“Collectively, these findings contribute towards an improved understanding of the potential role of miRNAs in cellular differentiation and shows promise as a novel regenerative strategy for endothelial repair,” said senior author Mark W. Feinberg, MD, of the Division of Cardiovascular Medicine. “Through this paper, we show how miRNAs are feasible targets for generating endothelial cells and consider this to be an important step toward miRNA-based treatment of cardiovascular disease.”

Read more in The FASEB Journal.

Spironolactone is Unlikely to be Associated with an Increased Risk of Cancer

Spironolactone, a synthetic steroid, is routinely used to manage heart failure, hypertension, and edema. Off-label, the drug is also used to treat acne, hidradenitis, alopecia, and hirsutism. Despite the research available on its applications, the drug’s potential for tumorigenicity is poorly understood. Researchers at the Brigham sought to determine the rate of occurrence of several types of cancer among spironolactone ever-users, patients exposed at least once to the drug. The team conducted a systematic review and meta-analysis of seven studies reporting the occurrence of malignancies in men and women of at least 18 years of age. The authors found no significant association between spironolactone use and the individual risk of  breast, ovarian, kidney, gastric, and esophageal cancers. Treatment with the drug was associated with a decreased risk of prostate cancer. The authors note, however, that additional research in diverse populations such as younger individuals as well as patients with acne or hirsutism is needed to further examine whether these findings generalize to other populations.

“Though the U.S. Food and Drug Administration cautioned that ‘unnecessary use of this drug should be avoided,’ our data are reassuring that spironolactone is unlikely to be associated with a meaningful risk of cancer when prescribed at clinical doses,” said senior author John Barbieri, MD, MBA of the Department of Dermatology. “Now that the meta-analysis has provided us with promising data, our next steps will be to conduct future studies in more diverse populations. Understanding the relationship between spironolactone and its potential for tumorigenicity will ultimately allow us to provide our patients with answers about the risk of cancer and improve the care we can deliver.”

Read more in JAMA Dermatology.