In this issue of the JCI, Capitano et al. demonstrate that the secreted form of the DNA-binding chromatin factor DEK regulates hematopoiesis. It is known that DEK can be secreted by macrophages and other cells, but no function has been attached to secreted DEK. Capitano et al. showed that extracellular DEK activates signaling through the CXCL2 receptor, which in turn enhances the proliferation of hematopoietic stem cells and decreases hematopoietic progenitor cell numbers both in vivo and in vitro. These results offer the opportunity to expand transplantable stem cells to improve outcomes in patients undergoing bone marrow transplant.
David M. Bodine
Growing evidence implicates altered mTORC1 signaling cascades in the pathophysiology of depression, suggesting that direct modulation of mTORC1 signaling may offer novel therapeutic potential. In this issue of the JCI, Kato and colleagues reported that administration of NV-5138, a recently developed synthetic leucine analog, has a rapid and sustained antidepressant action in rat models via activation of mTORC1 signaling. The investigators also found that the antidepressant effect of NV-5138 is mediated by upregulation of brain-derived neurotrophic factor (BDNF) signaling and that NV-5138 treatment produces rapid synaptic responses in the medial prefrontal cortex. These findings highlight the direct activation of mTORC1 signaling as a potential pharmacological intervention for the treatment of depression.
Yuto Hasegawa, Xiaolei Zhu, Atsushi Kamiya
Excessive excretion of oxalate in the urine results in the formation of calcium oxalate crystals and subsequent kidney stone formation. Severe forms of hyperoxaluria, including genetic forms and those that result from ethylene glycol poisoning, can result in end-stage renal disease. Therapeutic interventions are limited and often rely on dietary intervention. In this issue of the JCI, Le Dudal and colleagues demonstrate that the lactate dehydrogenase 5 inhibitor (LDH5) stiripentol reduces urinary oxalate excretion. Importantly, stiripentol treatment of a single individual with primary hyperoxaluria reduced the urinary oxalate excretion. Together, these results support further evaluation of LDH5 as a therapeutic target for hyperoxaluria.
Jacob S. Stevens, Qais Al-Awqati
The study of beige adipose tissue (BeAT) has recently gained popularity because of its potential as a therapeutic target for the treatment of obesity and other metabolic disorders. While BeAT regulation is well understood in adults, the critical signals regulating BeAT during infant development need to be better defined. The bioactive components in breast milk have been primarily studied in the context of immunity. In this issue of the JCI, Yu and Dilbaz et al. identify how a class of breast milk–specific lipid mediators referred to as alkylglycerols (AKGs) maintain BeAT in infants and prevent the transdifferentiation of BeAT into lipid-storing white adipose tissue (WAT).
Christy M. Gliniak, Philipp E. Scherer
The T cell receptor (TCR) repertoire is diverse, thus allowing recognition of a wide range of pathogens by T cells. In humans, the study of the formation of TCR repertoires is problematic because of the difficulty in performing investigations in vivo. In this issue of the JCI, Khosravi-Maharlooei and colleagues describe a new humanized mouse model that allows direct investigations on this topic. Using high-throughput and single-cell TCR–complementarity-determining region 3 β (TCR-CDR3β) sequencing, the authors were able to demonstrate that human thymic selection is a major driver of TCR sequence sharing, also implicating a preferential selection of shared cross-reactive CDR3βs during repertoire formation.
Antonio La Cava
For high-risk and refractory hematological malignancies, allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only available curative therapy, with benefits derived from the antigenic disparity between recipient cancer and the incoming immune system. This immunologic mismatch can also lead to lethal graft-versus-host disease (GVHD), and immunosuppression strategies, including high-dose posttransplantation cyclophosphamide (PTCy), have been developed to allow for safe alloHSCT delivery. In this issue of JCI, Wachsmuth et al. present the results of preclinical studies designed to evaluate the mechanisms that underlie efficacy of PTCy after alloHSCT. The results of this study challenge previous reports indicating that alloreactive T cell elimination and thymic clonal deletion are primary mediators of PTCy efficacy and provide strong evidence to support FoxP3+CD4+ Tregs as important effectors of PTCy benefits.
Vedran Radojcic, Leo Luznik
African Americans are at increased risk of cancer and associated mortalities compared with European American populations. Socioeconomic, cultural, and biological factors have been implicated in this discrepancy. In this issue of the JCI, Piyarathna et al. identify a set of genes that are upregulated in a number of tumor types in African American cancer patients as compared with European American patients. These genes were associated with enhanced oxidative phosphorylation and upregulation of transcription factors that promote mitochondrial biogenesis, resulting in greater numbers of mitochondria in tumor samples from African American subjects. Together, these results indicate that mitochondria dysfunction may underlie the increased cancer incidence and poor outcomes observed in African American patients.
Jennifer L. Beebe-Dimmer, Kathleen A. Cooney
Acute kidney injury (AKI) is one of the most important risk factors for chronic and progressive kidney disease, leading to end-stage kidney failure. Tubule epithelial regeneration leads to the resolution of renal failure in AKI. Failure of tubule epithelial regeneration leads to concomitant hypoxia from loss of microcirculation, which serves as a critical factor leading to chronic kidney disease. In this issue of the JCI, Li et al. show that hypoxia activates the stress-responsive transcription factor FoxO3. Increased FoxO3 protein abundance leads to alterations in tubular epithelial autophagy and metabolism, highlighting an important mechanism causing permanent renal damage even after an acute injury.
Xiangchen Gu, Archana Raman, Katalin Susztak
Vertical sleeve gastrectomy (VSG) is an effective therapeutic approach for obesity and type 2 diabetes but is associated with osteoporosis. In this issue of the JCI, Li et al. report that VSG rapidly reduces bone mass, as observed in humans, via rapid demineralization and decreased bone formation, independent of weight loss or Ca2+/vitamin D deficiency. VSG also reduces bone marrow adipose tissue, in part via increased granulocyte–colony stimulating factor (G-CSF). The interplay between VSG-mediated effects on systemic metabolism and bone biology remain to be investigated. These findings suggest novel mechanisms and therapeutic targets for bariatric surgery–induced osteoporosis.
Soravis Osataphan, Mary Elizabeth Patti
Glucocorticoids (GCs) are essential for proper glycemic control, but in excess, can lead to hyperglycemia and diabetes. In this issue of the JCI, Cui et al. elucidate a mechanism by which GCs regulate gluconeogenesis utilizing the transcription factor Krüppel-like factor 9 (KLF9) in physiology and disease settings. They report that KLF9 is a GC-inducible factor that ultimately increases the transcription of proliferator-activated receptor γ coactivator 1 α (PGC1α), resulting in gluconeogenesis. Given the high incidence of GC-induced diabetes, identification of this signaling axis provides, not only critical scientific insight, but also a foundation for preventative therapies for patients receiving chronic GC treatment.
David R. Sweet, Liyan Fan, Mukesh K. Jain
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