Commentary
Abstract
Lactation insufficiency in postpartum women has been associated with obesity and insulin resistance, among other risk factors. Challenges related to translating findings from animal models of lactation and the limited ability to study pregnant and lactating women in clinical trials have impeded more detailed mechanistic understanding of this relationship. In this issue of the JCI, Meng et al. combined studies in human milk samples and in vitro mammary epithelial cell models from humans and rodents to provide compelling evidence that mitochondrial dysfunction mediates the link between insulin resistance and lactation insufficiency. Notably, they observed that chronic exposure to high levels of insulin led to mitochondrial fragmentation and loss of volume in mouse mammary epithelial cells. This framework linking mitochondria, insulin signaling, and lactation should be extended to in vivo models and primary human tissues to better define the mechanisms supporting successful lactation.
Authors
Laura L. Hernandez
Abstract
Friedreich’s ataxia (FRDA) is a triplet repeat expansion disorder with multisystem, progressive symptoms caused by reduced frataxin protein levels and compromised mitochondrial function. Restoration of frataxin protein is a focus of clinical trials involving adeno-associated viral vectors, but substantial barriers exist because of the immune response they elicit. In this issue of the JCI, Sivakumar et al. harnessed CRISPR/Cas9 editing of endogenous hematopoietic stem and progenitor cells (HSPCs) to excise the frataxin gene (FXN) repeat expansion ex vivo, followed by autologous transplantation. A single, systemic infusion of corrected HSPCs resulted in long-term engraftment and sustained multiorgan benefit in a humanized mouse model of FRDA. This improvement in brain, cardiac, and pancreatic symptoms, mediated by myeloid progeny of the engrafted stem cells, provides strong support for the potential effectiveness of this approach in humans and bypasses the need to correct the FXN deficiency in the affected tissue and cells directly.
Authors
Lucy R. Osborne
Abstract
Trauma-related neuropsychiatric disorders are commonly treated with exposure-based therapy, an approach based on fear extinction, in which fear memory and expression are suppressed by repeated exposure to the inciting fear stimulus. Fear extinction–focused research often investigates mechanisms of fear inhibition, but positive affect may also contribute to facilitating extinction. In this issue of the JCI, Lin et al. used activity-dependent neuronal labeling in a model of fear extinction to tag extinction-activated medial prefrontal cortex (mPFC) ensembles, identifying functionally distinct projections to the zona incerta (ZI) and supramamillary nucleus (SuM). While mPFC-ZI projections governed extinction retrieval, mPFC-SuM projections encoded positive affect and reinforced fear extinction persistence. Additionally, Lin et al. discovered that SIRT1-expressing mPFC-SuM extinction-recruited projections control extinction relapse vulnerability, showing that SIRT1 overexpression can be leveraged to reduce fear relapse. Overall, this study shows that key cortico-hypothalamic projections manage extinction retrieval and positive affect to promote fear extinction.
Authors
Quan-Son Eric Le, Luis E. Rosas-Vidal
Abstract
Efferocytosis, or the clearance of apoptotic cells by macrophages, has been implicated in tissue resolution that promotes disease regression in atherosclerosis and other diseases of chronic inflammation. The mechanisms by which efferocytosis leads to pro-resolving macrophage reprogramming have not been fully defined. In this issue of the JCI, Avrampou and colleagues found that efferocytosis activates DNA-methyltransferase-3A (DNMT3A) to promote base excision repair and suppress oxidized DNA. Moreover, they provide evidence that DNMT3A enabled tissue repair in the context of plaque regression in a mouse model of atherosclerosis. Human studies have linked DNMT3A mutation–mediated clonal hematopoiesis (DNMT3A-CH) with atherosclerosis. The findings of Avrampou et al. linking DNMT3A function to efferocytosis-mediated tissue repair suggest that this pathway could be modulated therapeutically to minimize cardiovascular events in patients.
Authors
Aarti Asnani
Abstract
Rheumatoid factors (RFs) are autoantibodies directed against the tail region of IgG antibodies and are present in a majority of people with rheumatoid arthritis (RA). RF production is commonly assessed to help diagnose RA, but its performance is limited due to low specificity and sensitivity for reasons that have remained unclear. In this issue of the JCI, Hocaoğlu and Sawalha shed light on this matter using extensive phenome-, genome-, transcriptome-, and proteome-wide association analyses of RF-seropositive and -seronegative individuals. They report that RF production was controlled by a genetic signature that included HLA and non-HLA genes and an immune signature reflective of B cell dysregulation but distinct from the genetic and immune signatures associated with RA. These findings explain the limited diagnostic value of RF testing in RA and may help refine the clinical management of RA and development of interventions that prevent or delay disease.
Authors
Luc Van Kaer
Abstract
Another individual’s distress can provoke withdrawal and avoidance behaviors, yet, in social species, it can also motivate approach and caregiving behavior. In this issue, Geng et al. identified a vasopressin-sensitive neuronal circuit that converts distress signals from a cagemate into caregiving-like behavior in mice. Using fiber photometry, electrophysiological recordings, and optogenetic activation to dissect this circuit, they showed that vasopressin neurons in the paraventricular hypothalamus recruit vasopressin 1a receptor–expressing (V1aR-expressing) neurons in the medial central amygdala, which engage the ventral tegmental area to promote allogrooming and injury-directed licking. The findings link emotional state matching, prosocial action, reinforcement, and stress relief, while raising important questions about circuit specificity, sex as a biological variable, and translation.
Authors
Jonathan P. Fadok
Abstract
Autoimmune diseases share a genetic predisposition, and GWAS have identified certain HLA haplotypes as components of susceptibility. In this issue of the JCI, Eriksson et al. leveraged population-scale registry data from Sweden, encompassing 6.3 million individuals in combination with paired relatedness data from a remarkable 3.84 million sibling pairs drawn from 1.57 million nuclear families to create a unified model of the shared genetic risk across 22 common and rare autoimmune diseases. The resulting network of pairwise genetic relationships demonstrated that genetic predisposition alone could not explain the full spectrum of autoimmunity. Analyses exposed distinct patterns, confirmed expected genetic relationships, and revealed unexpected findings. By looking into the family to quantify shared genetic liability at a remarkable scale, this study not only reinforces established genetic components of autoimmune disease but also highlights variation that lacks shared genetic architecture, paving the way for future study of environmental mechanisms in autoimmunity.
Authors
Arielle Klepper, Mark S. Anderson
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is characterized by fragile, enlarged vessels with arteriovenous connections, which can form arteriovenous malformations (AVMs) that are prone to rupture. It is driven by mutations in TGF‑β pathway genes that disrupt endothelial cell responses and blood vessel remodeling. Two studies published in this issue of the JCI identify c‑KIT as a central mediator of HHT vascular pathology. Gahn et al. showed that SMAD4 loss derepressed c‑KIT, whose activity in the junctional mechanosensory receptor complex of endothelial cells reset the fluid shear stress set point to drive maladaptive vascular remodeling. Drapé et al. demonstrated that ALK1 loss in a mouse model of HHT induced a regional pro‑angiogenic c‑KIT+ endothelial state in brain AVMs. Both studies showed that pharmacologic c-KIT inhibition mitigated disease, revealing an unexpected, potentially ligand‑independent role for c‑KIT and highlighting a promising therapeutic target.
Authors
Ruilin Wu, Jason E. Fish
Abstract
Multiple myeloma is a systemic and spatially heterogeneous cancer of plasma cells. Available methods for diagnosing and monitoring disease do not fully capture its heterogeneity. For instance, bone marrow sampling is anatomically limited and [18F]FDG PET/CT reflects glucose metabolism rather than a specific target. In this issue of JCI, Gu et al. reported a prospective phase I study of [68Ga]Ga-PFBC01, a nanobody tracer targeting B cell maturation antigen (BCMA). The study presents a coherent translational pathway for [68Ga]Ga-PFBC01 PET and demonstrates high sensitivity, associations with tissue and circulating disease measures, and clinical management impact. By shifting myeloma imaging from metabolic assessment toward target biology, [68Ga]Ga-PFBC01 PET may visualize whole-body disease distribution and actionable target expression, while blood-pool activity may reflect systemic antigen biology (Figure 1).
Authors
Yangmeihui Song, Wenyu Song, Weibo Cai
Abstract
Polyendocrine metabolic ovarian syndrome (PMOS) affects one of every eight women worldwide and is associated with high rates of cardiovascular disease, type 2 diabetes, and infertility. Polycystic ovarian syndrome (PCOS), another term for this condition, reflects a historical focus on its effects on the female reproductive system. Recently, however, experts and patient groups have advocated renaming the condition PMOS, conveying increasing recognition that hyperandrogenism and insulin resistance contribute to its pathology. In this issue, Nguyen et al. took a systems genetic approach that combined data from murine models of PMOS and data from human studies, identifying the splicing factor 3b subunit 1 (SF3B1) and IGFBP2, both previously associated with metabolic disease, as molecular drivers of PMOS. SF3B1 inhibitors improved PMOS symptoms in mice, including decreased adiposity, hypoandrogenism, and insulin levels. These findings open therapeutic and mechanistic avenues in the study of PMOS, including exploration of splice variants as regulators of disease progression.
Authors
Michaela M. Morhaus, Lauren W. Yowelunh McLester-Davis, Judith A. Simcox
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