JCI Insight - Welcome Go to The Journal of Clinical Investigation About Editors Consulting Editors For authors Journal stats Publication ethics Publication alerts by email Transfers Advertising Job board Contact Physician-Scientist Development Current issue Past issues By specialty COVID-19 Cardiology Immunology Metabolism Nephrology Oncology Pulmonology All ... Videos Collections In-Press Preview Resource and Technical Advances Clinical Research and Public Health Research Letters Editorials Perspectives Physician-Scientist Development Reviews Top read articles JCI Insight Current issue Past issues Specialties Collections In-Press Preview Resource and Technical Advances Clinical Research and Public Health Research Letters Editorials Perspectives Physician-Scientist Development Reviews Top read articles Journal Details About Editors Consulting Editors For authors Journal stats Publication ethics Publication alerts by email Transfers Advertising Job board Contact Issue published August 10, 2026 Previous issue Volume 11, Issue 15 On the cover: Combination S100A1 and ARC gene therapy as a treatment for Duchenne muscular dystrophy cardiomyopathy Show summary Hammers et al. report a gene therapy approach that shows promise for treating the cardiomyopathy associated with Duchenne muscular dystrophy. The cover image shows an area of the left ventricle of an untreated canine model of Duchenne muscular dystrophy, with fibrotic and fatty infiltration of cardiomyocytes, as revealed by a hematoxylin and eosin staining. Image credit: Eli Zerpa and Karen Laurent. Go to section: Research Letters Review Series Research Articles Corrigendum Research Letters Macrophage-fibroblast signaling networks identified by single-cell RNA sequencing in juvenile systemic sclerosis Aneri Shethji, Theresa Hutchins, Anwesha Sanyal, Tianhao Liu, Wei Chen, Kathryn S. Torok Aneri Shethji, Theresa Hutchins, Anwesha Sanyal, Tianhao Liu, Wei Chen, Kathryn S. Torok View: Text | PDF Macrophage-fibroblast signaling networks identified by single-cell RNA sequencing in juvenile systemic sclerosis Text PDF Abstract Authors Aneri Shethji, Theresa Hutchins, Anwesha Sanyal, Tianhao Liu, Wei Chen, Kathryn S. Torok Periostin defines a pathological fibroblast program enriched in restrictive allograft syndrome Yudai Miyashita, Taisuke Kaiho, Yuriko Yagi, Taichi Nagano, Xin Wu, Yuanqing Yan, Haiying Sun, Carl Atkinson, GR Scott Budinger, Ankit Bharat, Chitaru Kurihara Yudai Miyashita, Taisuke Kaiho, Yuriko Yagi, Taichi Nagano, Xin Wu, Yuanqing Yan, Haiying Sun, Carl Atkinson, GR Scott Budinger, Ankit Bharat, Chitaru Kurihara View: Text | PDF Periostin defines a pathological fibroblast program enriched in restrictive allograft syndrome Text PDF Abstract Authors Yudai Miyashita, Taisuke Kaiho, Yuriko Yagi, Taichi Nagano, Xin Wu, Yuanqing Yan, Haiying Sun, Carl Atkinson, GR Scott Budinger, Ankit Bharat, Chitaru Kurihara Review Series From aging biology to cardiac biotechnology: emerging platforms for modeling cardiac aging Kritika Chaddha, Mabel Bartlett, Tzahi Cohen-Karni, Aditi Gurkar Kritika Chaddha, Mabel Bartlett, Tzahi Cohen-Karni, Aditi Gurkar View: Text | PDF From aging biology to cardiac biotechnology: emerging platforms for modeling cardiac aging Text PDF Abstract Aging is a major contributor to cardiovascular disease and mortality in older adults. Yet most preclinical and experimental cardiac studies fail to account for age as a primary biological variable, leaving a critical gap in our understanding of how aging contributes to disease progression. Bridging this gap requires integrating aging biology, cardiac pathophysiology, and cutting-edge biotechnology to uncover the mechanisms underlying age-related cardiac dysfunction. We offer a new approach methodologies (NAMs) perspective on how emerging bioengineering strategies may reshape the study of cardiac aging by enabling multidimensional monitoring of cardiac function, aging trajectories, and therapeutic responses. To capture this complexity, we propose the A×G×E×D framework, where A stands for age, G for genetics, E for environment, and D for drug exposure, as a multidimensional lens for understanding how these factors converge to determine cardiac vulnerability during aging. We highlight the integration of long-term cardiac microtissues with advancements in biotechnology to model age. This Perspective opens new frontiers for understanding how A×G×E×D interactions manifest at the molecular, cellular, and electrophysiological levels and for designing responsive, personalized interventions that align with each individual’s evolving physiology. By developing robust bioengineered platforms that recapitulate human cardiac aging, we can advance toward precision geromedicine for cardiovascular health. Authors Kritika Chaddha, Mabel Bartlett, Tzahi Cohen-Karni, Aditi Gurkar Research Articles Single-nucleus RNA sequencing reveals transcriptional heterogeneity in the blastema of favorable-histology Wilms tumor Mike Adam, Keri A. Drake, Naomi Pode-Shakked, Katherine VandenHeuvel, S. Steven Potter, James Geller Mike Adam, Keri A. Drake, Naomi Pode-Shakked, Katherine VandenHeuvel, S. Steven Potter, James Geller View: Text | PDF Single-nucleus RNA sequencing reveals transcriptional heterogeneity in the blastema of favorable-histology Wilms tumor Text PDF Abstract While Wilms tumors commonly arise from renal precursor cells and maintain features of the developing kidney, recent studies have demonstrated substantial genetic, histologic, and molecular heterogeneity. To further investigate tumor variability as well as unifying features in tumor biology, we performed single-nucleus RNA sequencing (snRNA-seq) on treatment-naive, favorable-histology Wilms tumors utilizing a reference atlas established from tumor-adjacent kidney samples and fetal kidney. Transcriptional profiles of blastemal, stromal, and epithelial components were correlated with tumor histology and demonstrated developmental-lineage plasticity, with PAX2 and PAX8 expression normally restricted to the nephron lineage of the fetal kidney found to be expressed in tumor stroma, as well as the stromal marker POSTN identified in tumor blastema. Further analyses of the blastema show shared transcriptional features with the differentiation trajectory of “uninduced” to “early differentiating” fetal nephron progenitor cells as well as aberrant expression of stromal signatures. A number of pathways from fetal nephron progenitors were maintained in the blastema, including regulation of stem cell maintenance and axonogenesis, whereas other pathways appear enriched in specific tumor samples, demonstrating the ability of snRNA-seq to identify both unifying transcriptional signatures and uncover distinct molecular targets in signaling pathways and/or biological drivers of Wilms tumorigenesis. Authors Mike Adam, Keri A. Drake, Naomi Pode-Shakked, Katherine VandenHeuvel, S. Steven Potter, James Geller Shared CD4+ T cell receptor specificity groups in Crohn’s disease and ulcerative colitis Joshua E. Chan, Azam Mohsin, Jens Krijgsman, Ciska Lindelauf, Qinghui Mu, Brianna Cavalla, Xuhuai Ji, Sarah E. Streett, Vincent van Unen, Mark M. Davis Joshua E. Chan, Azam Mohsin, Jens Krijgsman, Ciska Lindelauf, Qinghui Mu, Brianna Cavalla, Xuhuai Ji, Sarah E. Streett, Vincent van Unen, Mark M. Davis View: Text | PDF Shared CD4+ T cell receptor specificity groups in Crohn’s disease and ulcerative colitis Text PDF Abstract Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), is marked by chronic intestinal inflammation and dysregulated immunity. Although UC and CD affect different areas of the gastrointestinal tract, both diseases share aberrant CD4+ memory T cell responses, with HLA-DRB1 as a major genetic risk factor. HLA-DRB1 encodes MHC class II molecules that influence the CD4+ T cell receptor (TCR) repertoire, yet how these genotypes shape TCR specificity in IBD remains unclear. Here, we genotyped HLA-DRB1 and profiled 3.13 million TCRβ sequences from circulating memory CD4+ T cells in 33 IBD patients (20 UC, 13 CD) and 14 healthy controls. Using the GLIPH2 algorithm, we distilled 468,441 candidates based on CDR3 amino acid motifs into 440 high-confidence TCR specificity groups significantly enriched among individuals sharing HLA-DRB1 alleles. Notably, 5 specificity groups were IBD-enriched and were shared between UC and CD, suggesting common antigen targets in both diseases. We also observed increased frequencies of clonally expanded cytotoxic GZMB+PRF1+ memory CD4+ T cells and KIR+CD8+ T cells in a subset of risk-allele carriers with IBD. These findings elucidate distinct, HLA-linked TCR specificity groups in IBD and provide mechanistic insights that may advance antigen discovery and personalized medicine. Authors Joshua E. Chan, Azam Mohsin, Jens Krijgsman, Ciska Lindelauf, Qinghui Mu, Brianna Cavalla, Xuhuai Ji, Sarah E. Streett, Vincent van Unen, Mark M. Davis Distal enhancer-insulator module of GDF6 is essential for cochlear formation Mohammad Faraz Zafeer, Clemer Abad, Havva Ortabozkoyun, Memoona Ramzan, Guney Bademci, Maria C. Robayo, Duygu Duman, Rolen M. Quadros, Shengru Guo, Juan I. Young, Anthony J. Griswold, Channabasavaiah B. Gurumurthy, Derek M. Dykxhoorn, Katherina Walz, Mustafa Tekin Mohammad Faraz Zafeer, Clemer Abad, Havva Ortabozkoyun, Memoona Ramzan, Guney Bademci, Maria C. Robayo, Duygu Duman, Rolen M. Quadros, Shengru Guo, Juan I. Young, Anthony J. Griswold, Channabasavaiah B. Gurumurthy, Derek M. Dykxhoorn, Katherina Walz, Mustafa Tekin View: Text | PDF Distal enhancer-insulator module of GDF6 is essential for cochlear formation Text PDF Abstract Several genes guide inner ear development, and mutations in these genes can cause malformations that result in congenital hearing loss. However, the contribution of noncoding regulatory elements remains largely unclear. This study investigates the function of distal enhancer elements in the transcriptional regulation of GDF6, a gene implicated in cochlear development. Using mouse models with targeted deletions, human inner ear organoids, and CRISPR interference (CRISPRi), we identified a downstream regulatory interval harboring a developmental enhancer required to maintain GDF6 expression during otic epithelial maturation and cochlear morphogenesis. Deletion of this regulatory region or targeting of CRISPRi-based repressors to these regions resulted in decreased GDF6 expression, failure of otic-epithelium development, and prevention of hair cell–like differentiation, reflecting cochlear aplasia observed in patients with corresponding genomic deletions. These findings highlight the contribution of long-range regulatory elements to auditory development and illustrate how their disruption contributes to human deafness. Authors Mohammad Faraz Zafeer, Clemer Abad, Havva Ortabozkoyun, Memoona Ramzan, Guney Bademci, Maria C. Robayo, Duygu Duman, Rolen M. Quadros, Shengru Guo, Juan I. Young, Anthony J. Griswold, Channabasavaiah B. Gurumurthy, Derek M. Dykxhoorn, Katherina Walz, Mustafa Tekin A distinct form of fat fibrosis is linked to insulin resistance in people with HIV Diana L. Alba, Alaa Abdellatif, Moon Kyung Choi, Stephen M. Brown Mayfield, Thuy An T. Pham, David I. Berrios, Antonio E. Rodriguez, Marin Ewing, Tony R. Figueroa, Judy Gonzalez-Vargas, Ningyan Zhang, Zhiqiang An, Dawei Bu, Steven G. Deeks, Philipp E. Scherer, Peter W. Hunt, Suneil K. Koliwad Diana L. Alba, Alaa Abdellatif, Moon Kyung Choi, Stephen M. Brown Mayfield, Thuy An T. Pham, David I. Berrios, Antonio E. Rodriguez, Marin Ewing, Tony R. Figueroa, Judy Gonzalez-Vargas, Ningyan Zhang, Zhiqiang An, Dawei Bu, Steven G. Deeks, Philipp E. Scherer, Peter W. Hunt, Suneil K. Koliwad View: Text | PDF Clinical Research and Public Health A distinct form of fat fibrosis is linked to insulin resistance in people with HIV Text PDF Abstract BACKGROUND Despi…