The ureter, a vital tubular conduit responsible for transporting urine from the kidneys to the bladder, has remained an elusive component in lab-grown kidney models. Despite advancements in kidney organoid technology, the absence of a functional ureter has long hindered the ability to replicate the full physiological complexity and functionality of the urinary system. The inability to simulate urine flow and drainage has presented a significant barrier to the clinical translation of kidney organoids for transplantation.

To overcome this challenge, the team devised a sophisticated protocol to induce the differentiation of ureteral stromal progenitor cells from pluripotent stem cells. Utilizing these stromal progenitors in conjunction with ureteral epithelial progenitor cells—sourced either from mouse embryos or induced from pluripotent stem cells themselves—they engineered three-dimensional organoids that spontaneously self-organize into layered ureteral structures. Remarkably, these organoids exhibit peristaltic contractions, mimicking the rhythmic movements essential for urine propulsion observed in vivo.

This self-organization into a functional, three-layered ureteral architecture comprising stromal, epithelial, and muscle-like layers indicates the organoids’ potential to recapitulate the structural and physiological properties of natural ureters. The researchers documented rhythmic contractions resembling those of native urine flow, a feature never before demonstrated in stem cell-derived ureteral constructs. This functional mimicry suggests that the engineered ureters are not merely structural replicas but possess dynamic capabilities fundamental to their biological role.

Beyond structural and functional replication, the study also ventured into modeling congenital ureteral anomalies by introducing mutations in the TBX18 gene—a transcription factor crucial for ureter development. Organoids derived from TBX18-mutated cells displayed impaired development and morphological abnormalities, thereby establishing a novel platform for investigating the genetic underpinnings of urinary tract malformations. This disease modeling capacity provides an invaluable tool for exploring the pathogenesis of congenital disorders and assessing potential therapeutic interventions.

Professor Nishinakamura emphasized the transformative implications of this research, noting that integrating these ureter organoids with existing kidney organoids may finally fulfill the longstanding goal of producing transplantable kidneys capable of actual urine production and excretion. This synergy paves the way for regenerative therapies that do not merely replace kidney tissue but restore the comprehensive function of the entire urinary tract.

The creation of a functional ureter from pluripotent stem cells is a testament to the remarkable advances in developmental biology and stem cell technology. By recapitulating embryonic developmental pathways, the research team succeeded in coaxing pluripotent cells to differentiate into specialized progenitor populations and self-assemble into complex organ architectures. This bottom-up approach mirrors natural ontogeny and contrasts with previous methods that often relied on exogenous scaffolds or artificial constructs.

The methodology underpinning this breakthrough involved the careful orchestration of signaling pathways and microenvironmental cues to direct stem cell fate. By manipulating molecular gradients and timing differentiation stages precisely, the team generated stromal progenitors marked by specific lineage markers, such as TBX18, that are essential for ureter development. Combining these cells with epithelial progenitors allowed for the establishment of key cell-cell interactions vital for tissue maturation and organoid formation.

Importantly, the engineered ureter organoids demonstrated essential functional characteristics, including concentric smooth muscle-like layers responsible for contractility and an epithelial lining competent for barrier function and urine transport. The differentiation and maturation of these cell layers were validated through histological analyses and gene expression profiling, confirming their resemblance to natural ureteral tissue.

This milestone not only enhances the sophistication of kidney organoid models but also elevates the potential for their clinical application. Currently, kidney organoids—while capable of mimicking nephron structures—lack the ability to process and excrete urine effectively due to the absence of a ureter. The addition of functional ureters closes this gap, potentially enabling fully integrated renal organoids that replicate whole-organ physiology necessary for transplantation.

The success achieved by Kumamoto University’s team is part of the broader “International Leading Research: Creating A Kidney” project, an ambitious global initiative funded by the Japan Society for the Promotion of Science (JSPS) and other leading agencies. This consortium unites researchers worldwide to push the boundaries of organoid science, regenerative therapies, and organ transplantation, with a mission to overcome current organ shortages and improve patient outcomes.

The implications of this research extend beyond transplantation medicine. The ureter organoid system provides an unprecedented in vitro model for studying urinary tract development, physiology, and pathology. This platform could enable high-throughput screening for nephrotoxic drugs, investigation of urinary tract infections, and exploration of mechanisms underlying urinary tract obstructions and other diseases that currently lack robust experimental models.

Looking forward, challenges remain in scaling these organoids for clinical use, integrating them into vascularized systems, and ensuring long-term viability and functionality post-transplantation. Nevertheless, this study constitutes a crucial first step by demonstrating the feasibility of generating functional ureteral tissue from pluripotent stem cells, setting the stage for future breakthroughs that may revolutionize kidney regenerative medicine.

The convergence of stem cell biology, organoid technology, and developmental genetics encapsulated in this research highlights an era of unprecedented potential for personalized and regenerative therapies. Through meticulous engineering of cellular components and microenvironments, the longstanding dream of bioengineered, fully functional, transplantable kidneys incorporating complex urinary tract structures edges closer to realization.

Subject of Research: Cells

Article Title: In vitro generation of a ureteral organoid from pluripotent stem cells

News Publication Date: 20-Jun-2025

References:
Ibi et al., Nature Communications, DOI: 10.1038/s41467-025-60693-6

Image Credits: Ibi et al.

Keywords: Kidney, Pluripotent stem cells, Stroma, Somatic cells, Mesoderm, Progenitor cells, Organoids, Epithelial cells, Urine

HTLV-1 is a retrovirus linked to the development of adult T-cell leukemia/lymphoma (ATL), a malignancy characterized by aggressive clinical progression and poor prognosis. Despite infection being widespread in certain endemic regions, including parts of southwestern Japan, the majority of infected individuals remain asymptomatic for life. The virus’s ability to persist in a quiescent form inside host cells is a major factor underlying its evasion of immune clearance and its latent oncogenic potential. Until now, the molecular underpinnings responsible for this dormancy remained elusive.

The team at Kumamoto University, led by Professor Yorifumi Satou, determined that an intragenic region within the HTLV-1 genome serves as a viral silencer. This sequence recruits the host’s transcriptional regulation machinery, centering on the RUNX family of transcription factors, particularly RUNX1. By recruiting RUNX1 complexes, this viral element suppresses the transcriptional activity of HTLV-1 genes, silencing viral gene expression and therefore curbing active virus production. This stealth strategy ensures the virus remains undetected by the host immune system, securing long-term persistence within infected T-cells.

Through a series of meticulous experimental studies, the researchers demonstrated that genetic disruption or deletion of this viral silencer results in heightened viral transcriptional activation. This increased expression translates into greater immune visibility and accelerated clearance of infected cells in vitro. These findings confirm that the silencer acts as a crucial molecular brake to maintain HTLV-1 in a low-profile latent state. The ability to switch off viral gene expression using host transcription factors represents a finely tuned evolutionary adaptation unique to HTLV-1’s survival strategy.

Intriguingly, the team extended their analysis to the human immunodeficiency virus type 1 (HIV-1), another retrovirus with a contrasting survival tactic marked by active replication and immune system evasion through rapid mutation rather than latency. When the identified HTLV-1 silencer element was artificially inserted into the HIV-1 genome, the virus adopted a more latent phenotype. HIV-1 replication and cytopathic effects on host cells were significantly reduced, mimicking the dormancy that HTLV-1 exploits. This cross-viral functional integration hints at the broader applicability of silencer-based gene regulation among retroviruses and suggests potential novel therapeutic strategies for HIV-1 by inducing or enhancing latency.

The recruitment of the RUNX transcription complex is central to this silencing mechanism. RUNX1 is a well-studied transcription factor involved in hematopoiesis and immune regulation. By leveraging an essential host transcriptional regulator, HTLV-1 tightly controls its gene expression, preventing the activation of immune-inflammatory pathways that could lead to infected cell elimination. This research highlights how retroviruses can co-opt host factors not only for replication but also for immune evasion, reflecting an intricate virus-host co-evolutionary relationship.

Professor Satou emphasized the elegance of this viral adaptation: “HTLV-1’s intragenic silencer acts as a molecular cloak, enabling the virus to dwell silently within the host’s immune landscape. Understanding this natural invisibility cloak provides a vital blueprint for developing targeted therapies that disrupt viral latency and enhance immune-mediated clearance.” The potential for therapeutically modulating this silencer or its interactions with RUNX complexes could transform treatment strategies for HTLV-1 infections and associated malignancies.

This study also sheds light on the broader biological significance of latency in retroviral pathogenesis. Latency is a double-edged sword that allows persistent infection but complicates eradication efforts. By dissecting the molecular circuitry behind HTLV-1’s latent state, the research community gains critical insight that may inform cure strategies not only for HTLV-1 but potentially other retroviral infections and latent viral reservoirs in human diseases.

Another remarkable aspect is the contextual specificity of this silencer within the HTLV-1 genome. The intragenic nature of the silencing element distinguishes it from classical promoter or enhancer regions, revealing a layered complexity in viral gene regulation. This intragenic silencer forms part of the virus’s regulatory architecture that balances between gene activation necessary for viral transmission and the dormancy needed for survival within the host environment.

The implications of this discovery extend into epidemiology and public health, particularly for endemic areas where HTLV-1 infection rates are highest. Targeted interventions disrupting viral latency may enable earlier detection, treatment, and potential prevention of ATL progression. Furthermore, understanding how to manipulate viral silencing holds promise for reducing viral loads and associated inflammation, potentially improving patient outcomes.

The research methodology combined molecular genetics, virology, and immunology, leveraging human tissue samples and advanced transcriptional analysis techniques. These comprehensive experimental approaches ensured that the findings reflect biologically relevant mechanisms operational in vivo, dramatically strengthening the translational potential of the insights gained.

In summary, this landmark research illuminates a fundamental mechanism by which HTLV-1 orchestrates its stealth existence through an intragenic viral silencer element recruiting the RUNX transcription factor complex. By suppressing viral gene expression, HTLV-1 achieves immune invisibility, persistence, and latency, thereby contributing to its oncogenic potential. The discovery that this silencer can impose a similar latent phenotype on HIV-1 broadens the therapeutic horizon, suggesting new avenues in retroviral disease management aiming to control viral replication and latency.

As the scientific community continues to grapple with chronic viral infections, findings such as these underscore the critical importance of understanding viral gene regulation at a granular level. The capacity to intentionally toggle viral latency mechanisms could revolutionize antiviral therapies and immunomodulatory approaches, offering renewed hope to millions affected by persistent retroviral diseases worldwide.

Subject of Research: Human tissue samples

Article Title: Intragenic viral silencer element regulates HTLV-1 latency via RUNX complex recruitment

News Publication Date: 13-May-2025

Web References: http://dx.doi.org/10.1038/s41564-025-02006-7

Image Credits: Yorifumi Satou, Kumamoto University

Keywords: Retroviruses, Leukemia, Cancer, Human immunodeficiency virus, Viruses

The identification of Nipponopterus mifunensis arose from an integrative reevaluation process incorporating cutting-edge CT imaging technology, provided through the collaboration of Kumamoto University researchers, which allowed unprecedented visualization of the internal and external vertebral morphology. This approach revealed diagnostic characteristics that were previously indiscernible, enabling a detailed phylogenetic analysis situating the specimen within the Azhdarchidae family—a lineage that boasts some of the largest known flying vertebrates to have ever existed. The fossil’s display at the Mifune Dinosaur Museum now offers scholars and the public alike a tangible window into pterosaur diversity and evolution in a geospatial context hitherto unexplored.

Dr. Naoki Ikegami of the Mifune Dinosaur Museum heralded this finding as “a substantial leap forward” for Japanese paleontological research. Prior to this, formal taxonomic naming of pterosaur species in Japan relied primarily on fragmentary or isolated remains lacking sufficient diagnostic features to establish new taxa. The revelation of Nipponopterus profoundly augments our understanding of the morphological variance and evolutionary transitions among azhdarchid pterosaurs inhabiting East Asia during the Turonian to Coniacian stages, dating approximately between 93.9 and 86.3 million years ago.

Morphologically, Nipponopterus mifunensis presents a fascinating suite of distinctive anatomical traits that distinguish it from known azhdarchid species. Its sixth cervical vertebra bears a conspicuous dorsal keel that rises prominently along the posterior surface, stretching beyond the typical attachment point over the epipophysis to envelop the entire postexapophyseal peduncle. This elevated keel likely had significant functional implications, potentially relating to neck musculature attachment or mechanical reinforcement essential for flight-related head stabilization. Complementing this, the ventral side of the vertebra features an elongated groove or sulcus, a subtriangular condyle, and postexapophyses that are notably oriented laterally—a combination of traits previously undocumented in related pterosaurs.

Phylogenetic placement firmly anchors Nipponopterus within the Quetzalcoatlinae subfamily, a fascinating clade of azhdarchid pterosaurs that encompasses enigmatic taxa such as the Mongolian “Burkhant azhdarchid” and the colossal North American Quetzalcoatlus. This affiliation is not merely taxonomic but offers profound evolutionary insights, shedding light on biogeographic dispersal patterns and morphological diversification among large-bodied flying reptiles in the Late Cretaceous. The inferred wingspan of Nipponopterus—estimated between 3 to 3.5 meters—positions it as a comparatively smaller yet evolutionarily significant member of this lineage, potentially illuminating early stages of gigantism within azhdarchids.

The collaborative nature of this research exemplifies the increasingly interdisciplinary and transnational fabric of modern paleontology. Contributors hail from the Mifune Dinosaur Museum, Kumamoto University, and Hokkaido University in Japan; Shihezi University in China; and the Zoology Museum at the University of São Paulo in Brazil. This synergy bridged expertise in fossil morphology, advanced imaging, phylogenetics, and computational modeling. Professor Toshifumi Mukunoki of Kumamoto University emphasized how this international team “beautifully demonstrates how scientific inquiry transcends national borders and cultural differences, collectively unveiling chapters of Earth’s prehistoric chapters.”

From a methodological standpoint, the study showcases how state-of-the-art imaging modalities revolutionize fossil analysis. High-resolution computed tomography offered unparalleled three-dimensional visualization of the fossil’s internal microstructure without destructive sampling, elucidating complex osteological features previously inaccessible. This non-invasive technique facilitated precise anatomical reconstructions and comparative assessments, enabling the robust taxonomic reassessment that ultimately defined Nipponopterus as a new genus and species.

Ecologically, Nipponopterus mifunensis enriches our understanding of Late Cretaceous pterosaur faunas in East Asia. The morphological adaptations evident in the cervical vertebra may reflect specialized ecological niches or behaviors, possibly ranging from foraging strategies to aerial maneuverability. The vertebra’s unique morphology suggests biomechanical optimizations associated with neck mobility and head support, which are critical for feeding and flight dynamics. As such, Nipponopterus provides a pivotal data point for reconstructing the evolutionary trajectory and ecological diversification of azhdarchid pterosaurs during a period marked by significant environmental and faunal upheavals.

The Mifune Group locality, long overlooked in the annals of pterosaur research, is now thrust into prominence as a locus of exceptional paleontological interest. The unveiling of Nipponopterus stands as a testament to the potential for re-examination of legacy fossil collections using contemporary analytical technologies. This encourages a reevaluation of other fragmentary finds worldwide, fueling a renaissance in the discovery and description of previously unrecognized taxa.

Publication of the detailed scientific report occurred in the peer-reviewed journal Cretaceous Research on March 31, 2025. The article meticulously documents the anatomical characterization, phylogenetic methodology, and interpretive context underpinning the naming of Nipponopterus mifunensis. Supported by funding from institutions such as FAPESP and the Willi Hennig Society, the research underscores the vital role of sustained financial backing in advancing vertebrate paleontology.

Intriguingly, the discovery offers a broader window into the evolutionary dynamics operative in the Late Cretaceous ecosystems that dominated East Asia. It raises compelling questions about the biogeographical distribution of azhdarchid pterosaurs, their adaptive pathways, and interactions with contemporaneous vertebrate faunas. With its distinct combination of skeletal features, Nipponopterus challenges existing paradigms and invites further exploration into the morphological plasticity and ecological breadth of pterosaurs during a critically transitional epoch in Earth’s history.

In summary, the formal recognition of Nipponopterus mifunensis as a new azhdarchid genus and species originating from Japan is a landmark achievement. It simultaneously advances the scientific frontier of pterosaur paleontology and inspires multidisciplinary international cooperation. This pioneering discovery enriches our comprehension of prehistoric life and invigorates future paleobiological research avenues targeting ancient aerial vertebrates in East Asia and beyond.

Subject of Research: Not applicable

Article Title: Reassessment of an azhdarchid pterosaur specimen from the Mifune Group, Upper Cretaceous of Japan

News Publication Date: 31-Mar-2025

Web References:

• Kumamoto University: https://ewww.kumamoto-u.ac.jp/en/
• Mifune Dinosaur Museum: https://mifunemuseum.jp/
• Kumamoto University Faculty of Advanced Science and Technology: https://www.fast.kumamoto-u.ac.jp/en/home/

References:

• Journal: Cretaceous Research
• DOI: 10.1016/j.cretres.2024.106046

Image Credits: Zhao Chuang

Keywords: Paleontology, Phylogenetics, Evolutionary biology, Species, Biodiversity, Cretaceous period