ARPKD affects roughly one in 20,000 children. The disease causes liquid-filled cysts to form in the kidney, and those cysts can appear even before a child is born. For newborns, they can be life-threatening, and for some patients the damage accumulates until the kidneys fail before adulthood. The segment of the kidney primarily affected is the collecting duct, the network of tubules responsible for draining urine from the organ. Because the disease is rare and its cellular origins are difficult to access in living patients, researchers have long lacked the experimental systems needed to watch the disease unfold at the cellular level, let alone to screen potential therapies against it. Li’s project is designed to close that gap.

The strategy rests on two complementary types of lab-grown biological systems, both derived from human stem cells. The first is the organoid, a three-dimensional structure grown from a type of progenitor cell that gives rise to the collecting duct system. In a Petri dish, these organoids self-organize into elongated tubules that closely mimic the architecture and function of human collecting duct tissue. The second is the assembloid, a more complex construct grown by combining collecting duct progenitor cells with cells that develop into the kidney’s filtering units, allowing two distinct compartments of the organ to be modeled together. With success, the project’s organizers say, these systems could become a major enabling factor for basic, translational and clinical research tackling ARPKD.

The power of the organoid approach lies in scale and speed. Because the structures are grown from human cells in culture, researchers can manufacture hundreds of thousands of them cost-effectively, according to Li. That opens the door to high-throughput drug screening, in which vast libraries of candidate compounds can be evaluated simultaneously against diseased tissue. Instead of testing one drug at a time in slow and expensive animal studies, scientists can rapidly identify the most promising molecules in vitro and then advance only the strongest candidates. For a disease as rare as ARPKD, where commercial incentives for drug development are limited, such a screening platform could dramatically lower the barriers to discovering new therapies.

The assembloid arm of the project addresses a different and equally stubborn problem in drug development: the failure of treatments that looked promising in the lab but collapsed in clinical trials. Li points to two major reasons such failures occur, kidney toxicity and the biological differences between animal models and human patients. His team’s plan is to grow diseased human kidney tissue in the form of assembloids and transplant it into mice, creating what researchers describe as a humanized model of the disease living inside an animal host. Drugs tested against that tissue would, in principle, yield far more accurate predictions of both efficacy and safety in human patients than conventional animal models can provide, because the target tissue itself would be human.

The project does not begin from scratch. Li’s research group has already developed a collecting duct organoid that closely mimics the structure and function of human tissue, and the team has shown that it can effectively model a related, more common condition: autosomal dominant polycystic kidney disease, or ADPKD. ADPKD accounts for about 90 percent of all polycystic kidney disease cases and is generally a milder illness that tends to emerge during adulthood rather than before birth. Having modeled ADPKD both in Petri dishes with collecting duct organoids and in mice with assembloids, the researchers now plan to apply the same principles to ARPKD, adapting systems they have already validated to a rarer and more severe form of the disease.

International collaboration supplies another key ingredient. Cell lines carrying ARPKD-related mutations were provided by the two researchers who developed them: Yun Xia, PhD, of Singapore’s Agency for Science, Technology and Research, and Ryuji Morizane, MD, PhD, of Harvard Medical School. These mutated cell lines serve as the starting material from which the diseased organoids and assembloids will be grown, embedding the genetic defects that drive cyst formation into the lab-grown tissue itself. Li has described the generosity of these colleagues as a perfect example of how the research community works together to help patients, a reminder that progress on rare diseases often depends on scientists sharing hard-won tools across institutions and continents.

The grant also reflects a deliberate strategic bet by the funder. The PKD Foundation, founded in 1982, is the only organization in the United States solely dedicated to finding treatments and a cure for polycystic kidney disease, and it is the largest private funder of research into the illness. Susan Bushnell, the foundation’s president and CEO, said that the field is seeing unprecedented momentum in PKD research and that the organization believes this is the right time to invest boldly in the scientists working to change the future of the disease. Because of the generosity of donors, she noted, the foundation is able to increase its investment in promising research that represents hope for the millions of people and families living with PKD.

For Li, the ARPKD project is one milestone within a much larger scientific mission. For nearly 15 years, he has worked on coaxing stem cells to produce kidney-like structures, with the long-term goal of engineering an artificial kidney for patients awaiting an organ transplant. The scale of that unmet need is enormous: kidneys account for about 80 percent of the demand for donor organs, and more than 90,000 people are on the kidney donation waitlist in the United States alone. Engineering a transplantable kidney, Li has said, is the ultimate goal of his career, but along the way, developing kidney-like tissue in which disease can be modeled and new therapies found offers the chance to meaningfully benefit patients with kidney disease now.

The significance of the work extends beyond a single rare disease. If collecting duct organoids and kidney assembloids prove reliable models for ARPKD, the same platforms could accelerate research into ADPKD and other disorders of the kidney’s tubular and filtering systems, and could sharpen the preclinical testing pipeline for any drug destined for the kidney. The approach also illustrates a broader shift in biomedical science, as human stem cell-derived tissues increasingly replace or supplement animal models whose biology often fails to translate to patients. For the families facing ARPKD, a condition that currently offers few answers, the grant represents something concrete: a funded, technically grounded path toward the models that drug discovery requires, built from the very cells where the disease begins.

Subject of Research: Development of human stem cell-derived organoid and assembloid models for autosomal recessive polycystic kidney disease research

Article Title: PKD Foundation provides support for kidney disease research by USC Stem Cell’s Zhongwei Li

Article References: PKD Foundation provides support for kidney disease research by USC Stem Cell’s Zhongwei Li. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: polycystic kidney disease, ARPKD, organoids, assembloids, stem cells, kidney disease, PKD Foundation, drug screening, collecting duct, USC Stem Cell, genetic disease, transplantation

The historical roots of the field stretch back further than many researchers realize. As the tutorial recounts, the earliest experiments in tissue self-organization date to 1907, when Wilson demonstrated that dissociated sponge cells could reassemble into functional organisms. Decades later, work by Holtfreter, Weiss and Taylor established the concept of tissue affinity and the remarkable capacity of embryonic cells to reconstitute organized structures from single-cell suspensions. Steinberg’s differential adhesion hypothesis in 1970 provided a theoretical framework for why cells sort themselves into coherent tissues. These classical observations laid the conceptual groundwork for the modern organoid revolution, which arrived in earnest in 2008 and 2009 with two landmark achievements: Eiraku and colleagues’ self-organized formation of polarized cortical tissue from embryonic stem cells, and Sato and colleagues’ demonstration that single Lgr5-positive intestinal stem cells could build complete crypt-villus structures in vitro without any mesenchymal niche.

Those two founding systems, intestinal and brain organoids, form the backbone of the new tutorial, and the authors deliberately chose them because they represent opposite ends of the organoid spectrum. Adult stem cell-derived intestinal organoids, sometimes called miniguts, are genetically stable, expandable over years and remarkably faithful to the epithelium they came from. Human pluripotent stem cell-derived brain organoids, by contrast, are developmental models that recapitulate embryonic neurogenesis, offering access to human brain biology that no other experimental system can provide. By walking through both, the tutorial illustrates how organoid choice depends entirely on the biological question at hand, whether that question concerns tissue homeostasis in the adult or the choreography of human development.

One of the most technically rich sections of the tutorial addresses cell fate decisions, the process by which stem cells commit to specific differentiated identities. In the intestine, regional and local signaling gradients, particularly the Wnt, BMP and Notch pathways, control where and when cells become absorptive enterocytes, mucus-secreting goblet cells, hormone-producing enteroendocrine cells, or tuft cells. The tutorial highlights how organoids allow researchers to manipulate these gradients with unprecedented precision. Experiments have shown that enteroendocrine cells switch their hormone expression profiles along the crypt-to-villus BMP signaling gradient, and that induced quiescence of Lgr5-positive stem cells enables the differentiation of hormone-producing cells. In brain organoids, timed and combinatorial treatments with extrinsic signals can specify ventral telencephalic identities, while minimizing exogenous signals drives rostral hypothalamic differentiation, demonstrating that the same self-organizing logic governs tissues as different as gut and brain.

The tutorial also devotes substantial attention to decrypting cell-cell communication, one of the most challenging problems in tissue biology. Organoids provide a contained system in which signaling networks can be measured at single-cell resolution using multiplexed single-cell analysis, and in which genetic reporters can mark specific populations in living tissue. Fluorescent gene tagging without double-strand DNA cleavage, ASCL2-responsive minigenes that label stem cell activity, and biosensors that quantify single-cell ERK dynamics have all been deployed in organoid systems. Machine learning tools such as OrganoidTracker now allow researchers to follow cell fate dynamics in space and time across entire organoids, converting what was once a static snapshot technology into a live-imaging platform capable of resolving the oscillatory signaling events that control cell fate decisions during intestinal homeostasis.

Genetic disease modeling represents perhaps the most clinically resonant application, and the tutorial lays out the strategies in detail. CRISPR-Cas9 engineering of organoids has enabled researchers to introduce precise mutations into otherwise healthy tissue, generating isogenic disease models. Sequential introduction of cancer mutations in cultured human intestinal stem cells has recapitulated colorectal cancer progression, while CRISPR-mediated engineering of patient-derived organoids has allowed systematic dissection of tumor evolution. On the repair side, functional correction of the CFTR gene by CRISPR in intestinal stem cell organoids from cystic fibrosis patients demonstrated that gene editing could restore disease-relevant function. The forskolin-induced swelling assay, which measures CFTR channel activity in patient-derived rectal organoids, has matured into a validated diagnostic tool, and high-throughput versions of the assay now support drug repurposing for cystic fibrosis.

Infectious disease research has been transformed by organoids as well. The tutorial documents how human intestinal organoids supported the first productive infection of human gut enterocytes by SARS-CoV-2, and how brain organoids became the central platform for understanding Zika virus-induced microcephaly. Multiple groups showed that Zika depletes neural progenitors through activation of the innate immune receptor TLR3, and organoid-based drug screens identified compounds that combat infection. Microinjection platforms and microfluidic gut-on-chip systems now allow controlled exposure of organoids to defined microbes, including complex anaerobic communities, opening the door to systematic study of host-microbiome interactions that were previously inaccessible in vitro.

The tutorial’s treatment of brain organoids extends into territory that borders on the philosophical. Comparative studies using organoids from human, chimpanzee and macaque cells have identified species-specific differences in progenitor behavior that contribute to brain size, and human-specific genes such as ARHGAP11B, NOTCH2NL and SRGAP2 have been shown to expand cortical neurogenesis when tested in organoid systems. Assembloids, fused organoids representing different brain regions, now model interneuron migration, thalamocortical connectivity and even the ascending sensory pathway. Single-cell brain organoid screening has revealed developmental defects in autism, and patient-derived organoids have exposed aberrant neuronal development in schizophrenia and copy number variant disorders. Chimeric models, in which human organoids are transplanted into mouse brains, have produced vascularized, innervated human tissue that establishes subcortical projections in the host animal.

The authors are candid about the field’s remaining challenges. Organoids lack vasculature, immune cells and mechanical cues from their native environment, limiting their maturation and long-term viability. Batch-to-batch variability, particularly in brain organoids, complicates reproducibility, and stress responses within cortical organoids can impair molecular subtype specification. Matrigel, the animal-derived matrix on which most organoids are grown, remains poorly defined, spurring development of synthetic alternatives and engineered materials whose stiffness can itself direct stem cell behavior. The tutorial highlights emerging innovations, including optogenetic control of gene expression, scaffold-guided morphogenesis that produces homeostatic mini-intestines, microfluidic vascularization, and bioprinting platforms that enable drug screening at single-organoid resolution, as the technologies most likely to close these gaps.

The translational trajectory of the field is already visible. Patient-derived organoid biobanks have predicted treatment responses in metastatic gastrointestinal cancers, tumor organoid and T-cell co-culture systems are being used to evaluate engineered immunotherapies, and glioblastoma organoids now serve as real-time avatars for assessing CAR-T cell responses. Organoid transplantation has repaired colitis in mouse models, alleviated traumatic brain injury and addressed short bowel syndrome in preclinical studies. What the Munich tutorial ultimately conveys is that organoids have crossed a threshold: they are no longer a promising curiosity but a mature experimental ecosystem, one whose protocols, pitfalls and possibilities are now documented well enough that any competent laboratory can begin interrogating biology with them.

Subject of Research: Organoid technologies for interrogating fundamental biology and disease

Article Title: Tutorial: interrogating biology using organoid technologies

Article References: Bugter, J. M., Schafer, S. T., & Rad, R. (2026). Tutorial: interrogating biology using organoid technologies. Nature Protocols. https://doi.org/10.1038/s41596-026-01447-6

Image Credits: AI Generated

DOI: 10.1038/s41596-026-01447-6

Keywords: organoids, intestinal organoids, brain organoids, stem cells, CRISPR, disease modeling, self-organization, cell fate, host-microbe interactions, drug screening, assembloids, Nature Protocols

The stakes could hardly be higher. The endometrium sits at the centre of embryo implantation, pregnancy maintenance and broader reproductive and systemic health, yet conditions affecting it—endometriosis, adenomyosis, recurrent implantation failure, recurrent pregnancy loss and chronic endometritis—remain poorly understood and notoriously difficult to treat. The authors argue that the root of this knowledge gap lies in the tools the field has historically depended upon: animal models and two-dimensional cultures that systematically fail to reproduce the human endometrium’s intrinsic biology.

The problem with animal models begins with basic evolutionary divergence. Mice, the workhorse of biomedical research, do not menstruate, and their endometrial architecture, hormone responsiveness and decidualization programmes—divided into the stem-cell-rich basalis that regenerates the tissue each cycle and the functionally active functionalis that is shed during menstruation—differ in fundamental ways from those of humans. Even the spiny mouse, the only rodent known to menstruate, offers only a partial bridge. Baboons show spontaneous endometriosis, making them useful but expensive and ethically constrained. The review details how comparative studies between human and rat endometrial co-cultures have repeatedly exposed these species-specific gaps, underscoring why findings from mice frequently fail to translate into human clinical practice.

Two-dimensional cell culture, meanwhile, has its own structural limitations. Landmark studies dating back to the early twentieth century established the foundations of tissue culture, and endometrial research made enormous strides with immortalized cell lines such as Ishikawa and HEC-1 adenocarcinoma-derived cells, alongside primary cultures of endometrial epithelial glands and stromal cells isolated as early as the 1970s. These systems enabled researchers to dissect steroid metabolism, integrin expression, 17 beta-hydroxysteroid dehydrogenase regulation and paracrine signalling between epithelium and stroma. Yet flat monolayers strip away the three-dimensional geometry, cell polarity, extracellular matrix interactions and multicellular composition that define how the endometrium actually behaves—particularly during the precisely timed window of implantation, when epithelial polarity shifts and stromal cells undergo decidualization under progesterone control.

The inflection point arrived in 2017, when two independent teams grew long-term, hormone-responsive organoids from human endometrium in chemically defined media. These miniature, self-organizing structures, built from endometrial epithelial stem and progenitor cells, recapitulated key features of endometrial physiology, expanded over successive passages and responded to oestrogen and progesterone much as the native tissue does. Suddenly, researchers could grow living endometrial epithelium indefinitely, derive it from patients with disease, and interrogate its biology with genetic and pharmacological tools. Follow-up work showed that patient-derived organoids could capture clinical heterogeneity in endometrial disease and were amenable to drug screening—opening a genuine pathway toward personalized medicine in gynaecology.

The next generation of models has pushed further toward physiological realism. Multi-lineage assembloids now combine endometrial epithelium with stromal fibroblasts, immune components, endothelial cells and extracellular matrix in engineered assemblies that mimic the tissue’s natural architecture. Recent protocols for generating mouse and human endometrial assembloids allow epithelial–stromal crosstalk to be studied within a single three-dimensional construct, while air–liquid interface methods have yielded assembloids possessing a luminal epithelium—the very surface a blastocyst must breach during implantation. Studies using assembloids have already modelled how decidual senescence impairs embryo implantation and how adenomyosis-related endometrial receptivity is compromised, delivering mechanistic insights that flat cultures simply could not provide.

Bioengineering has multiplied these capabilities. Microfluidic endometrium-on-a-chip devices compartmentalize perivascular stroma and endothelial cells to create vascularized tissue architectures, and experiments within them have shown that hemodynamic forces enhance decidualization via endothelial-derived prostaglandin E2 and prostacyclin—demonstrating that mechanical cues from blood flow, absent in static cultures, are genuine regulators of endometrial function. Fully synthetic hydrogels have replaced animal-derived Matrigel in several systems, enabling precise control of matrix composition and permitting organoid co-cultures of epithelium and stroma to be studied in defined extracellular environments. Bioprinted, hormone-responsive bilayer models now reproduce the tissue’s layered structure, and engineered platforms incorporating a 28-day hormonal cycle have simulated the human menstrual cycle in vitro, capturing epithelial cell transitions during menstruation and regeneration.

Perhaps the most consequential frontier is implantation itself. Because direct observation of human embryo implantation is ethically impossible, the field has had to infer its mechanics from indirect evidence. That barrier is now falling. Stem-cell-derived blastoids and trophoblast organoids can be co-cultured with engineered endometrial models to recreate the first contact between embryo and maternal tissue. Recent studies have modelled the embryo–endometrial interface in three dimensions, produced human receptive endometrial assembloids designed to decode the implantation window, and developed microfluidic platforms that measure embryo adhesion in real time. The review highlights 2026 studies reporting three-dimensional post-implantation co-culture of human embryo and endometrium models, alongside paired investigations of implantation and implantation failure—work that together promises to reveal the molecular dialogue between embryo and mother at unprecedented resolution. Single-cell atlases of the endometrium and the maternal–fetal interface, including a recently published spatiotemporal dissection of the human maternal–fetal interface, are providing the reference maps against which these engineered systems can be validated.

The clinical implications radiate across women’s health. Endometriosis, a chronic systemic disease affecting an estimated one in ten women of reproductive age, has seen its cellular basis illuminated by single-cell transcriptomic studies of eutopic and ectopic tissue, multi-ancestry genome-wide association analyses and investigations of microRNA signatures in tissue, serum and extracellular vesicles—several of which show promise as non-invasive diagnostic biomarkers. Patient-derived organoids from endometriosis lesions and early peritoneal endometriosis models now allow drug testing on a patient’s own disease cells. Endometrium-on-chip platforms built from patient cells are being evaluated for assessing endometrial receptivity and guiding personalized fertility treatment, while recent organoid work has even traced the donor-derived cellular origin of endometrium after uterus transplantation. Insulin- and glucose-induced alterations in endometrial transcriptomes observed on-chip hint at mechanisms linking metabolic health to fertility, and scaffold-free organoids have been shown to respond to the excess androgens characteristic of polycystic ovarian syndrome.

The authors are candid that substantial challenges remain. Matrigel, the tumor-derived basement membrane matrix underpinning many organoid protocols, is chemically undefined and variable, motivating ongoing efforts to develop fully synthetic alternatives. Vascularization, immune cell incorporation and the biophysical environment of the uterus—contractions, blood flow, cyclic mechanical remodeling—are only partially captured by existing systems. Ethical governance is advancing alongside the science: revised international stem cell guidelines now specifically address stem-cell-based embryo models, and frameworks for embedded ethics and dynamic consent are being proposed for research that grows ever closer to reconstructing human development in a dish. Competition-of-interest disclosures and peer oversight remain part of the field’s infrastructure as its translational potential grows.

What emerges from this sweeping synthesis is a portrait of a field in the midst of a genuine paradigm shift. By uniting developmental biology, stem-cell science, tissue engineering and single-cell genomics, researchers are converging on engineered endometria that are hormone-responsive, multicellular, vascularized and patient-specific. Such systems could transform how infertility is diagnosed, how endometriosis is treated and how the safety of new therapeutics is tested—without recourse to animal models that so often mislead. More profoundly, they are rewriting what it means to understand human reproduction: replacing inference from mice with direct observation in human-like tissue, and giving clinicians, for the first time, a living laboratory in which the earliest events of human life can be watched, perturbed and, ultimately, protected.

Beyond implantation, the cyclical nature of the endometrium itself presents a modelling challenge that these new platforms are beginning to address. Unlike most human tissues, the endometrium undergoes scarless repair after each menstrual shedding, a process driven by adult stem and progenitor cells residing in the basalis. Organoid systems that sustain long-term expansion now allow this regenerative capacity to be examined directly, complementing single-cell reference atlases that have catalogued the tissue’s cellular diversity across the menstrual cycle.

The immune dimension is equally critical. Uterine natural killer cells and other maternal immune populations orchestrate fetal–maternal tolerance and guide the differentiation of invading trophoblast, yet most current models lack immune components entirely. Integrating these lineages into assembloids and chip platforms remains an active area of development, informed by single-cell reconstructions of the maternal–fetal interface.

For patients, the promise is tangible: organoids derived from diseased tissue preserve the molecular signatures of the individual they came from, enabling drug responses to be tested outside the body. As these models mature, they may reduce reliance on both animal experimentation and empirical trial-and-error in fertility clinics, offering a mechanistic bridge between a patient’s cellular biology and her clinical care.

Subject of Research: Bioengineered three-dimensional models of the human endometrium, including organoids, assembloids and microfluidic devices, for studying implantation, endometrial disease and personalized reproductive medicine.

Article Title: Engineering the human endometrium at the intersection of development and reproduction

Article References: Vélez-Avilés, A. N., Abel, A., Taylor, H. S., & Sozen, B. (2026). Engineering the human endometrium at the intersection of development and reproduction. Nature Biomedical Engineering. https://doi.org/10.1038/s41551-026-01789-2

Image Credits: AI Generated

DOI: 10.1038/s41551-026-01789-2

Keywords: human endometrium, organoids, assembloids, endometrium-on-a-chip, embryo implantation, endometriosis, tissue engineering, decidualization, stem cells, women's health, single-cell transcriptomics, personalized medicine