Spatial Maps of Adenomyosis
How Immune Cells and Ciliated Cells Drive a Mysterious Uterine Disease
The Enemy Within the Uterine Wall
Imagine your own tissue turning against you, burrowing deep into the muscular wall of your uterus, causing pain, heavy bleeding, and infertility. This isn't science fiction—it's the reality for millions of women worldwide who suffer from adenomyosis, a long-misunderstood gynecological condition.
For decades, this disease has remained in the shadows, often misdiagnosed and poorly treated. But now, revolutionary technology is finally illuminating what happens inside the uterine wall, revealing a dramatic cellular story of misplaced tissue, angry immune cells, and surprising actors: ciliated cells where they shouldn't be.
Recent breakthroughs using spatial transcriptomics—a cutting-edge method that maps exactly where genes are active within tissues—are rewriting our understanding of this painful condition. Scientists can now see the molecular conversations between different cell types in adenomyosis lesions, providing unprecedented insights into how and why this condition develops. These discoveries aren't just academic; they point toward future diagnostics and treatments for a condition that has long frustrated patients and clinicians alike.
What Exactly Is Adenomyosis?
Adenomyosis occurs when the inner lining of the uterus (the endometrium) grows into the muscular uterine wall (the myometrium). These displaced patches of endometrial tissue continue to behave as if they were in their proper location—thickening, breaking down, and bleeding during each menstrual cycle. Trapped deep within muscle tissue, this cyclic bleeding causes inflammation, pain, and eventual enlargement of the uterus.
The condition affects 20-35% of reproductive-aged women, causing symptoms that significantly impact quality of life:
| Symptom | Frequency | Impact |
|---|---|---|
| Severe menstrual cramps | 70-80% of patients | Often debilitating, requiring pain medication |
| Heavy menstrual bleeding | 50-60% of patients | Can lead to anemia and fatigue |
| Chronic pelvic pain | 30-40% of patients | Persistent discomfort throughout cycle |
| Infertility | 20-30% of patients | Difficulty conceiving or carrying pregnancy |
| Enlarged uterus | 70-80% of patients | Detectable via ultrasound or MRI |
Despite its prevalence, adenomyosis has been called the "elusive disease" of gynecology. Its exact causes have remained mysterious, with several theories proposed but none fully explaining all cases. The invagination theory suggests that the endometrial tissue tunnels into the uterine wall, while the metaplasia theory proposes that cells already within the muscle transform into endometrial tissue. Until recently, we lacked the tools to determine which theory was correct or what molecular players drove the process.
The Research Breakthrough: Spatial Transcriptomics
To understand the revolution in adenomyosis research, we need to understand spatial transcriptomics. Traditional methods of studying tissue involved grinding it up and analyzing all the genetic material together—like blending a fruit salad and trying to determine what the original apple versus orange looked like. Spatial transcriptomics, in contrast, lets researchers see exactly which genes are active in each specific spot within intact tissue—like having a detailed map showing where each piece of fruit was originally located.
When combined with single-cell RNA sequencing (which analyzes the genetic activity of individual cells), these techniques create incredibly detailed maps of cellular organization and function. Researchers can now identify not just what cell types are present, but exactly where they're located, what genes they're expressing, and even how they're communicating with their neighbors.
The Inflammatory Microenvironment: Immune Cells Gone Rogue
One of the most significant findings from recent spatial transcriptomics studies is the distinct immune inflammatory microenvironment in adenomyosis. The immune system, which normally protects us, appears to be playing a destructive role in this condition.
In both the eutopic (normal location) and ectopic (misplaced) endometrial tissue of adenomyosis patients, researchers have found altered populations of immune cells creating a pro-inflammatory state. This isn't just a passive observation—the inflammation appears to actively contribute to the pain and tissue damage characteristic of the disease. The dysfunctional immune environment may explain why conventional anti-inflammatory medications often provide limited relief for adenomyosis patients; the problem isn't just general inflammation but a specifically dysregulated local immune response.
Think of it like a neighborhood watch program that's gotten out of control—the very cells meant to protect the uterine environment are now causing collateral damage, creating a cycle of inflammation and tissue injury that drives disease progression.
Immune Dysregulation
The immune system mistakenly attacks healthy tissue, creating chronic inflammation that fuels disease progression.
Immune Cell Distribution in Adenomyosis
The Surprising Role of Ciliated Cells
Perhaps the most unexpected discovery in recent adenomyosis research involves ciliated cells. Normally, these hair-like cells are found in the surface layer of the endometrium, where their waving motion helps move fluids and particles. But in 2025, researchers made a startling discovery: they found significantly increased numbers of DNAH9+ ciliated cells in ectopic endometrial glands—deep within the uterine muscle where they shouldn't exist 1 2 .
| Cell Type | Normal Location | Adenomyosis Alteration | Potential Role in Disease |
|---|---|---|---|
| DNAH9+ ciliated cells | Surface epithelium | Increased in ectopic glands | May facilitate tissue invasion |
| Inflammatory immune cells | Distributed evenly | Accumulate in ectopic lesions | Create pro-inflammatory microenvironment |
| SFRP5+ epithelial cells | Endometrial glands | Found at invagination sites | Promote proliferation and angiogenesis |
| ESR1+ smooth muscle cells | Myometrium | Create migratory tracts | Enable invasion through collagen degradation |
Invagination Theory Supported
The presence of specialized ciliated cells deep within muscle tissue provides crucial evidence supporting the invagination theory—that surface endometrial tissue tunnels into the uterine wall 1 .
Active Role in Disease
These misplaced ciliated cells may be more than innocent bystanders—their mechanical beating could help create space within muscular tissue or direct inflammatory signals.
Why would ciliated cells appear in the wrong place? Their presence provides crucial cellular evidence supporting the invagination theory—the idea that surface endometrial tissue actually tunnels into the uterine wall 1 . If adenomyosis resulted purely from metaplasia (cells transforming into different types), we wouldn't expect to find these specialized ciliated cells deep within muscle tissue. Their presence suggests that fully differentiated endometrial tissue, complete with appropriate specialized cells, has migrated into the myometrium.
But these misplaced ciliated cells may be more than just innocent bystanders—they might actively contribute to the disease process. Their mechanical beating could potentially help create space within the muscular tissue or direct the flow of inflammatory signals, though the exact mechanisms remain under investigation.
A Closer Look at the Key Experiment
To understand how researchers made these discoveries, let's examine a pivotal 2025 study that combined spatial transcriptomics with single-cell RNA sequencing to map adenomyosis from the endometrial invaginating site to deep lesions 6 .
Methodology: Step by Step
Sample Collection
Researchers obtained uterine tissue samples from 16 adenomyosis patients undergoing hysterectomy, plus control tissues from 11 patients with uterine fibroids.
Spatial Transcriptomics
They selected tissue sections containing the characteristic invagination structure where endometrium penetrates the myometrium. Using the 10x Genomics Visium platform, they captured RNA from specific tissue spots just 55 micrometers in diameter—smaller than the width of a human hair.
Single-Cell Integration
The team integrated their spatial data with previously published single-cell RNA sequencing data from over 48,000 uterine cells to identify exactly which cell types were present in each location.
Computational Analysis
Using sophisticated algorithms called Cell2location, they mapped the precise distribution of cell types within the tissue architecture and identified characteristic gene expression patterns in different disease regions.
Key Results and Their Meaning
The study revealed that different molecular mechanisms dominate each stage of adenomyosis progression:
| Disease Stage | Location | Key Molecular Players | Biological Process |
|---|---|---|---|
| Invagination | Endometrial-myometrial interface | SFRP5+ epithelial cells secreting IHH | Tissue proliferation and angiogenesis |
| Invasion | Through myometrium | ESR1+ smooth muscle cells | Collagen degradation creating migratory tracts |
| Fibrosis | Deep lesions | CNN1+ stromal fibroblasts | Fibroblast-to-myofibroblast transition |
At the invagination site, certain epithelial cells appear to drive the initial penetration by promoting tissue growth and blood vessel formation. During the invasion process, smooth muscle cells facilitate the journey by breaking down collagen to create migration pathways. In established deep lesions, fibroblasts undergo transformation into myofibroblasts, driving the fibrosis that makes the lesions hard and painful.
The Scientist's Toolkit: Key Research Solutions
The breakthroughs in understanding adenomyosis rely on sophisticated research tools and techniques. Here are some of the key solutions enabling these discoveries:
| Research Tool | Function | Role in Adenomyosis Research |
|---|---|---|
| 10x Genomics Visium | Spatial transcriptomics platform | Maps gene expression in intact tissue sections from invagination to deep lesions |
| Single-cell RNA sequencing | Analyzes gene expression in individual cells | Identifies rare cell populations and cellular heterogeneity in endometrium and myometrium |
| Cell2location algorithm | Computational method for cell type mapping | Integrates single-cell and spatial data to pinpoint exact locations of cell types |
| Laser capture microdissection | Precisely isolates specific tissue regions | Allows analysis of pure cell populations from complex tissue architectures |
| Multiplex immunohistochemistry | Visualizes multiple protein markers simultaneously | Validates spatial distribution of key cell types like ciliated and immune cells |
These tools have enabled researchers to move beyond simply observing tissue structure to actively decoding the molecular conversations between different cell types in adenomyosis. For example, by applying the Cell2location algorithm to their integrated data, researchers could determine that certain stromal fibroblasts in deep lesions were expressing genes associated with fibrosis, explaining the tissue hardening that occurs in advanced disease.
New Directions for Diagnosis and Treatment
These fundamental discoveries about the cellular and molecular landscape of adenomyosis have profound implications for improving patient care:
Diagnostic Innovations
The distinct molecular signatures identified in adenomyosis tissues could lead to the development of non-invasive diagnostic tests. Rather than relying exclusively on imaging or ultimately hysterectomy for definitive diagnosis, clinicians might someday use specific blood tests or endometrial biopsies that detect characteristic genetic markers of the condition. The identification of DNAH9+ ciliated cells in ectopic locations, for instance, might form the basis of such a test.
Therapeutic Opportunities
Understanding the specific molecules and pathways active in different stages of adenomyosis opens up possibilities for targeted treatments:
- Drugs that block the proliferation signals driving initial invagination
- Agents that inhibit the collagen degradation facilitating invasion
- Compounds that prevent the fibroblast transition that causes fibrosis
- Immunomodulators that correct the dysfunctional inflammatory microenvironment
The discovery that WNT5A signaling mediates interactions between ectopic endometrial cells and local ovarian stromal cells in the related condition endometriosis suggests that similar pathway-specific interventions might be effective for adenomyosis 3 .
Conclusion: A New Era of Understanding
The application of spatial biology to adenomyosis has transformed our understanding of this enigmatic disease. No longer viewed as simply "endometriosis of the uterus," adenomyosis is emerging as a complex condition with distinct molecular drivers at different pathological stages. The discovery of misplaced ciliated cells provides strong evidence for the invagination theory, while the detailed characterization of the inflammatory microenvironment explains many of the disease's symptoms.
As these research tools become more sophisticated and widely available, we can expect even deeper insights into adenomyosis. The current findings represent not an endpoint, but a beginning—the foundation for developing the effective, targeted treatments that patients have long deserved. For the millions of women suffering from adenomyosis, these spatial maps of the disease may ultimately chart the path toward relief.