How Stromal Cells Build, Maintain, and Repair Our Tissues
Imagine a city with its dazzling buildings and bustling activity—but beneath this vibrant surface lies an intricate network of roads, power lines, and communication systems that keep everything functioning. In our bodies, this vital infrastructure is called the stroma, the connective tissue that forms the architectural framework of every organ. Long overlooked in favor of flashier cell types, stromal cells are now emerging as master regulators of health and disease.
The 2019 British Society for Matrix Biology Spring Meeting, titled "Stroma, Niche, Repair", brought together leading scientists who revealed groundbreaking discoveries about these cellular architects. Their research illuminates how stromal cells not only provide structural support but actively direct tissue regeneration, control stem cell behavior, and influence conditions ranging from cancer to osteoarthritis. This article explores these fascinating findings, revealing how understanding our body's hidden framework may unlock revolutionary approaches to medicine and tissue regeneration.
Stroma (from the Ancient Greek word for "layer" or "bed covering") constitutes the structural and connective components of tissues and organs 5 . Think of it as the scaffolding that supports the specialized, functional cells (called parenchyma) in any organ. While parenchymal cells—such as heart muscle cells or brain neurons—perform the organ's primary functions, stromal cells create the environment that enables them to work properly.
A complex meshwork of proteins and carbohydrates that provides structural support and biochemical cues.
Including fibroblasts that produce ECM components, immune cells, and blood vessels 5 .
This biological scaffolding does far more than just provide mechanical support—it actively communicates with surrounding cells, influencing their behavior, survival, and specialization through both physical cues and chemical signals.
In healthy tissues, stromal cells maintain tissue homeostasis—the delicate balance that keeps organs functioning properly. They achieve this through constant, dynamic interactions with their environment. During the BSMB meeting, Professor Peter Friedl from Radboud University presented fascinating research showing how the density of stroma can dictate cell behavior, particularly in cancer 1 .
His team discovered that matrix density can control what's known as "cell jamming"—a transition between fluid and solid states that either facilitates single cancer cell escape (unjammed) or collective invasion (jammed) 1 .
This process resembles commuters in a crowded subway: when the space is open, people move individually, but when packed tightly, they move as a collective mass.
Dysfunctional stromal cells contribute to various diseases. Michael Schmid from Liverpool discussed how in pancreatic ductal adenocarcinoma, specific macrophages recruit to the liver and create a "protected metastatic niche" that fosters cancer growth 1 . Meanwhile, Mandy Peffers from Liverpool revealed that small tRNA fragments in aging cartilage may explain why older people experience reduced protein homeostasis in osteoarthritis 1 .
| Condition | Stromal Function | Research Finding |
|---|---|---|
| Cancer Invasion | Regulates cell migration patterns | Matrix density controls "jamming transition" between single and collective cell invasion 1 |
| Liver Metastasis | Creates protective microenvironment | Progranulin-expressing macrophages sustain growth-promoting metastatic niche 1 |
| Osteoarthritis | Maintains tissue homeostasis | tRNA fragments in aged cartilage linked to reduced protein production 1 |
| Breast Cancer | Facilitates invasion | αVβ6 integrin crosstalks with EGFR to reprogram cancer cell behavior 1 |
Perhaps the most exciting revelation in stromal biology is their role as master organizers of stem cell niches—specialized microenvironments that house and regulate stem cells. These niches don't merely protect stem cells; they actively instruct them on when to divide, what types of cells to become, and when to remain quiet.
Research presented at the BSMB meeting highlighted how stromal niches employ sophisticated signaling systems. In the intestinal stem cell niche, stromal cells provide Wnt molecules that maintain stem cell proliferation and villus homeostasis 6 . Recent research has identified that a specific stromal lineage marked by Twist2 maintains crypt structure and provides an inflammation-restricting niche for regenerating intestinal stem cells 6 . When these stromal cells are disrupted, the entire regenerative system falters.
This niche function appears to be a universal principle across different organs:
Stromal cells respond to Hedgehog signals by producing both Wnt molecules (promoting proliferation) and BMPs (promoting differentiation), perfectly coordinating tissue repair 3 .
Stromal cells not only produce growth factors but also express hormone receptors, linking systemic hormonal signals to local stem cell behavior 3 .
One of the most compelling studies presented at the meeting investigated how bone marrow stromal cells (BMSCs) influence cellular behavior through their secreted factors and extracellular matrix 2 8 . Given the known heterogeneity of BMSCs, researchers sought to understand how different stromal subtypes communicate with other cells and which signals might drive distinct cellular behaviors.
The research team employed a sophisticated experimental approach:
They used two immortalized clonal BMSC lines isolated from the same donor but with distinct properties: Y201 (multipotent stem-cell-like) and Y202 (nullipotent, non-stem cell-like) 2 8
They collected conditioned media (containing all secreted factors) from Y201 cultures and applied it to Y202 cells 2
Using label-free quantitative phase imaging, they tracked morphology and migration of Y202 cells over 96 hours after exposure to Y201 signals 2
Through mass spectrometry, they quantified and compared all proteins in the secretome of both cell lines 2 8
They developed detailed methods to isolate and image the extracellular matrix produced by each cell type using both scanning electron microscopy and focused ion beam SEM 8
Finally, they used immunofluorescence to confirm the presence of identified proteins in actual mouse and human bone marrow samples 2 8
The findings were striking. When Y202 cells (the non-stem cell type) were exposed to secretions from Y201 stem-like cells, they underwent a dramatic transformation—their morphology changed and their migration increased to more closely resemble the stem-like Y201 cells 2 .
Proteomic analysis revealed why: Y201 cells secreted dramatically higher levels of extracellular matrix proteins. Specifically, aggrecan was detected at 104-fold higher levels and periostin at 71-fold higher levels in Y201 compared to Y202 secretomes 8 . Even more compelling, when researchers created decellularized ECM from Y201 cultures and grew Y202 cells on this matrix, the Y202 cells exhibited similar improvements in migration and morphology.
| Protein Category | Y201 (Stem-like) Secretome | Y202 (Non-stem) Secretome | Biological Significance |
|---|---|---|---|
| Aggrecan | 104-fold higher | Lower | Key structural component of cartilage, potentially important for niche integrity |
| Periostin | 71-fold higher | Lower | Matricellular protein that modulates cell-matrix interactions and signaling |
| Overall ECM Proteins | Significantly enriched | Less abundant | Creates more robust extracellular environment that influences cell behavior |
| Matrix Structure | Dense, well-organized network | Sparse, less organized | Quality of ECM correlates with functional stem cell characteristics |
Microscopy analysis confirmed that Y201 cells produced a more robust and organized ECM than Y202 cells. Most importantly, the team identified both aggrecan and periostin at rare sites on the endosteal surfaces of mouse and human bone, underlying CD271-positive stromal cells—suggesting these might be key components of the true stem cell niche in living bone marrow 2 8 .
This experiment demonstrates that stromal cell identity can be influenced by surrounding ECM components, revealing a previously underappreciated plasticity in stromal behavior. The findings suggest that the extracellular matrix isn't just passive scaffolding but an active instructor of cellular fate. This has profound implications for understanding tissue regeneration, developing better cell expansion protocols for therapy, and potentially manipulating stromal environments to treat diseases.
Studying stromal cells requires specialized approaches that account for their three-dimensional environment and complex interactions. Here are some essential tools and methods used in stromal research, based on techniques presented at the BSMB meeting:
| Tool/Method | Function | Application Example |
|---|---|---|
| 3D Biomimetic Scaffolds | Provides 3D structure mimicking natural environment | Studying lamina cribrosa changes in glaucoma 1 |
| Label-Free Quantitative Phase Imaging | Tracks cell morphology and migration without labels | Documenting changes in BMSC migration patterns 2 8 |
| Focused Ion Beam SEM | Creates detailed 3D images of extracellular matrix ultrastructure | Visualizing complex architecture of BMSC-derived ECM 2 8 |
| Mass Spectrometry Proteomics | Identifies and quantifies proteins in secretomes | Discovering aggrecan and periostin as highly enriched in stem cell secretomes 2 8 |
| Conditioned Media Transfer | Tests effect of secreted factors alone | Demonstrating soluble factors can change non-stem cell behavior 2 |
| Decellularized ECM | Isolates extracellular matrix without cells | Testing direct effect of ECM on cell phenotype 8 |
The understanding of stromal function has already fueled advances in tissue engineering. During the BSMB meeting's session on "Innovative material science to regenerate, reconstruct and interface with tissues," multiple researchers presented exciting developments:
Cian O'Leary from RCSI Ireland created a scaffold that mimics the tracheobronchial region for drug development and tissue regeneration 1 .
Stefanie Korntner from Galway generated tissue-like constructs for tendon repair using electrospun fibers that support matrix deposition 1 .
Olga Piskareva established a collagen-based 3D model of neuroblastoma to test potential treatments 1 .
Tim Johnson presented a "fascinating story" of how basic research on transglutaminase type 2 (TG2) as a pro-fibrotic protein led to the development of phase 1 approved antibodies that successfully target TG2 1 . This exemplifies how understanding stromal biology can yield direct clinical benefits, particularly for treating fibrotic diseases that involve excessive scar tissue formation.
Similarly, research on how stromal niches restrain cancer growth has opened new therapeutic possibilities. By understanding the molecular signals—such as BMPs in bladder cancer—that maintain normal tissue architecture, researchers might develop ways to reactivate these natural cancer-restraining mechanisms 3 .
The research presented at the British Society for Matrix Biology's 2019 meeting reveals a paradigm shift in how we view our bodies' structural elements. Stromal cells are no longer considered passive spectators but active directors of tissue health, regeneration, and disease. As the scientific toolkit for studying these complex interactions expands, we can expect:
Strategies that better mimic natural stromal environments
That target specific stromal pathways
That manipulate the tumor microenvironment
Approaches that incorporate stromal components
The 2019 British Society for Matrix Biology Spring Meeting was held at the University of Liverpool and organized by George Bou-Gharios and Dimitrios Zeugolis, featuring over 120 attendees and more than 70 poster presentations 1 .