In the intricate dance of stem cell development, it turns out that holding on is just as important as letting go.
Imagine a construction site where the bricks themselves decide whether they will become part of a wall or a walkway based on how tightly they cling to their neighbors. This isn't far from the reality unfolding in stem cell biology, where scientists are discovering that specialized "cellular glue" known as cadherins plays a surprising role in directing stem cell fate decisions.
For decades, stem cell research focused heavily on soluble chemical signals as the primary directors of cellular destiny. But a growing body of evidence reveals that physical interactions between cells—the very forces that hold tissues together—serve as sophisticated communication channels that guide stem cells toward their ultimate identities 1 3 5 .
Chemical signals as primary directors of cellular destiny
Physical interactions as sophisticated communication channels
At the heart of this cellular communication system are cadherins, a family of proteins that mediate calcium-dependent cell-cell adhesion. Among these, two stand out as particularly influential in mesenchymal stem cell fate decisions: CDH2 (N-cadherin) and CDH11 (OB-cadherin) 1 .
These proteins function as both structural elements and signaling hubs. Their extracellular domains reach out to neighboring cells, while their intracellular tails connect to the cytoskeleton and signaling molecules inside the cell 1 .
Widely expressed in neuronal cells, mesenchymal cells, and developing tissues. It's known to regulate spatially polarized signals through distinct pathways and is considered a mechanoresponsive adhesion receptor 1 .
Initially identified in osteoblasts, plays critical roles during gastrulation—the embryonic process that generates the three germ cell layers—where it enables spatial recognition and cell segregation as they move to form primitive tissue structures 1 .
| Feature | CDH2 (N-cadherin) | CDH11 (OB-cadherin) |
|---|---|---|
| Primary Expression | Neuronal cells, mesenchymal cells | Osteoblasts, mesenchymal cells |
| Role in Development | Left-right axis development, neural tube formation | Gastrulation, brain and spinal cord development |
| Mechanosensitivity | High - responds to mechanical forces | Involved in directional migration |
| Connections | Links to β-catenin, p120 catenin, actin cytoskeleton | Associates with similar cytoplasmic complexes |
Cadherins do far more than simply glue cells together. They form adherens junctions that serve as mechanosensing platforms, translating physical forces into biochemical signals that influence cell behavior 1 .
These connections allow cadherins to participate in crosstalk with growth factor receptors. For instance, fibroblast growth factor receptors stimulate CDH2 during neurite outgrowth, while CDH11 can influence macrophage development and function 1 6 .
Recent research has revealed that substrate stiffness can regulate AJ formation through pathways like c-Janus N-terminal kinase (JNK). Stiffer substrates activate JNK leading to AJ disassembly, while softer matrices suppress JNK activity promoting AJ formation 1 .
Interactive diagram showing cadherin signaling pathways would appear here
The importance of cell-cell adhesion in fate decisions becomes particularly evident when examining how stem cells behave in different culture environments. A fascinating study investigated the difference between cells cultured as a monolayer (2D) versus as aggregates (3D) 8 .
Researchers observed that proliferating human mesenchymal stem cells (hMSCs) in monolayer culture expressed lower levels of CDH2 and increased CDH11 expression at cell-cell contact sites over time—a pattern not seen in aggregate cultures 8 .
To determine the functional significance of these expression patterns, the team employed knockdown experiments using specific molecular tools to reduce the expression of each cadherin, then observed how the stem cells responded during differentiation.
| Experimental Phase | Methods Used | Purpose |
|---|---|---|
| Culture Conditions | Monolayer (2D) vs. Aggregate (3D) | To examine how spatial organization affects cadherin expression |
| Cadherin Modulation | Knockdown of CDH2 and CDH11 | To determine necessity of each cadherin for differentiation |
| Lineage Commitment | Adipogenic and osteogenic differentiation protocols | To assess differentiation efficiency under different conditions |
| Analysis | Molecular and cellular characterization | To evaluate differentiation outcomes |
Flat, single-layer cell growth with limited cell-cell contacts
Three-dimensional cell clusters with extensive cell-cell contacts
The results of the cadherin knockdown experiments revealed a sophisticated regulatory system:
These findings demonstrate that CDH2 and CDH11 play distinct but complementary roles in regulating hMSC differentiation, and their importance varies depending on both the target lineage and the cellular microenvironment.
| Condition | Adipogenic Differentiation | Osteogenic Differentiation |
|---|---|---|
| CDH2 Knockdown | Impaired in both monolayer and aggregate | Enhanced in both monolayer and aggregate |
| CDH11 Knockdown | Impaired in both monolayer and aggregate | Impaired in monolayer but not aggregate |
| Control (No Knockdown) | Normal differentiation | Normal differentiation |
Studying cadherin function requires specialized research tools. Here are key reagents scientists use to unravel the mysteries of cell adhesion in stem cell biology:
Used to detect, visualize, and quantify CDH2 and CDH11 expression in cells and tissues through techniques like immunohistochemistry and flow cytometry 6 .
Purified cadherin proteins used to study binding interactions and function, often incorporated into synthetic substrates 1 .
Specialized media containing M-CSF (macrophage colony-stimulating factor) to study immune cell development and function 6 .
Engineered surfaces with controlled chemistry and topography to study how physical cues influence cadherin-mediated adhesion 1 .
Advanced microscopy techniques to visualize cadherin localization and dynamics in live cells and tissues.
Understanding how CDH2 and CDH11 guide stem cell fate decisions has profound implications for tissue engineering and regenerative medicine 1 3 5 .
Researchers are already developing engineering strategies to control stem cell fate decisions by fine-tuning the extent of cell-cell adhesion through surface chemistry and microtopology 1 . These approaches may lead to improved biomaterials and scaffolds that can direct tissue regeneration in three-dimensional contexts.
Beyond regenerative medicine, cadherins have been implicated in various disease processes. CDH11 is expressed on macrophages in fibrotic lung tissue and plays a role in pathogenesis of pulmonary fibrosis 6 . Interestingly, CDH11 deficiency represses the M2 macrophage program and impairs phagocytic function, suggesting potential therapeutic avenues 6 .
In cancer biology, the balance between different cadherins can influence tumor aggressiveness. In chordomas, increased CDH2 expression combined with decreased E-cadherin strongly correlates with worse patient outcomes 2 . This cadherin switch may underlie the transition from less to more aggressive tumor phenotypes 2 .
Balanced cadherin expression maintains tissue architecture
Initial cadherin expression changes begin
Increased CDH2 with decreased E-cadherin
Altered cadherin profile correlates with metastasis
The story of CDH2 and CDH11 reveals a fundamental biological principle: cells talk through touch. The physical connections between cells form a sophisticated communication network that guides developmental decisions, maintains tissue integrity, and when disrupted, contributes to disease.
As research continues to decipher this adhesion code, we move closer to harnessing these mechanisms for therapeutic benefit—whether by directing stem cells to repair damaged tissues, preventing pathological fibrosis, or developing new strategies against aggressive cancers.
The once simple view of cellular glue as mere structural material has given way to a rich understanding of cadherins as master regulators of cellular fate, reminding us that in biology as in human relationships, how we connect shapes who we become.