Key Takeaways & Executive Findings
- •• Integrin signaling is crucial for mesenchymal stem cell (MSC) differentiation into adipocytes, chondrocytes, and osteoblasts, with distinct pathway activation in each lineage. • The extracellular matrix (ECM) and its interaction with integrins regulate MSC fate, influencing tissue homeostasis and repair. • Understanding integrin-mediated mechanotransduction and downstream signaling can optimize MSC-based tissue engineering and therapeutic applications. • Targeting integrin pathways holds promise for enhancing stem cell-based regenerative therapies.
Abstract
This review provides an overview of the integrin signaling pathways and their roles in mesenchymal stem cell differentiation into adipocytes, chondrocytes, and osteoblasts. In these three differentiated cells, the cell extracellular matrix plays an important role in regulating the integrin signaling pathway, as the presence of growth factors and other molecules in the extracellular matrix will affect the cell differentiation. The focus of this review is to elucidate the role of the integrin signaling pathway in adipogenesis, chondrogenesis, and osteogenesis, highlighting its diverse contributions to tissue homeostasis and repair. By synthesizing current knowledge, this paper aims to inspire further research into the therapeutic potential of targeting integrin pathways in stem cell-based tissue engineering.
1. Introduction
Cell surface receptors play a key role in the adhesion of cells to the extracellular matrix (ECM). Among them, integrins are important transmembrane receptors made up of two subunits: one α and one β glycoprotein. These αβ heterodimers are non-covalently linked and mediate both cell-to-cell and cell-to-matrix interactions [24]. Integrins form a dynamic connection between the intracellular cytoskeleton and the ECM, which helps regulate essential cellular processes such as growth, proliferation, and migration [48].
Mesenchymal stem cells (MSCs) are fibroblast-like, multipotent stem cells that can be isolated from tissues including bone marrow, adipose tissue, synovial membrane, dental pulp, and brain [17, 61]. The minimal criteria for identifying human MSCs include the expression of surface markers CD105, CD73, and CD90, along with the absence of hematopoietic markers such as CD34 and CD45 [56]. Additionally, MSCs must demonstrate the capacity to differentiate into at least three lineages including adipocytes, chondrocytes, and osteoblasts.
The activation of downstream pathways by integrin in adipocytes, chondrocytes, and osteoblasts is very distinct, as shown in Fig. 1. In adipocytes, the interaction of ECM and integrin regulates adipogenesis by the activation of the Wnt/β-catenin pathway and inhibition of focal adhesion kinase (FAK) activity. These activations reduce the expression of adipogenic markers such as AP2, AdipoQ, and CEBPα. In chondrocytes, the integrin receives the signals from inflammation and produces the inflammatory response.
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Dafina Najwa Mohd Arizam, Fazlina Nordin, Azlina Ahmad, Khairul Bariah Ahmad Amin Noordin (2026). Integrin signaling pathways in mesenchymal stem cells. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04608-8
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Frequently Asked Questions
What is the role of integrin signaling in mesenchymal stem cell differentiation?
Integrin signaling mediates cell-ECM interactions and regulates MSC differentiation into adipocytes, chondrocytes, and osteoblasts through distinct downstream pathways, influencing tissue homeostasis and repair.
How does the extracellular matrix affect integrin signaling in MSCs?
The ECM provides biochemical and mechanical cues that modulate integrin signaling, affecting MSC adhesion, migration, and differentiation. Growth factors and other ECM molecules can alter integrin activation and downstream pathways.
What are the key downstream pathways activated by integrins in adipogenesis?
In adipogenesis, integrin signaling activates the Wnt/β-catenin pathway and inhibits focal adhesion kinase (FAK) activity, leading to reduced expression of adipogenic markers such as AP2, AdipoQ, and CEBPα.
Why is understanding integrin signaling important for tissue engineering?
Understanding integrin signaling is crucial for optimizing MSC-based tissue engineering because it allows researchers to control differentiation and enhance regenerative outcomes by manipulating cell-ECM interactions.
What is the therapeutic potential of targeting integrin pathways in stem cell therapy?
Targeting integrin pathways can potentially improve the efficiency and specificity of stem cell differentiation, leading to better tissue repair and regeneration, and offering new strategies for treating degenerative diseases.
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