Extracellular matrix, integrins, and growth factors as tailors of the stem cell niche

doi:10.1016/j.ceb.2012.07.001

Current Opinion in Cell Biology

Volume 24, Issue 5, October 2012, Pages 645-651

https://doi.org/10.1016/j.ceb.2012.07.001 Get rights and content

It is widely acknowledged that integrins, the major receptors for the extracellular matrix (ECM) proteins, exert an extensive crosstalk with many growth factor and cytokine receptors. Among them, growth factor receptors, such as the EGFR, MET, PDGFR and VEGFR, and the IL-3 receptor have been shown to be physically and functionally associated to integrins. The connection between integrins and other transmembrane receptors is bidirectional, integrins being essential for receptor signalling, and receptors being involved in regulation of integrin expression or activation. Moreover, there is accumulating evidence for direct binding of specific growth factors and morphogens to the ECM proteins, suggesting that ECM might spatially integrate different types of signals in a specific microenvironment, facilitating integrin/transmembrane receptors connection. These interactions are crucial in controlling a variety of cell behaviours including proliferation, survival and differentiation. The increasing interest for cell therapy in regenerative medicine has recently emphasized the role of cell-ECM adhesion as stem cell determinant. The relevance of ECM, integrins and growth factor receptor network in the establishment of stem cell niche, in maintenance of stem cells and in their differentiation will be analyzed in the present review.

Highlights

► ECM molecules bind specific growth factors and morphogens regulating their bioavailability, and organizing a dynamic microenvironment for local integration of adhesive and growth factor signalling. ► Integrins, the major receptors for ECM proteins, exert an extensive crosstalk with growth factor and cytokine receptors that generates an intracellular network of signalling pathways and modulates key aspects of cell behaviour. ► ECM proteins/integrins are key components shaping the stem cell niche to maintain stem cell homeostasis and to direct lineage commitment.

Introduction

Integrins are a large family of heterodimeric transmembrane receptors that mediate cell binding to the ECM and to counter receptors, connecting the extracellular environment to the intracellular cytoskeleton. The assembly of eighteen alpha subunits and eight beta subunits gives rise to 24 distinct heterodimers that have cell-type-specific expression and overlapping substrate specificity [1]. Upon binding to their ligands, integrins induce a variety of signalling molecules, assembling multiprotein complexes that reorganize the cytoskeleton and activate pathways that regulate cell migration, proliferation, survival and differentiation [2].

An area of growing interest is to understand how ECM and integrins cooperate within the stem cell niche to build the niche architecture and to control the balance between cell renewal and differentiation. In the first part of this review we will briefly summarize the ability of integrins to functionally and physically interact with growth factor and cytokine receptors, generating an interconnected network of signalling pathways. In the second part we will report the current knowledge on the regulatory role of ECM/integrin and growth factors in the stem cell niche.

Section snippets

Interaction and cooperation between integrins and transmembrane receptors

Reciprocal growth factor/cytokine/integrin signalling is involved both in normal physiology and in pathological processes. Integrins belonging to the beta1, alphav, beta7 and beta4 subfamilies have been shown to potentiate signalling pathways in response to many growth factors (reviewed in [2, 3, 4, 5]), IL-3 [6, 7] and TGFbeta (reviewed in [5, 8]). The cooperation between integrins and other receptors is essential in at least four interlinked processes: (i) receptor transactivation (integrin

ECM proteins as a reservoir of growth factors

The biological relevance of ECM/integrin interaction in regulating cell adhesion and signalling has been extensively documented [1]. However, more recently, several lines of evidence sustain that ECM proteins also regulate growth factor bioavailability by establishing stable gradients of growth factors [21]. ECM proteins like fibronectin, vitronectin, collagens and proteoglycans (PGs) themselves, or in combination with heparin and heparin sulphate, avidly bind many growth factors, such as FGFs,

ECM in maintaining stem cell identity

Stem cells reside in a dynamic, specialized microenvironment, denoted as stem cell niche that provides extracellular cues to allow stem cell survival and to maintain a balance between self-renewal, and differentiation [28, 29]. ECM proteins are key components shaping the niche and maintaining stem cell homoeostasis. ECM can organize a platform for molecular complex assembly, ultimately leading at integrating signalling emanated from soluble and matrix-bound factors and from cell-matrix

Beta1 integrin regulatory role in the stem cell niche

ECM instructs stem cells by interacting with specific integrin heterodimers, mainly belonging to the beta1 subfamily (reviewed in [47, 48, 49]). Long before its identification as an essential regulator of hematopoietic stem cell (HSC) (for a review, see [50]) and spermatogonial stem cells homing [51], beta1 integrin has been described as an epidermal stem cell marker [52]. From then on, stem cell identification and purification, independently of their tissue origin, have benefited by beta1

ECM biomechanical stiffness and cell fate determination

In the stem cell niche the balance between self-renewal and differentiation does not simply depend on the biochemical ECM composition. Indeed, physical and mechanical forces in the local stem cell microenvironment modulate ECM nanoscale features, leading to changes in cell shape and geometry. For example, as ECM molecules are flexible and extendable, mechanical tension can uncover cryptic sites within them. All these biophysical signals are transduced by integrins to trigger contractility of

Conclusions

In this review we highlighted recent evidences that closely link ECM/integrin interaction to several aspects of stem cell niche morphogenesis and function. We also underlined the relevance of ECM/integrin adhesion in regulating stem cell growth factor/cytokine bioavailability, and in tuning membrane receptor signalling to control stem cell homeostasis. A deeper understanding of ECM structural composition, integrin repertoire and biochemical and biomechanical signals in defining the stem cell

Acknowledgements

We thank Dr Patrizia Dentelli for her help with the preparation of the figures. This work was supported by AIRC, Regione Piemonte — Progetti Sanità, Oncoprot, PiSTEM, Druidi and CIPE, Compagnia San Paolo, Torino and Progetto d’Ateneo 2011.

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Extracellular matrix, integrins, and growth factors as tailors of the stem cell niche

Highlights

Introduction

Section snippets

Interaction and cooperation between integrins and transmembrane receptors

ECM proteins as a reservoir of growth factors

ECM in maintaining stem cell identity

Beta1 integrin regulatory role in the stem cell niche

ECM biomechanical stiffness and cell fate determination

Conclusions

Acknowledgements

Cell

J Biol Chem

Cell

Cell

Cell

Prev Med

Am J Pathol

Dev Cell

Biophys J

Cell

Curr Opin Cell Biol

Cell

Cell Stem Cell

Cell

Blood

Cell Stem Cell

J Biol Chem

Curr Biol

Biomaterials

Cancer Cell

Cancer Cell

Cancer Cell

Genetic and cell biological analysis of integrin outside-in signaling

Genes Dev

Sensing the environment: a historical perspective on integrin signal transduction

Nat Cell Biol

Positional control of cell fate through joint integrin/receptor protein kinase signaling

Annu Rev Cell Dev Biol

Cooperation between integrins and growth factor receptors in signaling and endocytosis

Annu Rev Cell Dev Biol

{beta}1 Integrin and IL-3R coordinately regulate STAT5 activation and anchorage-dependent proliferation

J Cell Biol

Inhibition of beta1 integrin and IL-3Rbeta common subunit interaction hinders tumour angiogenesis

Oncogene

Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing

EMBO Rep

Integrins induce activation of EGF receptor: role in MAP kinase induction and adhesion-dependent cell survival

EMBO J

Induction of membrane circular dorsal ruffles requires co-signalling of integrin-ILK-complex and EGF receptor

J Cell Sci

Beta3 integrin-EGF receptor cross-talk activates p190RhoGAP in mouse mammary gland epithelial cells

Mol Biol Cell

Convergence of integrins and EGF receptor signaling via PI3K/Akt/FoxO pathway in early gene Egr-1 expression

J Cell Physiol

Integrin signalling adaptors: not only figurants in the cancer story

Nat Rev Cancer

Integrins in cancer: biological implications and therapeutic opportunities

Nat Rev Cancer

Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies

J Cell Biol

Beta1 integrin controls EGFR signaling and tumorigenic properties of lung cancer cells

Oncogene

Ligand-independent activation of c-Met by fibronectin and alpha(5)beta(1)-integrin regulates ovarian cancer invasion and metastasis

Oncogene

Transforming growth factor beta induces clustering of HER2 and integrins by activating Src-focal adhesion kinase and receptor association to the cytoskeleton

Cancer Res