Extracellular matrix: a dynamic microenvironment for stem cell niche

Abstract

Background: Extracellular matrix (ECM) is a dynamic and complex environment characterized by biophysical, mechanical and biochemical properties specific for each tissue and able to regulate cell behavior. Stem cells have a key role in the maintenance and regeneration of tissues and they are located in a specific microenvironment, defined as niche.

Scope of review: We overview the progresses that have been made in elucidating stem cell niches and discuss the mechanisms by which ECM affects stem cell behavior. We also summarize the current tools and experimental models for studying ECM-stem cell interactions.

Major conclusions: ECM represents an essential player in stem cell niche, since it can directly or indirectly modulate the maintenance, proliferation, self-renewal and differentiation of stem cells. Several ECM molecules play regulatory functions for different types of stem cells, and based on its molecular composition the ECM can be deposited and finely tuned for providing the most appropriate niche for stem cells in the various tissues. Engineered biomaterials able to mimic the in vivo characteristics of stem cell niche provide suitable in vitro tools for dissecting the different roles exerted by the ECM and its molecular components on stem cell behavior.

General significance: ECM is a key component of stem cell niches and is involved in various aspects of stem cell behavior, thus having a major impact on tissue homeostasis and regeneration under physiological and pathological conditions. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.

Keywords: Cell receptor; Extracellular matrix; Growth factor; Stem cell; Stem cell niche; Tissue engineering.

Fig. 1

Regulation of cell behavior by ECM. The effects exerted on cells by ECM can be differently mediated. The ECM can directly bind different types of cell surface receptors or co-receptors (red, orange, black), thus mediating cell anchorage and regulating several pathways involved in intracellular signaling and mechanotransduction. Moreover, the ECM can act by non-canonical growth factor (cyan) presentation and be remodeled by the action of enzymes (yellow pie), which can release functional fragments (green).

Fig. 2

Players in stem cell niche. The stem cell niche is a specialized and dynamic microenvironment in which a number of inputs regulate stem cell (green) behavior. These include signals departing from blood vessels, neural and supportive cells, as well as secreted factors and ECM components.

Fig. 3

Strategies for engineering stem cell niches. (A) Schematic representation of the engineering techniques used to reproduce the chemical, physical and mechanical microenvironment of stem cell niche. (B) Schematic diagram of high-throughput ECM microarrays. Hundreds of thousands of printed artificial ECM niches can be created in one single experiment by the use of automatic pipettes that mix together stem cells and different combinations of niche components.

Fig. 4

3D environment recapitulates in vivo niches. (A) Cells on a rigid planar surface organize focal adhesions and actin stress fibers at the basal surface of the cell and transfer contractile forces to their surface and to other cells. With their apical side, cells interface with secreted factors present in the medium, whereas with their basal side they interact with the ECM, which confers mechanical properties. (B) Inside a 3D microenvironment, the curvature and the softness of matrix materials limit the formation of actin stress fibers. Cells inside a 3D environment experience stress around the whole structure, both in planar and perpendicular directions to the cell basal surface. Secreted factors can be highly concentrated in the inner compartment. In addition, ECM displays a non-linear behavior and gradient of mechanical stiffness.

Fig. 5

Stem cell niches and their ECM. The diagrams show four different stem cell niches, together with their cellular and ECM components. ECM molecules playing major roles in the different niches are indicated. (A) HSC niche consists of two anatomically distinct (dotted line) cellular entities, the “endosteal niche”, populated mainly by osteoblasts, and the “vasculature niche”, located in the perivascular space. HSCs can move through those two niches and interact with ECM molecules. A variety of cells, including osteoblasts, Cxcl12-abundant reticular (CAR) cells, nestin-positive mesenchymal stem cells (MSC), Lepr-expressing perivascular cells, and endothelial cells, were shown to be active components of the niche. (B) Diagram of the hair follicle. Multipotent stem cells are located in the bulge, which lies in the outer root sheath just below the sebaceous gland, and contribute to the lineages of the hair follicle, sebaceous gland, and the epidermis (arrows). The ECM surrounds the dermal papilla, a cluster of specialized mesenchymal cells in the hair bulb. (C) In skeletal muscle, satellite cells reside in the niche between myofiber plasma membrane and basal lamina. The myofiber basal lamina is a network of ECM components, including collagen IV, laminin, collagen VI, fibronectin and proteoglycans, which facilitate satellite cell adhesion via binding to receptors such as α7β1 integrin and syndecan-4. (D) In the adult brain, the SVZ niche is composed of three cell populations that lie immediately beneath a monolayer of ependymal cells lining the lateral ventricle and corresponding to the relatively quiescent NSCs (a), mitotically active transit amplifying cells (b), and neuroblasts (c). NSCs are intercalated into the ependymal layer and are also closely associated with the vasculature. NSCs within the SVZ are in contact with endothelial cells, microglia and astrocytes. NSCs are also in contact with fractones, structures rich in ECM molecules and continuous with the basal lamina of blood vessels.