Review
Matrigel: Basement membrane matrix with biological activity

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Abstract

The basement membrane extracellular matrix contacts epithelial, endothelial, fat and smooth muscle cells. Because this extracellular matrix is so thin, it had been hard to study its composition, structure, and function. An extract of a tumor was found to contain all of the components present in basement and to be very biologically active. This extract, termed Matrigel, Cultrex, or EHS matrix, promotes cell differentiation, and is used to measure the invasive activity of tumor cells. In vivo, it is used for measuring angiogenic inhibitors and stimulators, to improve graft survival, repair damaged tissues, and increase tumor growth.

Section snippets

The road to Matrigel's invention

The Laboratory of Developmental Biology and Anomalies (LDBA) was formed in 1972 in the National Institute of Dental Research, NIH, as an off shoot of the Laboratory of Biochemistry where much of the work defining collagen was carried out by Karl Piez and his colleagues. The LDBA also had an interest in the role of extracellular matrix components in development and in disease. As part of that interest, Barbara Smith (currently at Boston University) carried out studies on a transplantable rat

The EHS tumor

Roslyn Orkin (currently at Harvard Med School) studied another mouse tumor with an abundant extracellular matrix, originally identified as a poorly differentiated chondrosarcoma [2]. Ultrastructural and amino acid analyses along with other studies, suggested that the tumor matrix was distinct from cartilage and instead resembled basement membrane. We named it the EHS tumor to acknowledge J. Engelbreth-Holm of Denmark, who discovered it, and Richard Swarm, who maintained and characterized it.

Matrigel

Hynda Kleinman joined LDBA in 1975 to work on the molecular interactions of cells with extracellular matrix components. The attachment activity of laminin was studied in LDBA and the protein was found to promote epithelial, endothelial, and tumor cell attachment while fibroblasts did not attach to laminin [13]. In 1983, Hynda Kleinman had begun to work with extracts of the EHS tumor. In these studies, EHS tumor tissue was washed free of cell- and serum-derived proteins with 20% NaCl and the

Differentiation and cell culture

Matrigel promotes the differentiation of many different cell types as well as the outgrowth of differentiated cells from tissue explants (Table 2) [21], [22], [23], [24], [25], [26], [27], [28], [29], [30]. It is stored as a frozen solution, usually 10–15 mg/ml media, is thawed overnight at 4 °C, and gels at 24–37 °C in 30 min. The gel does not re-dissolve readily on cooling. Cells are generally plated on top of the gelled material, but can be mixed with the matrix prior to gelling. Many cell

Tissue explants

Matrigel has also been used with tissue explants (Table 2). Chick spinal ganglia explanted on plastic produce an outgrowth of neuronal cells with accompanying Schwann cells, but the Schwann cells appear flat and fibroblasts are often present. On Matrigel, the outgrowth is more extensive and the Schwann cells wrap around the neurons, migrate along neurite outgrowths, and produce myelin [32]. Many researchers have also studied angiogenesis factors using aortic ring explants cultured in the

Tumor cell interactions and activity with basement membrane matrix

Randall Kramer (University of California, San Francisco) showed that HT1080 cells invaded Matrigel [35]. In contrast to fibroblasts, which formed small non-invasive colonies, the HT1080 cells rapidly invaded into the gel, formed multiple tunnels, and proliferated rapidly, a vivid example of their invasive and degradative activities (Fig. 2).

Given the major differences observed between malignant and normal cells on Matrigel, a simple, rapid, and quantitative assay measuring tumor cell invasion

Stem cells and Matrigel

Basement membrane components are the first extracellular matrices synthesized in the developing embryo with laminin expressed at the two-cell stage and a basement membrane apparent at gastrulation. Since basement membranes are the first extracellular matrix that stem cells contact, it would be expected that such matrices would have a profound effect on their differentiation. Michael Bilozur and Elizabeth Hay in 1988 reported that Matrigel promoted the outgrowth of neural crest cells [43]. Since

Mechanism underlying the effects observed with cells on and in Matrigel

The multiple responses observed with cells on Matrigel are not well understood but undoubtedly involve a variety of mechanisms. Cells in or on Matrigel associate and become polarized, in contrast to their behavior under other culture conditions. Matrigel, as well as basement membranes, represent a rich store of angiogenic and growth factors, which are released by proteases produced by tumor and other cells. Fragments of laminin-1, collagen IV, and other matrix proteins contribute angiogenic-

Summary

Development of the basement membrane matrix was facilitated in a laboratory focused on the structure and function of the extracellular matrix. Although developed some 20 years ago, Matrigel is still widely used for studies on cell differentiation, angiogenesis, and tumor growth (Table 3). Various models of differentiation have been developed, some of which have led to widely used assays, such as the capillary-like tube formation for angiogenesis. Additional assays for angiogenesis and tumor

Acknowledgement

We thank Dr. Randall Kramer for providing the photos in Fig. 2.

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    Due to the large number and diversity of reports using Matrigel, we apologize to our colleagues for our omissions.

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