Enter the Matrix

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" ... For example, the mature forms of fibrillar collagens in hydra are

similar to those in people with Ehlers-Danlos ( " stretchy skin " ) syndrome.

" In hydra, flexibility is desirable because the organism continuously

contracts and extends. An abnormality in [humans] is the normal condition in

hydra, " Sarras says.... "

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Enter the Matrix

More than just filling space, the extracellular matrix affects human health

| By Ricki

Courtesy of Philip B. Messersmith

 WHAT A TANGLED WEB: Fibroblasts are cellular workhorses of extracellular

matrix production, spinning out the majority of collagens, the most abundant

proteins in the animal kingdom.

Appreciation in biology can come slowly. Researchers once deemed as junk the

parts of genes not represented in proteins; likewise, neuroglia were thought

to be mere bystanders to neurons. So it is with the extracellular matrix

(ECM), the " scaffolding " and " glue " that fill the spaces among cells. New

ways of excavating the ECM reveal that it is much more.

An eclectic collection of molecules, the ECM was once relegated to the

backwater of connective tissues in histology texts. But, ECM's status is

shifting. Henry E. Young, an associate professor in anatomy at the Mercer

University School of Medicine in Macon, Ga., calls it " a three-dimensional

'spider web' latticework-like structure within a fourth-dimensional time

continuum. " The various guises of ECM are dynamic, with profound influences

on cells. Were it not for the ECM, those cells couldn't attach, divide,

differentiate, communicate, or move, says Young.

Fibrous networks of ECM pervade the human body, from toenails to tooth

enamel. Disturb its delicate balance of components, and disease results.

Long hidden from microscopy because of its transparency and sensitivity to

fixatives, the elusive ECM is now coming under closer scrutiny through the

lens of gene-expression profiling, while model organisms, such as the hydra,

are finally giving the invisible mediator its due.

NOT JUST GLUE Over a lifetime, the ECM oversees the intricate intercellular

choreographies that shape the embryo, guide wound healing, and maintain

adult organs. And timing is everything. Adult tissue expressing

embryonic-ECM proteins could be in a dire situation. " They tend to be

re-expressed in pathological conditions, such as wound healing or cancer, "

says Fred Bosman, professor of pathology at the University of Lausanne in

Switzerland.

DNA-microarray technology is revealing the biochemical steps behind ECM

actions. " Prior to the availability of such a powerful high-throughput

technology, scientists would have to work on individual genes separately, by

techniques such as Northern blotting, " says Shu Chien, director of the

Whitaker Institute of Biomedical Engineering at the University of

California, San Diego.

Microarrays bearing suites of the 2,000-plus human ECM genes can monitor

sweeping gene-expression changes as well as glimpse fleeting events. Chien's

team, for example, profiled human aorta cells exposed to 24 hours of shear

stress, modeling blood's rush from the heart. Genes controlling division and

inflammation were downregulated; those enhancing survival, angiogenesis, and

vascular remodeling were upregulated.1

MATRIX EVOLUTION ECM recipes vary: A plant has cellulose, lignin, and

pectin; a fungus has chitin, cellulose, and glucans; an animal has mostly

collagens. The cellular slime mold Dictyostelium discoideum uses ECM to

aggregate single-celled selves into a multicellular mobile slug, and in a

fruit fly embryo, segment-specific ECM dictates differentiation.

Sarras, professor of anatomy and cell biology at the University of

Kansas Medical Center, studies the simplest known animal with tissue layers,

the hydra, whose epithelial bilayer sandwiches a matrix of sheetlike layers

surrounding a fibrillar interior. The matrix forms during development when

collagens from the outermost layer communicate with laminin from the

innermost layer. Integrins, specialized cell-surface receptors, mediate the

signaling. " With the development of defined tissue came the presence of an

ECM, with structural similarities to all subsequent animal groups, " says

Sarras, whose team observes that new individuals arise from pellets of

cells.

Hydra uses the same ECM components as other animals, but in characteristic

ways. For example, the mature forms of fibrillar collagens in hydra are

similar to those in people with Ehlers-Danlos ( " stretchy skin " ) syndrome.

" In hydra, flexibility is desirable because the organism continuously

contracts and extends. An abnormality in [humans] is the normal condition in

hydra, " Sarras says.

THE ECM TOOLBOX In the human body, armies of fibro-blasts and contractile

myofibro-blasts churn out 20 types of collagen, which self-assemble into

varied fibrils, networks, and beads and provide tensile strength. Other

proteins, such as elastin and fibrillin, impart resilience.

From the collagen frameworks extend adhesive glycoproteins, such as the

cross-shaped laminins and multipronged tenascins. Proteoglycans emanating

from cell surfaces sport polysaccharide chains that bind enzymes, growth

factors, cytokines, and matrix proteins. Matrix metalloproteinases dismantle

parts of the ECM, a process crucial in tissue remodeling.

During development, as tissues fold into organs, ECM establishes

characteristic architectures. In the heart, the mostly- collagen ECM

coordinates the pulsating cells, whereas the liver's scaffolding connects

the parenchyma tissue to the circulation, essential for regeneration. At

least four collagens, five glycoproteins, and a half-dozen proteoglycans

build the liver's framework.

ECM is crucial to kidney function. In the glomeruli, the tiny tangles of

capillaries that are the initial filtering sectors for each of a human

kidney's million nephrons, ECM composition constantly adjusts to bloodstream

contents. " In the glomerulus, [the] endothelial, mesangial, and epithelial

cells enable the ECM to maintain a filtration rate of water that is higher

than in any other capillary bed. Unfortunately, our knowledge of this

complexity, both in normal and disease states, is primitive, " says H.

Humes, professor of internal medicine at the University of Michigan Medical

Center in Ann Arbor. Model organisms could help to unravel that complexity;

the cellular bilayer sandwiching ECM in the kidney's subunits is highly

reminiscent of hydra, says Sarras.

THE ECM-CANCER LINK The ECM-cancer connection was sown when English surgeon

Paget evoked a " seed and soil " metaphor in 1889 to explain why

primary tumors spread only to certain organs. In suggesting that the

secondary sites beckon the errant cells, Paget was describing the stroma,

the ECM that hugs epithelia, where many cancers arise.2 " If one could modify

the ECM around tumor cells to resemble the ECM of a nonpropagating body

location, then this might prevent tumor progression, " says Yarwood,

lecturer in the division of biochemistry and molecular biology at the

University of Glasgow.

Courtesy of Ferry

 A STUDY IN SIMPLICITY: The sandwich-like layering of cells and fibers in

the stretchy hydra provides a simple model for studying the extracellular

matrix.

The stroma participates in cancer early on. " Invasion of epithelial cells

necessitates cross-signaling between epithelial cells and their stromal

neighbors. Unraveling those factors is a major research challenge, " says

Olivier De Wever, a researcher in the laboratory of experimental cancerology

at Ghent University Hospital in Belgium. Then, under the influence of an

altered stroma, cell adhesion ebbs, cancer cells pile up into tumors, and

differentiation fades. Later, the stroma entices angiogenesis and clears

pathways for metastasis.

In epithelia and elsewhere, DNA microarrays are illuminating the molecular

interactions behind cancer cell activities. For example, researchers from

the Barrow Neurological Institute in Phoenix ran microarrays on glioma cells

to look for ECM proteins that promote cell motility. The profiles fulfilled

expectations for migrating brain cancer cells: diminished factors that

promoted adhesion, division, and apoptosis.3

A QUESTION OF BALANCE Excess ECM drowns organs in collagen and other matrix

proteins, first causing fibrosis as fibers accumulate, then sclerosis as the

material hardens. Variations on these themes arise throughout the body.

In the kidneys, diabetes mellitus causes mesangial cells to overproduce

fibro-nectin and underproduce collagenase, gumming up the filtration

apparatus and setting the stage for renal failure. Extra ECM in blood-vessel

walls causes atherosclerosis; in the heart, it causes arrhythmia. Fibrosis

following a heart attack prevents rupture of the affected area, but

eventually it hardens the tissue, impairing cardiac function. Widespread

fibrosis in the liver precedes cirrhosis.

But fibrosis is physiological too, says Shukti Chakravarti, assistant

professor of medicine and ophthalmology at the s Hopkins Medical

Institute. She works with a mouse model of inflammatory bowel disease. " As

soon as the cell senses danger it makes ECM molecules. We don't know if they

are laid down as ECM, but the molecules play a role in cell behavior. ECM

controls cell proliferation and apoptosis, too, " she says.

Too little ECM also hampers health. In Schwartz-Jampel syndrome, deficient

perlecan, a proteoglycan in basement membranes, causes a mask-like face.

Normally, perlecan delivers the enzyme that degrades acetylcholine in

neuromuscular junctions. Without it, facial muscles contract abnormally.

Appreciation of the ECM's role in pathology will likely flower further as

stem-cell biology moves forward. For example, Ichiro Nishimura's group, at

the Weintraub Center for Reconstructive Biotechnology at the UCLA School of

Dentistry, is tracking gene-expression changes that accompany the

specialization of stem cells from liposuction aspirates into bone cells. " We

hope to establish the ECM microarray as an essential testing protocol for

future stem cell-based therapeutics, such as tissue engineering, " says

Nishimura.

And so the intercellular substance formerly known as amorphous and inert has

achieved a new status as a vital part of a multicellular organism's body.

Bryon sen, assistant professor of pathology, immunology, and laboratory

medicine at the University of Florida in Gainesville, works with liver stem

cells and says that the mechanisms governing the communication between cell

and scaffolding are varied and conjure many unanswered questions. " It is

clear that the answer to these questions entails, to a large degree, the

differential response of the ECM components, and the cells that produce

these proteins, to various stimuli. The ECM is more than the mortar that

holds the bricks together. "

Ricki (ralewis@...) is a science writer in Scotia, New York.

References

1. B.P.C. Chen et al., " DNA microarray analysis of gene expression in

endothelial cells in response to 24-h shear stress, " Physiol Genomics,

7:55-63, 2001.

2. S. Paget, " The distribution of secondary growths in cancer of the

breast, " Lancet, 1:571-3, 1889.

3. L. ni et al., " Glioma cell motility is associated with reduced

transcription of proapoptotic and proliferation genes: a cDNA microarray

analysis, " J Neurooncol, 53:161-76, 2001.