This image shows endothelial cells on 3D scaffolds: the scaffold is in green, the cells in red and the nucleus in blue. Image: Laura Indolfi |
Tissue implants made of cells grown on a
sponge-like scaffold have been shown in clinical trials to help heal arteries
scarred by atherosclerosis and other vascular diseases. However, it has been
unclear why some implants work better than others.
Massachusetts Institute of Technology (MIT)
researchers led by Elazer Edelman, the Thomas D. and Virginia W. Cabot
Professor of Health Sciences and Technology, have now shown that implanted
cells’ therapeutic properties depend on their shape, which is determined by the
type of scaffold on which they are grown. The work could allow scientists to
develop even more effective implants and also target many other diseases,
including cancer.
“The goal is to design a material that can
engineer the cells to release whatever we think is most appropriate to fight a
specific disease. Then we can implant the cells and use them as an incubator,”
says Laura Indolfi, a postdoctoral researcher in Edelman’s laboratory and lead
author of a paper on the research published online in Biomaterials.
Aaron Baker, a former postdoctoral
researcher in Edelman’s laboratory and now an assistant professor at the
University of Texas at Austin, is also an author of the paper.
Shape matters
For the past 20 years, Edelman has been working on using endothelial cells
grown on scaffolds made of collagen as implantable devices to treat blood
vessel damage. Endothelial cells line the blood vessels and regulate important
process such as tissue repair and inflammation by releasing molecules such as
chemokines, small proteins that carry messages between cells.
Several of the devices have been tested in
clinical trials to treat blood vessel damage; in the new Biomaterials
study, Edelman and Indolfi set out to determine what makes one such tissue
scaffold more effective than another. In particular, they were interested in
comparing endothelial cells grown on flat surfaces and those grown on more
porous, 3D scaffolds. The cells grown on 3D structures tended to be more
effective at repairing damage and suppressing inflammation.
The researchers found that cells grown on a
flat surface take on a round shape in which the cells’ structural components
form a ring around the perimeter of the cell. However, when cells are grown on
a scaffold with surfaces of contact whose dimensions are similar in size to the
cells, they mold to the curved surfaces, assuming a more elongated shape. In
those cells, the structural elements—made of bundles of the protein actin—run
parallel to each other.
Those shapes determine what types of
chemokines the cells secrete once implanted into the body. In this study, the
researchers focused on a chemokine known as MCP1, which recruits inflammatory
cells called monocytes.
They found that the architecture of the
cytoskeleton appears to determine whether or not the cell turns on the
inflammatory pathway that produces MCP1. The elongated cells grown on porous
surfaces produced eight times less of this inflammatory chemokine than cells
grown on a flat surface, and recruited five times fewer monocytes than cells
grown on a flat surface. This helps the tissue implants to suppress
inflammation in damaged blood vessels.
The researchers also identified biomarkers
that correlate the cells’ shape, chemokine secretion, and behavior. One such
parameter is the production of a focal adhesion protein, which helps cells to
stick to surfaces. In cells grown on a flat surface, this adhesion protein,
known as vinculin, accumulates around the edges of the cell. However, in cells
grown on a 3D surface, the protein is evenly distributed throughout the cell.
These distribution patterns serve as molecular cues to inhibit or activate the
pathway that recruits monocytes.
The study goes a long way toward answering
the question of how to engineer immune responses through endothelial cell
transplantation, says Donald Elbert, an associate professor of biomedical
engineering at Washington University in St. Louis. “Cells exhibit profoundly
different responses based on their local environment, and this report
demonstrates an important molecular mechanism for the improved response within
intricately designed 3D scaffolds,” says Elbert, who was not involved in the
research.
Precise control
The findings could help scientists manipulate their scaffolds to tailor cells
to specific applications. One goal is using implanted cells to recruit other
body cells that will do a particular task, such as inducing stem cells to
differentiate into a certain type of cell. “By designing the matrix before we
seed the cells, we can engineer which factors they are going to secrete,”
Indolfi says.
The work should also help researchers
improve on existing tissue-engineered devices and test new ones, Edelman says. “Without this kind of understanding, we can’t extend successful technologies to
the next generation,” he says.
