Signal gradients in 3-D guide stem cell behavior

Sep. 18, 2013 Scientists know that physical and biochemical signals can guide cells to make, for example, muscle, blood vessels or bone. But the exact recipes to produce the desired tissues have proved elusive.

Now, researchers at Case Western Reserve University have taken a step toward identifying that mix by developing an easy and versatile way of forming physical and biochemical gradients in three dimensions.

Ultimately, one of their goals is to engineer systems to manipulate stem cells to repair or replace damaged tissues and organs.

"If we can control the spatial presentation of signals, we may be able to have more control over cell behavior and enhance the rate and quality of tissue formation," said Eben Alsberg, an associate professor of biomedical engineering and orthopaedic surgery at Case Western Reserve and senior author of the research. "Many tissues form during development and healing processes at least in part due to gradients of signals: gradients of growth factors, gradients of physical triggers."

Alsberg, postdoctoral scholar Oju Jeon and graduate student Daniel S. Alt of Case Western Reserve, and Stephen W. Linderman, a visiting undergraduate on a National Science Foundation Research Experience for Undergraduates summer fellowship, tested their system on mesenchymal stem cells, turning them toward bone or cartilage cells. They report their findings in Advanced Materials.

Regulating the presentation of certain signals in three-dimensional space may be a key to engineering complex tissues, such as repairing osteochondral defects, damaged cartilage and bone in osteoarthritic joints, Alsberg said.

"There must be a transition from bone to cartilage," he said, "and that may require control over multiple signals to induce the stem cells to change into the different kinds of cells to form tissues where you need them."

In their first test, the researchers found that stem cells changed into cartilage or bone cells in the directions of two opposing soluble growth factor gradients: one that promotes cartilage, called TGF-beta 1, and another that promotes bone, called BMP-2. The stem cells were placed in a solution of modified alginate, a material derived from seaweed that can form a jello-like material called a hydrogel when exposed to low level ultraviolet light.

The solution was divided between two computer-controlled syringe pumps, with BMP-2 in one syringe and TGF-beta 1 in the other. By controlling the rate of injection with the pumps and using a mixing unit, a hydrogel with a BMP-2 gradient starting with a large amount and tapering to nearly none and an opposing TGF-beta 1 gradient from low-to-high was formed.

The hydrogels were further modified in such a way that the growth factors were retained for a longer period of time. This enabled prolonged exposure of stem cells to the growth factors and further control over their differentiation into bone or cartilage cells.

See the article here:
Signal gradients in 3-D guide stem cell behavior