Training Stem Cells to Differentiate Properly

Pluripotent stem cells have the ability to differentiate into a whole host of adult cell types. Unfortunately this ability to differentiate into any adult cell type also comes with it the tendency to form tumors. Controlling stem cell differentiation requires that you give a little “push” in the right direction. What is the nature of that push? It varies from stem cell to stem cell and it also depends on what type of cell you want you stem cells to make. Therefore, pluripotent stem cell differentiation is sometimes a matter of art as much as a matter of science.

A research group at Stanford University School of Medicine have designed an experimental protocol that uses the signals in the body to direct the differentiation of stem cells to a desired end.

Stanford University professor Michael Longaker, who is also the director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University, explained it this way: “Before we can use these cells, we have to differentiate or ‘coach,’ them down a specific developmental pathway.” Longaker continued: “But there’s always a question as to exactly how to do that, and how many developmental doors we have to close before we can use the cells. In this study, we found that, with appropriate environmental cues, we could let the body do the work.”

Allowing the patient’s body to direct differentiation of pluripotent stem cells could potentially speed approval of stem cell-based treatments by the US Food and Drug Administration (FDA). If Longeker’s protocol pans out, it could eliminate long period of extended laboratory manipulation in order to force stem cells to differentiate into the desired cell type.

“Once we identify the key proteins and signals coaching the tissue within the body, we can try to mimic then when we use the stem cells,” said Longaker. “Just as the shape of water is determined by its container, cells respond to external cues. For example, in the future, if you want to replace a failing liver, you could put cells in a scaffold or microenvironment that strongly promotes liver cell differentiation and place the cell-seeded scaffold into the liver to let them differentiate in the optimal macroenvironment.”

Longaker does not work on liver, but bone. As a pedatric plastic and reconstructive surgeon who specializes in craniofacial malformations, finding ways to coax pluripotent stem cells to make bone is his research Holy Grail. “Imagin being able to treat children and adults who require craniofacial skeletal reconstruction, not with surgery, but with stem cells,” opined Longaker.

In this experiment, Longaker and his colleagues removed a four-millimeter circle of bone taken from the skulls of anesthetized mice and implanted a tiny, artificial scaffold coated with a bone-promoting protein called BMP-2 (bone morphogen protein-2) that was seeded with one million human pluripotent stem cells.

According to Longaker, these implants formed bone and repaired the defect in the skulls of the mice even the original stem cells were not differentiated when added to the wound. These human stem cells made human bone that was then replaced by mouse bone as time progressed. This shows that the repair was physiologically normal.

This bone growth was stimulated by the presence of BMP-2 and the microenvironment that induced the stem cells to differentiate into bone-making cells that made normal bone.

In this experiment, Longaker and his group used human embryonic stem cells and induced pluripotent stem cells and both stem types seemed to work equally well at repairing the skull defect.

Teratomas (tumors made by pluripotent stem cells) were observed but only rarely (two of the 42 animals that received the stem cell implants developed tumors). Interestingly, the few teratomas that formed developed in two laboratory animals that received embryonic stem cell implants and not induced pluripotent stem cell implants. This is surprising, since most stem cells researchers consider induced pluripotent stem cells to be more tumorigenic than embryonic stem cells. Standard tests of these stem cells (implantation under the kidneys of immunodeficient mice) showed that they did produce teratomas under these conditions.

Longaker commented: “We still have work to do to completely eliminate teratoma formation, but we are highly encouraged.” Longaker also thinks that by combining this technique with other strategies, he and his group might be able to completely prevent teratoma formation. For example, including other cell types that can act as shepherds for the stem cells as they differentiate into the desired cell type can also increase differentiation into a desired cell type.

Longaker said, “I want to see how broadly applicable this technique may be.” He was referring to tissues that do not heal well. For example, cartilage heals very poorly if at all. Longaker wonders if you could “add some cells that can form replacement tissue in this macroenvironment while you’re already looking at the joint.”

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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).

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