Compound from Sully Putty Might Advance Neural Stem Cell Therapies


According to a University of Michigan engineering team, human pluripotent stem cells differentiate differently in response to the sponginess of the surface upon which they grow.

University of Michigan assistant professor of mechanical engineering, Jianping Fu, and his colleagues, efficiently directed human embryonic stem cells to differentiate into working spinal cord cells by growing the cells on a carpet of poly(dimethylsiloxane), which is one of the main ingredients in the toy known as “Silly Putty.” This study established the importance of physical signals in the control of stem cell differentiation.

According to Fu, these data could be the beginning of a series of investigations that uncovers the most efficient way to guide pluripotent stem cells to differentiate into nervous tissues that can be used to replace diseased cells in patients with Alzheimer’s disease, Huntington’s disease or amyotrophic lateral sclerosis (Lou Gehring’s disease).

In Fu’s system, he and his co-workers engineered the poly(dimethylsiloxane) carpets by using this compound to form fine threads that were strung between microscopic posts. By varying the height of the posts, Fu discovered that he could vary the stiffness of the surface. Shorter posts gave a more rigid, stiff carpet and longer posts gave softer more plush carpets.

When embryonic stem cells were grown on poly(dimethylsiloxane) carpet strung between tall posts, they differentiated into neurons much more quickly and at a higher percentage than when they were grown on the more rigid and stiffer poly(dimethylsiloxane) carpets.  After 23 days, colonies of spinal cord motor neurons that control how muscles move grew on the softer micropost carpets.  These cell assemblages were four times more pure and 10 times larger than those growing on either traditional plates or rigid carpets.

“To realize promising clinical applications of human embryonic stem cells, we need a better culture system that can reliably produce more target cells that function well,” said Fu.  He added: “Our approach is a big step in that direction, by using synthetic micro-engineered surfaces to control mechanical environmental signals.”

Fu is presently collaborating with U-M Medical School professor of neurology, Eva Feldman.  Dr. Feldman is an expert in amyotrophic lateral sclerosis (ALS), and firmly believes in the power of stem cells to help ALS patients grow new stem cells that can replace the diseased, death or damaged nerve cells.  Feldman is also applying Fu’s ingenious technique to make neurons from a patient’s own cells.  Mind you, these results are purely exploratory at this point, since Feldman simply wants to determine the feasibility of this procedure.

Even if this technique does not pan out for regenerative treatments, it provides a very workable model system to study the electrical behavior of neurons from ALS patients in comparison to neurons from non-ALS individuals.

Fu’s system also has identified a cell signaling pathway that is involved in the regulation of mechanically sensitive behaviors.  This signaling pathway – the Hippo/Yap pathway – is also involved in controlling organ size and suppression of tumor formation.

Corresponding proteins in Drosophila and mammals are shown in the same colours. When organs are growing (Hippo pathway OFF), nuclear Yki/Yap binds to unknown DNA-binding factor(s) X and regulates the transcription of growth targets. When organs have reached the correct size (ON), the Hippo signalling pathway is activated (unknown ligand Y–Fat– Merlin–Expanded–Hippo interactions, in the Drosophila case; ligand Y–FatJ–NF2–FDM6–Mst½–Lats½ in mammals), and Yki and YAP is inactivated by localizing to the cytoplasm in response to Wts phosphorylation and 14-3-3 binding. ? indicates regulatory relationships that still need to be investigated. Figure adapted from reference 2.
Corresponding proteins in Drosophila and mammals are shown in the same colors. When organs are growing (Hippo pathway OFF), nuclear Yki/Yap binds to unknown DNA-binding factor(s) X and regulates the transcription of growth targets. When organs have reached the correct size (ON), the Hippo signalling pathway is activated (unknown ligand Y–Fat– Merlin–Expanded–Hippo interactions, in the Drosophila case; ligand Y–FatJ–NF2–FDM6–Mst½–Lats½ in mammals), and Yki and YAP is inactivated by localizing to the cytoplasm in response to Wts phosphorylation and 14-3-3 binding. ? indicates regulatory relationships that still need to be investigated. Figure adapted from reference 2.

The work of Fu and Feldman could certainly provide significant advances in our understanding of how pluripotent stem cells differentiate in the body.  This work also suggests that physical signals are important in patterning the nervous system, especially since the cells of the nervous system become specialized for specific tasks according to their physical location within the body and nervous system in general.

Advertisements

Published by

mburatov

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).