It was disclosed this month in the
Journal of Neuroscience that a study conducted by researchers has
unlocked the complex cellular mechanics that instruct specific brain
cells to continue to divide. A significant technical hurdle has been
overcome by this discovery for potential human stem cell therapies.
This ensures that an abundant supply of cells will be available to
study and ultimately treat people with diseases.
"One of the major factors
that will determine the viability of stem cell therapies is access to
a safe and reliable supply of cells,"
said University of Rochester Medical Center (URMC) neurologist Steve
Goldman, M.D., Ph.D., lead author of the study.
"This study demonstrates that
– in the case of certain populations of brain cells – we now
understand the cell biology and the mechanisms necessary to control
cell division and generate an almost endless supply of cells."
Cells called glial progenitor cells (GPCs) found in the white matter of the human brain where the focus of the study. These stem cells give rise to two cells found in the central nervous system: oligodendrocytes, which produce myelin, the fatty tissue that insulates the connections between cells; and astrocytes, cells that are critical to the health and signaling function of oligodendrocytes as well as neurons. At the root of a long list of diseases, such as multiple sclerosis, cerebral palsy, and a family of deadly childhood diseases called pediatric leukodystrophies is the damage to the myelin. It is believed by the scientific community that regenerative medicine ~ in the form of cell transplantation ~ holds great promise for treating myelin disorders.
It has been shown by Goldman and his colleagues in numerous animal model studies that transplanted GPCs can proliferate in the brain and repair damaged myelin. The difficulty in creating a plentiful supply of necessary cells has been a barrier in moving forward in the treatment of humans with myelin disease, in this case GPCs. Scientists have been able to get these cells to divide and multiply in the lab, but only for limited periods of time. This resulted in a limited number of usable cells.
"After a period of time, the cells stop dividing or, more typically, begin to specialize and form astrocytes which are not useful for myelin repair," said Goldman. "These cells could go either way but they essentially choose the wrong direction."
This problem required that Goldman's lab master the precise chemical symphony that occurs within stem cells, and which instructs them when to divide and multiply, and when to stop this process and become oligodendrocytes and astrocytes.
A protein called beta-catenin is one
of the key players in cell division. Beta-catenin is regulated by
another protein in the cell called glycogen synthase kinase 3 beta
(GSK3B). GSK3B is responsible for altering beta-catenin by adding an
additional phosphate molecule to it's structure, essentially giving
it a barcode that the cell then uses to sort the protein and send it
off to be destroyed. When cell division is necessary during
development, the process is interrupted by another signal that blocks
GSK3B. The beta-catenin protein is spared destruction when this
occurs, it eventually makes its way to the cell's nucleus where it
starts a chemical chain reaction that ultimately instructs the cell
to divide.
However, this process slows
after a period of time and instead of replicating, the cells start to
commit to becoming one type or another.
Essentially
the scientists had to find another way to trick these cells into
continuing to divide, and without risking the uncontrolled growth
that could result in tumor formation.The new discovery hinges on a receptor called protein tyrosine phosphatase beta/zeta (PTPRZ1). PTPRZ1 has long been suspected by Goldman and his team as playing an important role in cell division; the receptor shows up prominently in molecular profiles of GPCs. They found that the receptor worked in concert with GSK3B and helped “label” beta-catenin protein for either destruction or nuclear activity, after a six year effort. The breakthrough was identifying a molecule called pleiotrophin that essentially blocked the function of the PTPRZ1 receptor. By regulating the levels of pleiotrophin they found they were able to essentially “short circuit” PTPRZ1's normal influence on cell division, allowing the cells to continue dividing.
The cells used in the experiments were derived from
human brain tissue. However, the authors contend that the same
process could be applied to GPCs derived from embryos or from
“reprogrammed” skin cells. Potentially this would greatly expand
the number of cells derived from single patient samples, whether for
use in other patients or transplanted back to the same individual.
William D.
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Reference: MSRC - Multiple Sclerosis Resource Center
