Mar 29, 2002
In two sessions at the American Association for the Advancement of Science meeting in Boston on stem cells and adult neuronal production, Dr. Steven Goldman, Nathan Cummings Professor of Neurology at Weill Cornell Medical College, reported several new discoveries pertaining to the use of stem cells and progenitor cells for treating the diseased human brain.
The research holds tremendous promise for a wide range of neurodegenerative and demyelinating diseases, as well as destructive disorders such as stroke, trauma, cerebral palsy, and spinal cord injury.
Goldman observed that neural stem cells and progenitor cells - far from disappearing once a person reaches adulthood - "are dispersed widely throughout the adult brain."
He reported the discovery that glial progenitor cells of the brain, which are normally found in the brain's white matter, are actually a type of multipotential progenitor. The results of harvesting these cells through fluorescence activated cell sorting (FACS), are as follows, he said:
"We found that adult human white matter progenitor cells, extracted by FACS from the adult human brain, can indeed generate neurons as well as both major glial cell types - astrocytes and oligodendrocytes - when raised in culture under conditions of high purity and low density. Under these conditions, the cells are effectively removed from other cells, and from the proteins that other cells may secrete. ...They can continue to divide and expand for several months in culture.
"These findings constitute the first isolation of a multipotential neural progenitor cell from the parenchyma of the adult human brain." Previous isolations, he explained, came from precursor cells derived from the germinative layers of the ventricular wall and hippocampus - "the adult vestiges of the embryonic neuroepithelium."
The new findings, he concluded, "point to an abundant and widespread source of cells that may be used both as a target for pharmacologic induction and as a cell type appropriate for therapeutic engraftment to the diseased adult human brain." The findings may have significance for treating such diseases as multiple sclerosis, stroke, and trauma.
Goldman also described two novel and innovative strategies of brain repair: transplantation of purified isolates of defined human precursor cells into disease sites, and induction of resident progenitor cells by virally delivered growth factors.
The first set of experiments (the transplantation experiments) focused on the type of cell known as oligodendrocytes, which are lost in demyelinating diseases of the brain such as multiple sclerosis. He and his colleagues Neeta Roy and Martha Windrem found that in "shiverer" mice, which lack any ability to myelinate (or produce insulating covers for neuronal fibers), "implanted human progenitors achieved both wide dispersion and efficient remyelination throughout the entire forebrain, out to 12-16 weeks after perinatal cell implantation."
The other set of experiments was to attempt to induce the growth of neurons by using viral gene therapy to deliver the gene encoding a growth factor called brain-derived neurotrophic factor (BDNF) to the brains of adult rats. "We found that a single, one-time injection of an adenovirus expressing BDNF into the forebrain ventricles of adult rats induced the production of new neurons from neural progenitor cells in the ventricular lining, the subependyma.
"Most of the new neurons migrated to the olfactory bulb, which is a normal site of neuronal addition in the rodent brain. But surprisingly, a large number of BDNF-induced new neurons also invaded an area of the brain known as the neostriatum, a region of the brain that is critically important to the direction and coordination of movement. The adult neostriatum, like most regions of the brain, normally does not produce or accept new neurons. But in the injected rats, the striatum not only added large numbers of new neurons, but these neurons integrated one specific cell type, called medium spiny neurons. These are the cells that are typically lost in Huntington's disease."
Goldman and his students Eva Chmielnicki and Amer Samdani then examined whether striatal neuronal production might be further stimulated by the suppression of glial differentiation by using noggin, an inhibitor of proteins that mediate glial production. They found that the combined use of both noggin and BDNF "strongly induced striatal neurogenesis."
He predicted that the two therapeutic strategies - both progenitor cell transplantation as a means of repairing brain and spinal cord injury, and neuronal induction, for the reconstruction of precise neural circuits in patients with neurodegenerative diseases - may be sufficiently advanced to allow clinical trials within the next decade, at least for carefully defined and selected patient populations. This article was prepared by Gene Therapy Weekly editors from staff and other reports.
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