By David N. Leff

"Can the leopard change its spots?" asks the Bible rhetorically.

The short answer is that it hasn't happened yet. What has just happened is that brain cells changed into blood cells.

Neuroscientists report this improbable conversion in the current issue of Science, dated Jan. 22, 1999. Their paper bears the title "Turning brain into blood: A hematopoietic [i.e., blood-forming] fate adopted by adult neural stem cells in vivo." Its senior author is neuroscientist Angelo Vescovi, who heads the laboratory of neuropharmacology at Italy's National Neurobiological Institute, in Milan.

Did he and his co-authors actually take stem cells from the central nervous system, the job of which is to produce neurons, and reinvent them to churn out assorted blood cells in the spleen and bone marrow? "It took us a while to believe our own data," Vescovi told BioWorld Today. "The tissue of the body has always been seen as unchangeable."

Stem cells are the founding ancestors of all the cells that make up the tissues and organs of the body. Embryonic stem cells give that body its prenatal head start in life; adult ones supply the constant turnover of cells in the regenerating blood, gut, skin and nails, among other things. That replenishment is more problematic in the central nervous system's brain and spinal cord. (See BioWorld Today, Jan. 12, 1999, p. 1, and Nov. 6, 1998, p. 1.)

Experiment Began With A Single Cell

The team's unlikely experiment began with a single cell.

"The stem cells in the adult brain," Vescovi noted, "are normally located around the ventricular region, particularly in the forebrain. What we did was to isolate one single cell from the brain of an adult transgenic mouse."

That animal's stem cells have the unique faculty of synthesizing a bacterial enzyme, beta-galactosidase, which served the investigators as a molecular tracer on their itinerant cells.

"We were able to get that neural stem cell from a cell line," Vescovi said, "simply by tissue dissection and growth-factor stimulation. We were not in any way transforming or engineering the stem cells, but simply exploiting their inherent self-renewal capacity to expand the target population from one cell to many.

"We tested part of those neural stem cells for their capacity to generate somatic brain cells," he continued. "So, when we removed the growth factors from that culture, the prepotential brain stem cells spontaneously differentiated into neurons, astrocytes and oligodendrocytes. The tricky part was trying to prevent them from differentiating; and we did that with the growth factors. The leftover cells from the transgenic mice that we didn't differentiate, we injected into other mice, which had previously undergone sub-lethal whole-body irradiation.

"We chose lenient or permissive sub-lethal rather than the usual totally lethal irradiation, particularly because we were thinking that if the animals died, their cells might not have had the time to do what they were supposed to do," he said. "By irradiating the mice, we killed proliferating cells, amongst them the stem cells in various tissues, including the hematopoietic bone-marrow cells. So that created a vacancy in the stem-cell compartment of those tissues."

The co-authors speculated that by injecting their neural stem cells into the tail veins of the mice, those cells might be able to reach the bone marrow. "There," Vescovi said, "they might have been able to respond to the peculiar environment created by cell irradiation. We figured, OK, maybe the stem cells from the brain might be able to respond to the same cues in the bone marrow, and do the same job - which apparently is what happened."

Specifically, instead of their day job creating neurons, astrocytes and oligodendrocytes in the brain, the transferred neural stem cells churned out a range of blood-cell types instead, in the bone marrow and spleen. These included B and T lymphocytes, neutrophils, monocytes and macrophages.

The co-authors noted that their results complement those of the Scottish gene cloners, who in 1997 announced success in replicating a ewe. In both experiments, adult cells returned to their totipotential primordial states and began new lives. One became Dolly, and the other became a blood-producing brain cell.

Vescovi does not assert or assume that stem cells are so totipotent that they will operate in any environment.

"That would be an extension of our present work," he said. "At the present point, based on our data, the only safe statement we can make is that there appears to be a neural stem cell with a genomic potential broader than expected, encompassing also the hematopoietic state. If one goes by speculation, I would imply that there may be other cell lineages that could be generated, but that needs to be assessed properly. I don't see why they should be limited to hematopoietic states, but one never knows."

Therapy In Patients 'At Hand' But 'Not Easy'

Turning to the potential clinical application of his group's findings, Vescovi observed: "On a very practical perspective, we are trying to determine whether the bank of human neural stem cells have the same capacity for trans-differentiation as murine ones. Whether they can do the same thing as their mouse counterpart. Because if that works, a step toward the clinical application may be a short step at this point - close at hand."

But, in the same breath, he added, "It won't be easy. Because what I propose is that one may use human neural stem cells in a hematopoietic context for the therapy of tumors. That seems counter-intuitive. Some may deem it preferable to use peripheral blood cells to treat the brain, not the brain cells, which are not easily obtainable to treat the blood. Nevertheless, that approach would appear to be the first implication of this study. If the human neural stem cells do prove similar to their mouse counterpart, they may actually be used in transplantation strategies, replacing bone marrow transplants, for instance, to treat leukemia.

"By the way," he said, "leukemia patients undergo radiation therapy. Inevitably, they find their bone marrow in a state very similar to that of the mice in our study. And they have vacancies in their stem-cell compartment.

"You have to bear in mind," he concluded, "this is a very basic finding. Trying to draw an immediate clinical application is relatively farfetched at this point."

The University of Calgary, Alberta, holds patent rights to Vescovi's technology, developed while he and his first author, graduate student Christopher Bjornson, were doing this research at that institution. n

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