When it comes to fixing damaged neurons in the brain, mice are more adept than people.
A firsthand witness to this state of affairs is neuroscientist Eva Mezey, at NINDS - the National Institute of Neurological Disorders and Stroke.
Two years ago, she and a parallel team at Stanford University both reached the same conclusion: that there were new nerve cells in the brains of the mice after they received a bone marrow transplant. When Mezey tested the same performance in human brains, she was somewhat chagrined to find that the generation rate of replacement brain neurons was well below that of the rodents.
She is senior author of the paper reporting this finding in the Proceedings of the National Academy of Sciences (PNAS), released online Jan. 20, 2003. Its title: "Transplanted bone marrow generates new neurons in human brains."
"I think the most important message of our PNAS article," Mezey told BioWorld Today, "is that there are cells in the adult human bone marrow that have a capability to enter the brain and differentiate into nerve cells there. To my best knowledge," she added, "it's an absolutely novel finding. We had shown the same thing in mice two years ago, but I wanted to see if it's relevant in humans at all. So I think that in terms of humans it's pretty new data.
"The importance of this finding," she continued, "is that first of all, in spite of the old dogma that we don't make new nerve cells after we are born, we in fact do. And the report gives us a chance to exploit this phenomenon, and correct the damage caused by stroke and neurodegenerative diseases, such as Alzheimer's and Parkinson's.
"Now we have to find out if this therapeutic goal is just the beginning of a very long bumpy road. We need to determine how the body delivers these factors into the brain from the circulation, directed to the site where they are needed. Then we may imagine injecting them into an area of damage, and boost this normal process to an extent where it can repair the brain trauma."
Donor Male Y Chromosomes Blaze Cell Path
Mezey and her co-authors examined brain tissue taken at autopsy from four female patients - two adult women and two children - who had received replacement bone marrow transplants from four donor male relatives, after their original marrow was killed by irradiation to eliminate the underlying disease. The transplants had been performed to treat leukemia and other non-neurological diseases. The four survived from one to nine months following their marrow replacements.
The team searched the autopsied brain tissue for male cells, which by definition carry a Y chromosome. These Y cells served as markers to distinguish donor-derived cells from those of the female recipients. They found Y chromosome-containing cells in all four patients. Most of their brain cells were glia (non-support cells) and other non-neurons. However, a few neurons from each brain also contained Y chromosomes, showing that those cells had developed from the transplanted male bone marrow. Most of those neurons were found in the cerebral cortex, the outer brain layer, which is responsible for conscious thought, and in the hippocampus, a region that deals with memory and cognition.
"Those four samples came to us from storage files at the Johns Hopkins School of Medicine," Mezey noted. "They were all archived paraffin-embedded tissue from more than 10 years ago. Back then, they used whole bone marrow to do transplants as opposed to taking stimulated stem cell-enriched peripheral blood, which is done now."
Of the four patients, the youngest was a child with Omenn's syndrome - a rapidly fatal immunodeficiency disease. She was transplanted at 10 months of age, and died nine months later. Patient 2 was transplanted for Hodgkin's disease at age 34. Patient 3 received her transplant at 10 years of age for acute lymphocytic leukemia. Patients 2 and 4 both died within two months of receiving their transplants.
"As a second marker," Mezey recounted, "we used antibodies that recognize proteins generated only by neurons. The antibodies detected Y chromosome-positive donor cells that exhibited two specific neuronal markers in the hippocampus and neocortex. In three of the four viewable patients, the numbers of double-labeled cells were much lower than previously reported in rodents.
"We found two to seven Y-positive neurons per 10,000 human neurons vs. 50 to 200 per 10,000 rodent neurons," Mezey recalled. The sections with the highest number of newly formed neurons - 7 per 10,000 - was from Patient 1, the youngest studied. She received her transplant in infancy, and also had the longest post-transplant survival time - nine months later. The other three patients lived only weeks after their transplant, and there was no significant difference in the number of donor-positive cells in their brains."
Educated Speculation Foresees Brain Fix
Mezey's ongoing research has two aims:
"On one hand I am trying to see if patients who lived much longer than these would acquire a higher number of brain cells. That might answer the question: Is this a continuously ongoing event? So that's one direction. The other direction is that we are trying to find out which kind of stem cells in the bone marrow would give rise to the brain cells that then become neurons. We are getting some new patient samples from the Mayo Clinic," she noted. "I don't have them yet. These tissues live much longer than the patients we reported in this PNAS paper. Mayo indicated they have a few that survived years after transplant."
Conceptually, Mezey pictures the eventual therapeutic application of her approach. "I hope that many years down the road we might be able to use it to help the brain repair itself. But this is really only the beginning. Patients who are sick today probably will not be helped by it.
"I think it's really important to find the growth factors and differentiation factors, then induce the bone marrow cells to proliferate, and increase the number of circulating stem cells recruited into the brain, in a high enough number to repair what's missing. But this," she concluded, "is all speculation."