Jun 20, 2002
By Karla Gale
NEW YORK (Reuters Health)
Multipotent adult progenitor cells (MAPCs), isolated from bone marrow, are capable of differentiating in vivo into most tissue-specific cell types, a University of Minnesota research team reports in the advance online publication of Nature for June 23.
In a report in the same issue of Nature, investigators describe how they have generated, for the first time, functional dopaminergic neurons from embryonic stem cells.
"After depleting bone marrow of hematopoietic cells, we find MAPCs, which are rare descendants of embryonic cells that have the potential to grow indefinitely in culture," Dr. Catherine M. Verfaillie, from Minneapolis, said in a press conference. She projected that MAPCs may become a viable substitute for embryonic stem cells in treating disease. These cells may also become important in drug discovery and in screening drugs for toxicity.
Dr. Verfaillie reported that in humans between the ages of 2 and 55 years, the proportion of MAPCs is approximately 1 per million bone marrow cells. Her team has isolated MAPCs from about three quarters of the individuals from whom they obtained bone marrow samples.
"These cells are capable of dividing without senescence and without differentiation," she noted. In vitro culture with lineage-specific cytokines permitted rodent-derived MAPC differentiation into cells characteristic of each of the three germ layers. Morphologic, phenotypic and functional characteristics of specific tissue types were generated.
The Michigan-based researchers microinjected murine MAPCs into 3.5-day-old mouse blastocysts, which were implanted into foster mothers. Microscopic examination of the mice that were born showed that single MAPCs can grow into brain, retina, lung, myocardium, myocytes, liver, intestine, kidney, spleen, blood and skin. In the brain, the cells gave rise to neurons and astrocytes throughout the entire organ.
The researchers also found that intravenous delivery of MAPCs led to engraftment and differentiation into tissue-specific cells. However, differentiation capability was not as extensive as in the injected macrocysts.
No donor-derived tumors developed, unlike what has been observed when embryonic stem cells are engrafted. Therefore, Dr. Verfaillie's team concludes that undifferentiated MAPCs have the potential to treat such systemic disorders as inherited enzyme deficiencies or muscular dystrophy. Organs grown from MAPCs may also be used to replace organs damaged by cancer or other disease states, Dr. Verfaillie added.
In the second study, Dr. Ron McKay and colleagues at the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland, transduced embryonic stem cells with the transcription factor "nuclear receptor related-1 (Nurr1)," which is required by midbrain precursors for differentiation into dopamine neurons. They then manipulated the cells through a multi-stage differentiation process by treating them with factors such as fibroblast growth factor 8 and sonic hedgehog.
Dr. McKay pointed out that researchers have engrafted fetal cells into the midbrain of patients with Parkinson's disease, resulting in beneficial effects. However, cell numbers were insufficient and dopamine neurons were generated for only up to 1 week.
Dr. McKay and his associates were able to enrich the proportion of fetal neuron precursors from a normal of 3% up to 80%. When engrafted into mice whose dopamine neurons had been destroyed, the cells multiplied for approximately 4 weeks and then the number stabilized up to the end of the study period. No teratomas developed.
The cells developed functional synapses and displayed electrophysiological characteristics similar to normal mesencephalic neurons. Behavioral tests at 9 weeks showed significant improvement in motor deficits.
The NINDS researchers believe that the cells have the potential to treat patients with Parkinson's disease and hope to generate serotonergic neurons using similar techniques that may treat mood disorders and schizophrenia.
Dr. Verfaillie said that she expects that it will be at least 2 years before either Dr. McKay's embryonic stem cells or her group's MAPCs will be engrafted into non-human primates. "Even if we are optimistic, it will take several years after that before human trials can begin. But it's not unimaginable if we have the collective dedication that will be required," she added.
Nature 2002. Advance online publication. http://www.nature.com/nature/
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