'Critical Factor' Found that Sets Bone Marrow Stem Cells into Action

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Discoveries may advance stem cell therapy for Parkinson's, cancer

patients

Two studies in the Jan. 27, 2006 Cell have yielded evidence that

could prove a boon for stem cell therapies aimed at patients with

Parkinson's disease and those with compromised immune systems due to

intensive cancer therapy or autoimmune disease, according to

researchers. The basic findings in mice revealed critical factors

that determine the fate of one type of nerve cell progenitor and that

set bone marrow stem cells into action.

Researchers at the Karolinska Institutet in Sweden discovered

a " master determinant " that turns embryonic stem cells into bona fide

dopamine neurons, brain cells that degenerate in those with

Parkinson's disease. The findings hold promise for the future of cell

replacement therapy for the debilitating and incurable disease

characterized by tremors, said study authors Perlmann and

Johan son. The results also underscore the general importance of

a thorough understanding of development for producing authentic cells

of a desired type from stem cells.

" The use of cell replacement therapy in the treatment of Parkinson's

disease is fraught with many problems, " Perlmann said. " However,

clinical trials have provided important proof of principle that

transplantation of dopamine neurons might work in patients. "

" Ethical and practical issues associated with transplantation of

fetal dopamine neurons to patients with Parkinson's disease has

triggered intense interest in the possibility of the use of in vitro-

engineered stem cells as an unlimited cellular source for

transplantation, " the researchers added.

To investigate whether the identification of determinants underlying

the specification of dopamine neurons during development could be

exploited for generating dopamine neurons from stem cells, the

researchers first looked for genes expressed in the dopamine

progenitor cells in the developing midbrains of embryonic mice.

The researchers uncovered two transcription factor proteins, Lmx1a

and Msx1, that are selectively expressed in dopamine progenitor

cells. Further study found that Lmx1, but not Msx1, is sufficient and

required for the formation of dopamine neurons in the midbrains of

chicks. Early activity of Lmx1a induces expression of Msx1, leading

to other events important to the differentiation of these nerve

cells, they show.

Moreover, the researchers report that expression of Lmx1a in

embryonic stem cells results in a robust generation of dopamine

neurons with a correct midbrain identity.

" We spent a lot of effort and are now confident that these are

authentic dopamine neurons, " son said. " If we want to treat

Parkinson's patients with stem cells, it will only work if we are

able to generate authentic dopamine cells. "

" In the use of stem cells for therapy, it is of utmost importance to

make the correct cell type, " added Perlmann. " In the brain, there are

at least 1000 different types of neurons, only one of which is

clinically relevant to Parkinson's disease--a fact which emphasizes

the complexity of the problem. Our data establish Lmx1a and Msx1 as

critical intrinsic dopamine-neuron determinants in vivo and suggest

that they may be essential tools in cell replacement strategies in

Parkinson's disease. "

Further study will elucidate the utility of the stem cell-derived

neurons for treating rats with Parkinson's disease, they said. The

researchers will also conduct studies to examine whether the findings

in animals will hold for humans.

A second group at Mount Sinai School of Medicine in New York found

that the sympathetic--or " fight or flight " branch--of the nervous

system plays a critical role in coaxing bone marrow stem cells into

the bloodstream. So-called hematopoietic stem cells in the bone

marrow are the source for blood and immune cells.

Hematopoietic stem cell transplants are now routinely used to restore

the immune systems of patients after intensive cancer therapy and for

treatment of other disorders of the blood and immune system,

according to the National Institutes of Health. While physicians once

retrieved the stem cells directly from bone marrow, doctors now

prefer to harvest donor cells that have been mobilized into

circulating blood.

In normal individuals, the continuous trafficking of the stem cells

between the bone marrow and blood fills empty or damaged niches and

contributes to the maintenance of normal blood cell formation,

according to the researchers. Although it has been known for many

years that the mobilization of hematopoietic stem cells can be

enhanced by multiple chemicals, the mechanisms that regulate this

critical process are largely unknown, they said.

One factor in particular, known as hematopoietic cytokine granulocyte-

colony stimulating factor (G-CSF), is widely used clinically to

elicit hematopoietic stem cell mobilization for life-saving bone

marrow transplantation, said senior author of the study,

Frenette.

Several years ago, Frenette's group reported that a second compound,

fucoidan, which is synthesized by certain seaweeds, could also spur

the stem cells into action. The group speculated that the seaweed

derivative might work by imitating a similar compound, called

sulfatide, naturally present in mammalian tissues.

To test the idea, the researchers examined mice lacking the enzyme

responsible for making sulfatide.

" Lo and behold, mice lacking the enzyme Cgt did not mobilize

hematopoietic stem cells at all when treated with the stimulating

factor G-CSF or fucoidan, " Frenette said. " You don't get such

dramatic results that often in science. We knew we had stumbled onto

something important. "

To their surprise, further study failed to connect the stalled stem

cell movement to sulfatide. Rather, they found, the deficiency

stemmed from a defect in the transmission of signals sent via the

sympathetic nervous system. The products of Cgt contribute to the

myelin sheath that coats and protects nerve cells, they explained.

Mice with other nervous system defects also exhibited a failure to

mobilize bone marrow stem cells, they found. Moreover, drugs that

stimulate the sympathetic nervous system restored stem cell movement

into the blood stream in mice with an impaired ability to respond to

norepinephrine, the signature chemical messenger of the sympathetic

system.

" The nervous system plays an important role in producing signals that

maintain the stem cell niche and retention in bone marrow, " Frenette

said.

" The new findings add another dimension of complexity to the

processes involved in stem cell maintenance and mobilization and

emphasize the interrelationships among the nervous, skeletal and

hematopoietic systems, " he added. " They all have to work together –

to talk to each other – to produce blood and maintain stem cells. "

The results suggest that differences in the sympathetic nervous

systems of stem cell donors may explain " conspicuous variability " in

the efficiency with which they mobilize hematopoietic cells into the

bloodstream, the researchers said. Furthermore, drugs that alter the

signals transmitted by the sympathetic nervous system to the stem

cells in bone may offer a novel strategy to improve stem cell

harvests for stem cell-based therapeutics, they added.

" The new findings suggest that the nervous system, which has the

inherent ability to integrate information from throughout the

organism, may govern the local relationship between stem cells and

their niches, " said Jonas Larsson and Scadden of the Harvard

Stem Cell Institute in a preview.

The unexpected findings by Frenette and his colleagues

further " suggest that the pharmacological manipulation of the

sympathetic nervous system may be a means of therapeutically

targeting the stem cells in their niche for the purpose of either

mobilization or, conversely, attracting stem cells to the niche

following transplantation, " they added.