Identifying Blood Stem Cells Is a SLAM Dunk

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From Research Institute July 01, 2005

Identifying Blood Stem Cells Is a SLAM Dunk

Researchers have developed a simple technique to identify

hematopoietic, or blood-forming, stem cells based on a set of

characteristic markers that the cells display on their surface. The

elucidation of this distinctive stem-cell code is the first time that

researchers have been able to identify specific stem cells by looking

at surface markers drawn from a single family of genes.

Stem cells are immature cells that can develop into a variety of

adult cells. In this case, hematopoietic stem cells can develop into

all blood and immune system cell types and are already used

therapeutically to restore the hematopoietic system of patients after

chemotherapy or radiation therapy.

The new technique to identify hematopoietic stem cells (HSCs) will

enable scientists to determine where stem cells are located in blood-

forming tissues and to trace the developmental routes these stem

cells take as they mature into blood cells. If the researchers'

studies in mice apply to blood-forming stem cells in humans, the

technique may enable safer transplants of stem cells, by improving

purification of the stem cells prior to transplantation, said the

scientists.

J. on, a Medical Institute investigator at

the University of Michigan, led the research team, which published

its findings in the July 1, 2005, issue of the journal Cell. Other

members of the team included graduate students Mark Kiel and Omer

Yilmaz as well as postdoctoral fellow Toshihide Iwashita from the

on laboratory. Another co-author of the paper is from Harvard

Medical School.

The method developed by on and his colleagues can distinguish

different types of blood-forming progenitors based on differences in

their expression of members of a family of highly similar protein

receptors, called SLAM family receptors. The receptors nestle in the

surface of the cell membrane and detect external chemical signals and

translate those signals into cellular responses.

According to on, specific SLAM family members were known to be

expressed in white blood cells and to play a role in their function.

However, it was not appreciated that specific members of the SLAM

family could be used to distinguish HSCs from other types of

progenitor cells. Until now, the problem in using cell surface

proteins to identify HSCs has been that the combinations of such

markers have been complex and difficult to manage, said on.

In their analyses of SLAM proteins on HSCs, the researchers found

that they could distinguish HSCs by the presence or absence of a few

specific members of the SLAM family. This provided a simpler and more

robust way to identify HSCs.

The researchers demonstrated that the HSC SLAM markers appeared to be

universal in mice by showing that they distinguished HSCs from

different genetic strains of mice, which show variation in other HSC

markers that have been used previously. The scientists also found

that the SLAM markers distinguished HSCs in mice whose immune systems

had been activated, or mobilized, by immune triggers called

cytokines.

" Thus, these SLAM family members are so precisely, differentially

expressed that we can now purify HSCs much more simply and, in some

contexts, much more rigorously, " said on. " The SLAM markers

that we have identified work in every context that we have looked so

far — different mouse strains, old mice, young mice, cytokine-

mobilized mice and non-mobilized mice. Using this simple combination

of markers, we have achieved very high levels of purity in these

cells, " said on.

The simplicity of the technique enabled the researchers to tag the

SLAM markers to trace the localization of HSCs in their " niches " in

tissues. Niches are " microenvironments " of supporting cells in which

stem cells are induced by chemical signals to produce mature blood

cells, in a process called hematopoiesis.

" A major impediment to understanding hematopoiesis has been the

inability to identify these niches, " said on. " So, in the past

we needed to use very complicated combinations of markers to

rigorously purify the stem cells - that is too complicated to use in

staining tissue sections. "

Using antibody stains that revealed SLAM markers, the researchers

could visualize where in the bone marrow and spleen HSCs localized.

They found that most HSCs migrated to tiny blood vessels in the bone

marrow and spleen called sinusoids, where the HSCs remained in

contact with the endothelial cells surrounding these sinusoids.

" That finding suggests that most stem cells are sustained most of the

time by their interaction with these sinusoidal endothelial cells;

implying that the sinusoidal endothelial cells may be secreting

factors that help maintain stem cells or regulate their function, "

concluded on. Such findings offer important clues to the role

of such endothelial cells in maintaining HSCs, he said.

More broadly, similar vascular endothelial cells have been found to

provide such niches in the nervous system and other tissues, said

on. " These studies suggest that vascular endothelium may be

generally important in creating stem cell niches in a variety of

different tissues; and that sinusoidal endothelium, a specialized

form of endothelium found only in hematopoietic tissue, may be

specialized to support the maintenance of HSCs, " said on.

The presence of HSCs in such endothelium helps explain a mystery of

how stem cells - which are manufactured in the bone marrow — can

enter the blood stream within minutes of being treated with certain

drugs. " Our data suggest that the reason stem cells can get into the

circulation so fast might be that at least a subset of them is

sitting right on top of the sinusoids that they would use to enter

circulation, " said on.

These insights represent only the beginning of new research pathways

in stem cell biology enabled by the SLAM markers, said on.

Researchers can now use imaging techniques to explore precisely how

HSCs interact with supporting niche cells and isolate the chemical

signals from these cells that regulate their maintenance and trigger

their maturation.

on said that future studies will aim to determine the function

of the SLAM family of receptors. The researchers will also explore

whether other members of the SLAM family can also be used to identify

stem cells. And, they will use their technique to identify cells that

create stem cell niches and the chemical signals they secrete.

Regarding clinical applications, on said that " the big question

is whether these SLAM family receptors are differentially expressed

in human HSCs. If they are, their use might dramatically improve the

purity of isolated HSCs, as they have in our mouse studies. Such an

improvement in purity might improve the safety and effectiveness of

HSC transplants. We are optimistic that these markers are also

expressed on human HSCs, and we are now testing that possibility, " he

said.