By By Nelson Chao, MD
2009-03-01
Dr. Chao indicated no relevant conflicts of interest.
Lo Celso C, Fleming HE, Wu JW, et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature. 2009;457:92-6.
That is a truism if there ever was one. The field of stem cells, not
just hematopoietic stem cells, is defined by the actual pluripotent or
multipotent cells and the necessary niches in which they reside.
Elegant experiments with Drosophila melanogaster, Caenorhabditis
elegans, zebrafish, and other organisms clearly demonstrated the
importance of a single nurse cell (a specialized cell in Drosophila
that contributes to the formation of oocytes and acts as the niche) in
determining self-renewal and differentiation of the stem cells. Signals
imparted from these cells directly contribute to the fate of the stem
cells, whether by direct signaling or gradients of secreted factors and
extracellular matrix. The importance of niches for hematopoiesis has
been established through alterations of osteoblasts or vascular beds
(with limited knowledge of localization) and through the use of
immunohistochemistry (without knowledge of function).
Before describing the findings, it is useful to describe the
available technology. Two-photon microscopy is a relatively novel
approach that allows intravital microscopy. Living tissues can be
visualized to a depth of approximately 1 mm. The concept is based on
the idea that two photons of low energy can excite a fluorophore in a
quantum event resulting in the emission of a fluorescent photon that is
of higher energy than either of the two photons. These low-energy
photons do not cause damage outside the focal area. Because two photons
are needed to excite the fluorophore, the fluorescence is much greater
when the beam is tightly focused and, therefore, there is less
background noise. The fluorescence is collected by a photomultiplier
tube and recorded as a pixel. Scanning through the desired region forms
the image. Using infrared light with long wavelengths to generate the
photons results in less scatter and high-resolution images. This
technology allows movement away from static images to actual movies.
The paper by Lo Celso, et al., from David Scadden’s laboratory, now
brings into clearer focus the relationships between the stem cells and
the microenvironment. Using both confocal and two-photon video
microscopes, these investigators were able to image the homing of
individual hematopoietic cells in the calvarium of an irradiated mouse
and its interaction with the blood vessels, osteoblasts, and endosteal
surfaces. They observed that the interactions between the
stem/progenitor cells and the osteoblasts in microvessels were dynamic
and non-random. Different hematopoietic cell subsets localized to
distinct locations, depending on the stage of differentiation and
guided by autonomous and non-autonomous factors. When expansion or
engraftment was studied, the hematopoietic stem cells localized to
areas in close proximity to the osteoblasts.
These initial studies provide direct visualization of
previously observed colocalization of hematopoietic stem cells with the
osteoblasts, defining one of the bone marrow niches. These technologies
will allow for further studies of hematopoietic stem/progenitor cells
and open up new ways of understanding hematopoiesis and malignancies.
For example, single mutations that affect hematopoiesis can now be
tracked in vivo. Malignant cells can also be studied in this
manner and their associations with the osteoblasts or the vascular
niche, and other immune cells that are found in the marrow cavity can
also be analyzed in their responses to antigenic challenge. YouTube
will be busy.
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