Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche

Abstract

Haematopoietic stem cells are found in a specialized regulatory environment or niche in bone marrow. The precise location and characteristics of this niche are now made clearer by two sophisticated imaging studies. Lo Celso et al. performed live-animal tracking of individual haematopoietic cells and find that osteoblasts are enmeshed in microvessels and that different haematopoietic cell populations are localized in different areas according to their stage of differentiation. Xie et al. used newly developed ex vivo real-time imaging technology and immunoassays to trace the homing of fluorescently labelled haematopoietic stem cells in response to irradiation. They report that the membrane lining the medullary cavity of bone forms a special zone that normally maintains haematopoietic stem cells, but promotes their expansion in response to bone marrow damage. High resolution combined confocal and two-photon video imaging of individual haematopoietic cells is performed in the bone marrow of living animals, examining their relationship to blood vessels, osteoblasts and endosteal surface as they home and engraft. It is found that osteoblasts were enmeshed in microvessals and different populations of haematopoeitic cells were localized in different areas according to their stage of differentiation. In settings of engraftment as well as expansion, marrow stem/progenitor cells were in closer proximity to bone and osteoblasts. Stem cells reside in a specialized, regulatory environment termed the niche that dictates how they generate, maintain and repair tissues1,2. We have previously documented that transplanted haematopoietic stem and progenitor cell populations localize to subdomains of bone-marrow microvessels where the chemokine CXCL12 is particularly abundant3. Using a combination of high-resolution confocal microscopy and two-photon video imaging of individual haematopoietic cells in the calvarium bone marrow of living mice over time, we examine the relationship of haematopoietic stem and progenitor cells to blood vessels, osteoblasts and endosteal surface as they home and engraft in irradiated and c-Kit-receptor-deficient recipient mice. Osteoblasts were enmeshed in microvessels and relative positioning of stem/progenitor cells within this complex tissue was nonrandom and dynamic. Both cell autonomous and non-autonomous factors influenced primitive cell localization. Different haematopoietic cell subsets localized to distinct locations according to the stage of differentiation. When physiological challenges drove either engraftment or expansion, bone-marrow stem/progenitor cells assumed positions in close proximity to bone and osteoblasts. Our analysis permits observing in real time, at a single cell level, processes that previously have been studied only by their long-term outcome at the organismal level.