Abstract
Although we know a great deal about the phenotype and function of haematopoietic stem/progenitor cells, a major challenge has been mapping their dynamic behaviour within living systems. Here we describe a strategy to image cells in vivo with high spatial and temporal resolution, and quantify their interactions using a high-throughput computational approach. Using these tools, and a new Msi2 reporter model, we show that haematopoietic stem/progenitor cells display preferential spatial affinity for contacting the vascular niche, and a temporal affinity for making stable associations with these cells. These preferences are markedly diminished as cells mature, suggesting that programs that control differentiation state are key determinants of spatiotemporal behaviour, and thus dictate the signals a cell receives from specific microenvironmental domains. These collectively demonstrate that high-resolution imaging coupled with computational analysis can provide new biological insight, and may in the long term enable creation of a dynamic atlas of cells within their native microenvironment.
Highlights
We know a great deal about the phenotype and function of haematopoietic stem/progenitor cells, a major challenge has been mapping their dynamic behaviour within living systems
To understand how haematopoietic stem and progenitor cells behave in living tissues, we developed a real-time imaging strategy to visualize cells in high-resolution over extended periods of time
We used fluorescent protein-expressing transgenic mice to observe the spatial orientation of the bone marrow cavity, and a typical confocal microscope to view inside the mouse calvarium (Fig. 1a)[20]
Summary
We know a great deal about the phenotype and function of haematopoietic stem/progenitor cells, a major challenge has been mapping their dynamic behaviour within living systems. While these studies have provided valuable new ways to visualize the haematopoietic compartment and to generate three-dimensional spatial models of the bone marrow microenvironment in living animals, there is a continued need for increasing spatiotemporal resolution and a strategy to track endogenous cells without transplantation and a means by which the ‘big data’ that is generated by such imaging approaches can be analysed to reveal new biological patterns This would enable us to better map the interactions, signals and mechanisms that govern haematopoietic cell behaviour and function in vivo, and thereby understand how this can fail in disease and degeneration. These data show that high-resolution imaging coupled with an effective high-throughput computational approach can provide new biological insight into the dynamics of haematopoietic cells in their microenvironment, and can be used to establish a baseline to study the changes in haematopoietic cell interactions within the niche during regeneration and oncogenesis
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