Researchers have helped resolve a long-standing debate about which precursors in the developing mammalian embryo give rise to blood cells, after tracking the birth of these cells using in-vivo imaging that lasts for days, according to a report in this week's Nature.
The study is one of a handful of papers to come out in recent months to examine the question of hematopoietic cell origin. "I would say the nice thing about the latest paper is that everything is seen live -- which hasn't been possible before," said Francoise Dieterlen-Lievre of the Cellular and Molecular Embryology Institute in Nogent-sur-Marne, France, who was not involved in the study.
One challenge with tracking the cells' origin is that blood cells can migrate within the organism quite literally in a heartbeat, said Timm Schroeder of the GSF-Institute of Stem Cell Research in Neuherberg, Germany, the study's main author. "The problem is that we roughly know where these cells appear," he said, adding that "If you don't continuously watch it happen, then you can never exclude that the [blood] cells migrated from a different site."
Researchers have long debated which precursor cells give rise to hematopoietic cells during development. Some have hypothesized that blood cells arise from the developing mesoderm, while others place the origin in a transient region of endothelium termed the hemogenic endothelium. Researchers have also debated the role of early blood cell precursors in the yolk sack. Knowing the origin of these cells would help researchers narrow in on which sources to tinker with to manipulate the growth of hematopoietic stem cells.
The group imaged embryonic endothelial cells in culture, after first tagging the cells with endothelial and hematopoietic markers. By imaging the cells continuously over several days, they were able to demonstrate individual cells essentially shedding their endothelial nature and acquiring hematopoietic qualities instead.
Using independent and very distinct approaches, said Luisa Iruela-Arispe of the University of California, Los Angeles, who was not involved in the study, the recent batch of papers, including this one, all lead to "the conclusion that hemogenic endothelium is indeed a cell type that, if expressed during a transient period of time, can give rise to hematopoietic cells."
Iruela-Arispe's own group used genetic tracing to identify an endothelial origin, whereas another group pinpointed the role one transcription factor in forming the hemogenic endothelium, and second in generating hematopoietic cells from it.
Schroeder said that the group did not use special hardware, but just optimized their wide-field epifluorescence microscope, fiddled with incubation of the cells, and wrote some cell-tracking software. "In imaging you always have to compromise," he said. "Everything that"s good for the image is bad for your cells. Everything good for your cells is bad for the image."
Still, the study doesn't definitively identify the hemogenic endothelium as the source of blood cells in the developing organism, said Schroeder. "I think we can close the debate on whether or not endothelial cells -- some of them -- have the potential to make blood cells," he said. "What we clearly don't want to exclude is that maybe there are other sources of blood cells in the embryo."
Iruela-Arispe agreed, but noted that this paper and the batch of others coming to the same conclusion "open a tremendous possibility" for developing therapies by demonstrating "that one can generate true hematopoietic cells from endothelial cultures." The true proof in the translational pudding, though, will involve reprogramming mature endothelial cell to generate hematopoietic cells, she said.
"That would revolutionize [treatment for] any blood malignancies. Even blood transfusions would be out the window."
The video shows cells with clear endothelial morphology shown giving rise to blood cells. Left panel: phase contrast. Right panel: fluorescence detecting Histone 2B-Venues expression. 1st pause in video: single mesodermal cell starting the colony. 2nd pause: all cells in the colony exhibit a clear endothelial sheet morphology. 3rd pause: some cells lose tight integration into the endothelial sheet but keep adhering to endothelial cells. 4th pause: Blood cells detach and are free-floating. The arrow is following the starting cell and one daughter cell after each cell division until the end of the video. Timescale: days -- hours:minutes:seconds
Video and caption courtesy of Eilken et al., Nature, 457:896-900, 2009.
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