In Vitro Culture System Yields Clues About Embryonic Blood Cell Development

Developmental researchers employed a robust in vitro culture system, which models HSC (hematopoietic stem cell) development in the embryo, to study how these cells give rise to the various types of blood cells found in the adult.

Developing HSCs are embedded in the complex embryonic AGM (aorta–gonad–mesonephros) microenvironment. The AGM region is derived from the mesoderm layer of the embryo. During organogenesis (around the fourth week in human embryos), the visceral region of the mesoderm, the splanchnopleura, transforms into distinct structures consisting of the dorsal aorta, genital ridges, and mesonephros. For a period during embryonic development, the dorsal aorta produces hematopoietic stem cells, which eventually colonize the liver and give rise to all mature blood lineages in the adult. By birth, the dorsal aorta has become the descending aorta, while the genital ridges have formed the gonads. The mesonephros have formed nephrons and other associated structures of the kidneys.

The location for HSC development suggested that this process may require signals derived from different compartments of the AGM region. Investigators at the University of Edinburgh (United Kingdom) sought to test this hypothesis. However, the analysis of HSC development in vivo was significantly hampered by low accessibility of embryos developing in utero, fast maturation of HSCs into mature blood cells, and lack of uniquely specific markers for HSC precursors and their low numbers in the AGM region.

To overcome these difficulties, the investigators developed a cell culture system that modeled HSC development in the embryo, and used it in combination with functional HSC analysis using long-term reconstitution assays in mice.

Results obtained with these tools were published in the March 8, 2016, online edition of the journal Nature Communications. The investigators reported that stage-specific reciprocal dorsoventral inductive interactions and lateral input from the urogenital ridges were required to drive HSC development in the aorta. Furthermore, the results suggested that these inductive interactions in the AGM region were mediated by the interplay between spatially polarized signaling pathways. Specifically, Shh (Sonic hedgehog) produced in the dorsal region of the AGM, stem cell factor in the ventral and lateral regions, and BMP (Bone morphogenetic protein) inhibitory signals in the ventral tissue were integral parts of the regulatory system involved in the development of HSCs.

Senior author Dr. Alexander Medvinsky, professor of hematopoietic stem cell biology at the University of Edinburgh, said, "There is a pressing need to improve treatments for diseases like leukemia and this type of research brings us a step closer to that milestone. The more we understand about how embryos develop these blood stem cells, the closer we come to being able to make them in the lab."

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