Science Spotlight - Heart Shock
Localized Heat Shock Reveals New Sources of Dendritic Cells
By Autumn Jennings
In mammalian development there are three successive waves of hematopoiesis, the last of which generates the hematopoeitic stem cells (HSCs) that are the life-long source of blood cells. While DCs were previously thought only to derive from HSCs, recent studies have shown that some other hematopoeitic progenitors are made before HSCs are established3. In the zebrafish embryo, endothelium-derived hematopoeitic progenitors (EHPs) made in the posterior blood island and in the aorta-gonad-mesonephros (AGM) give rise to multiple hematopoeitic lineage cells before HSCs are established4,5. This raised the possibility that EHPs may also be an HSC-independent source of DCs.
To address this hypothesis, Lin and colleagues needed to find a sensitive and reliable method to identify DCs. Using RNAscope staining, they found that DCs express flt3 and irf8 while other immune cell populations are flt3-negative. Using this signature, they found DCs present in the thymus as early as 3 days post fertilization, before HSCs are established. To determine the source of this early DC population, they used a method developed previously in the lab that allows for a cell population to be marked at a specific time, a very handy tool for looking at developmental processes6. The method uses an infrared laser to locally activate a heat-inducible CreERT2 transgene which in turn induces expression of a leukocyte-specific reporter. The authors induced reporter expression in each of three embryonic hematopoeitic regions: the rostral blood island, the posterior blood island and the AGM. They then looked for reporter expression in thymic DCs at larval stages. At 6 days post fertilization, they observed reporter-expressing DCs in the thymus after inducing expression in the posterior blood island and the AGM, but not after inducing expression in the rostral blood island. Since the posterior blood island and AGM, but not the rostral blood island, are known to be sources of EHPs, they concluded that early DCs are produced by EHPs. They confirmed this by looking for the thymic DCs posterior blood island-labeled fish. Knowing that EHP-derived hematopoietic cells decline during late juvenile stages, they reasoned that if this population was EHP-derived, it would follow this known trajectory. Indeed, they found that thymic DCs derived from the posterior blood island declined after one month of age, while DCs derived from the AGM, which contains both EHP and HSC progenitors, persisted into adulthood. This showed two distinct waves of DC development, the known HSC-derived population which persists to adulthood, and this new EHP-derived population which diminishes during juvenile stages.
Next, the researchers asked whether these two populations of DCs develop using the same genetic pathway. In mammals, DCs depend on Fms-like tyrosine kinase 3 (Flt3) for their proper development7-9. Using a flt3 mutant zebrafish, Lin and colleagues found a that HSC-derived DCs are depleted, consistent with a conserved mechanism, but that EHP-derived thymic DCs were unaffected. This demonstrates that HSC- and EHP- derived DCs are governed by separate genetic mechanisms.
This study raises new questions about DC development. Do EHP-derived thymic DCs have different functions than their HSC-derived counterparts? And what is the flt3-independent mechanism that governs the development of the early EHP-derived DC population? This study has enlightened our understanding of how embryonic origins can affect immune cell development. It sits at the intersection of immunity and developmental biology, illuminating the road for future studies with new technologies.
Zilong Wen is a principal investigator at Southern University of Science and Technology located in Shenzhen, China. He is a Professor of the School of Life Science. His research focuses on the understanding the mechanisms that underlie the formation and maintenance of blood cells as well as how disruptions of this process lead to disease.
Autumn Jennings is currently pursuing a B.S. in Biology at Northern Michigan University, where she conducts research in Dr. Danny LeBert’s lab. She is applying to Ph.D. programs with the goal of becoming a research faculty member. Her interests focus on post-transcriptional gene regulation, particularly as it relates to immune system function.
References
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3 Yokomizo, T. et al. Independent origins of fetal liver haematopoietic stem and progenitor cells. Nature 609, 779-784, (2022).
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6 Xu, J. et al. Temporal-Spatial Resolution Fate Mapping Reveals Distinct Origins for Embryonic and Adult Microglia in Zebrafish. Dev Cell 34, 632-641, (2015).
7 Waskow, C. et al. The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues. Nature immunology 9, 676-683, (2008).
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9 McKenna, H. J. et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 95, 3489-3497, (2000).