by Bill Hathaway, Yale University

nHSPC development and blood lineages are altered in miR-128^Δ/Δ. a, WISH against cmyb at 32 hpf and 3 dpf in WT or miR-128^Δ/Δ (128^Δ/Δ) AGM (n = 39 (WT) and 42 (128^Δ/Δ) embryos; P < 0.0001) and CHT (n = 33 (WT) and 48 (128^Δ/Δ) embryos; P = 0.0151) (3 independent experiments, two-tailed Mann–Whitney test). b, WISH against cmyb at 6 dpf in WT (thymus n = 36 and KM n = 36 embryos; P = 0.0133) and 128^Δ/Δ (thymus n = 35 and KM n = 36 embryos; P = 0.0033; 3 independent experiments; two-tailed Mann–Whitney test). c, WISH against gata2b (n = 27 (WT) and 35 (128^Δ/Δ) embryos; P = 0.0005) and runx1 (n = 32 (WT) and 30 (128^Δ/Δ) embryos; P = 0.0009; 3 independent experiments; two-tailed Mann–Whitney test). d, Confocal images of Tg(kdrl:mCherry^s896,cmyb:GFP^zf169) (n = 18 (WT) and 19 (128^Δ/Δ) embryos; P < 0.0001) and Tg(kdrl:mCherry^s896,runx1:GFP^y509) (n = 29 (WT) and 31 (128^Δ/Δ) embryos; P < 0.0001) AGM at 27 and 32 hpf, respectively. Quantification represents runx1+, kdrl+ (hemECs) and cmyb+, kdrl+ (nHSPCs) cells (3 independent experiments; two-tailed Mann–Whitney test). e–g, WISH of gata1a (n = 40 (WT), 37 (128^Δ/Δ), 34 (MO-ctrl) and 31 (Mo-128) embryos; P < 0.0001) (e), ikaros (n = 48 (WT); 48 (128^Δ/Δ), 37 (MO-ctrl) and 34 (Mo-128) embryos; P < 0.0001) (f) and lcp1 (n = 29 (WT), 32 (128^Δ/Δ), 36 (MO-ctrl), 38 (Mo-128) embryos; P = 0.0511 and 0.4257) (g) at 4.5 dpf with their quantification (3 independent experiments; two-tailed Mann–Whitney test). h, Confocal live imaging of Tg(fli1a:Gal4^ubs4,UAS:Kaede^rk8), ± UV (photoconversion) in the AGM. Quantification represents the red thymus area (MO-ctrl, 20; Mo-128, 19 embryos; P = 0.0151) and the number of red cells in the CHT (MO-ctrl, 19; Mo-128, 22 embryos; P = 0.0462; 3 independent experiments; two-tailed Mann–Whitney test). i, Flow cytometry analysis of 1-month-old dissected whole (W)KM WT, 128^Δ/Δ. j, Quantification of cell population identified by flow cytometry (n = 8 (WT), 8 (128^Δ/Δ), 8 (MO-ctrl) and 9 (MO-128) zebrafish; two-way ANOVA with multiple comparisons). All quantifications are represented with mean ± s.e.m. NS, not significant: P > 0.05, *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001. Arrowheads indicate cells stained by WISH and IF and cells photoconverted in h. T, thymus; DA, dorsal aorta; PCV, posterior cardinal vein; SSC-A, side scatter A; FSC-A, forward scatter A. Credit: Nature Cell Biology (2023). DOI:10.1038/s41556-023-01187-9

All humans have a diverse set of blood stem cell types which dictate the composition and function of our blood and immune cells and ultimately help govern overall health. Older people tend to lose this diversity of blood stem cells, which can make them more susceptible to blood cancers, cardiovascular diseases, and all-cause mortality. But exactly when and how this diverse group of stem cells first arise has been unclear.

A group of researchers at Yale School of Medicine has found that levels of diversity of blood stem cells are determined during the development of the embryo, they report July 17 in the journal Nature Cell Biology. They also found that stem cell levels can be manipulated during childhood, suggesting ways that blood composition might be improved, and overall health monitored throughout life.

"The findings are quite powerful," said Stefania Nicoli, associate professor in internal medicine and genetics at Yale School of Medicine and senior author of the paper.

Scientists had thought that this diversity of stem cells arose later in development with the formation of bone marrow. However, Joey Ghersi, a postdoctoral associate in Nicoli's lab, working in collaboration with Christopher Sturgeon at Mount Sinai School of Medicine, showed that different types of blood stem cells were determined very early in development.

"And each of us maintain this level of diversity through adulthood," Nicoli said. "This varying level of blood stem cell diversity can be 'programmed' and may help to change susceptibility to cardiovascular and immune diseases."

For example, Nicoli and colleagues manipulated levels of one microRNA within embryonic endothelial cells that line blood vessels and enhanced production of blood stem cells that increase the level of red blood- and T-cells in zebrafish and human pluripotent stem cells.

"The zebrafish with manipulated blood stem cells remained healthy through life," Nicoli said.

As more is learned about how stem cell populations affect health, the ability to manipulate those populations will become more important in health care, Nicoli predicted.

More information: Ghersi, J.J., et al. Haematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic endothelium. Nature Cell Biology (2023). DOI: 10.1038/s41556-023-01187-9 www.nature.com/articles/s41556-023-01187-9

Provided by Yale University