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Lifelong haematopoiesis is established by hundreds of precursors throughout mammalian ontogeny

Abstract

Current dogma asserts that mammalian lifelong blood production is established by a small number of blood progenitors. However, this model is based on assays that require the disruption, transplantation and/or culture of embryonic tissues. Here, we used the sample-to-sample variance of a multicoloured lineage trace reporter to assess the frequency of emerging lifelong blood progenitors while avoiding the disruption, culture or transplantation of embryos. We find that approximately 719 Flk1+ mesodermal precursors, 633 VE-cadherin+ endothelial precursors and 545 Vav1+ nascent blood stem and progenitor cells emerge to establish the haematopoietic system at embryonic days (E)7–E8.5, E8.5–E11.5 and E11.5–E14.5, respectively. We also determined that the spatio-temporal recruitment of endothelial blood precursors begins at E8.5 and ends by E10.5, and that many c-Kit+ clusters of newly specified blood progenitors in the aorta are polyclonal in origin. Our work illuminates the dynamics of the developing mammalian blood system during homeostasis.

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Figure 1: Sample-to-sample variance reliably estimates the number of initiating events.
Figure 2: Mouse-to-mouse peripheral blood Confetti variance reliably estimates the number of repopulating units after transplantation.
Figure 3: Estimates of haematopoietic precursor numbers and activity during distinct stages of haematopoietic development.
Figure 4: Onset of Confetti labelling in ROSA26+/ConfettiVav1+/Cre embryos.
Figure 5: Haemogenic endothelium is specified between E8.5 and E10.5 of murine ontogeny.
Figure 6: Intra-aortic cell clusters are polyclonal in origin.

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Acknowledgements

We thank W. Clements, P. Holmfeldt, F. Camargo, S. Patel, L. Grimes, B. Hadland, I. Bernstein and the McKinney-Freeman laboratory and Department of Hematology at St Jude Children’s Research Hospital (St Jude) for critical discussions and reading of the manuscript; D. Ashmun, S. Schwemberger and J. Laxton for FACS support; C. Davis-Goodrum, Krista Millican and C. Savage for help with injections and timed pregnancies; V. Frohlich and J. Peters for help with confocal imaging; Cdh5+/ERT2-Cre mice were a gift from the laboratory of R. Adams (Max Planck Institute for Molecular Biomedicine, Germany) by way of A. Zovein (UCSF, California, USA). Vav1-Cre+/T mice were a gift from the laboratory of T. Graf (Center for Genomic Regulation, Spain) by way of N. Speck (University of Pennsylvania, Pennsylvania, USA). VE-cadherin-Cre+/T mice were a gift from the laboratory of G. Oliver (Northwestern University, Illinois, USA). This work was supported by the American Society of Hematology (S.M.-F.), the Hartwell Foundation (S.M.-F.), the NIDDK (K01DK080846 and R01DK104028, S.M.-F.), the American Lebanese Syrian Associated Charities (ALSAC) (S.M.-F. and St Jude Cell & Tissue Imaging Center), and the NCI (P30 CA021765-35, SJCRH Cell & Tissue Imaging Center). The St Jude Cancer Center Core Cytogenetics laboratory is supported by the National Cancer Institute at the National Institute of Health (P30 CA21765) and ALSAC.

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Authors

Contributions

M.G. designed the study, analysed Confetti mice, generated and performed iCC experiments, analysed intra-aortic clusters, performed and analysed transplants, collected and analysed data, and wrote the paper. T.H. performed and analysed transplants, contributed to study design, and analysed data. D.F. performed computer simulations to derive the formula for estimating cell numbers, analysed data, contributed to study design, and wrote relevant sections of the paper. A.C. analysed Confetti+ blood and resulting data, G.K. performed statistical analyses, S.M.-F. designed the study, analysed data and wrote the paper. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Shannon McKinney-Freeman.

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Integrated supplementary information

Supplementary Figure 1 Representative iCC Confetti analysis and Confetti-based estimate fidelity.

(a) CFP, GFP, YFP or mCherry positive HL60 cells were used as single color controls during flow cytometry Confetti analysis. (b) Untreated and 4-OHT treated iCC cultures are shown to illustrate gating strategy for distinct Confetti colors. (c) Results of computer simulation of variance in the proportion of Confetti colors across a range of starting cell numbers (10 to 10,000 cells) and a range of starting percentages of a given Confetti color. The Log10(CV) vs. Log10(cell number) is shown. Simulated data was fixed at each percentage and sampled 15,000 times for each sample size of each percentage. The resulting regression lines were stable with respect to slope (−0.5) across all percentages except the 10% simulation measured the minimum number of times (top line). (d,e) Immortalized fibroblasts, like iCCs, are susceptible to polyploidy or chromosomal duplication during in vitro culture. Thus, a subset of cells acquire extra Confetti alleles and can be labeled with multiple Confetti colors after exposure to 4-OHT (e. g. RFP + CFP + cells in b). (d) About 2% of iCCs displayed >4N DNA content. (e) Karyotype confirms presence of polyploid iCCs.

Supplementary Figure 2 Limiting dilution transplantation to assess fidelity of Confetti-based estimates, efficiency of Confetti labeling in adult PB of +/Cre mice and Log10(CV)s of Confetti frequency in AGM explant recipient PB.

(a) 5 × 106-2 × 104CD45.2 + ROSA26+/ConfettiFlk1+/Cre WBM was transplanted at limiting dilution into irradiated CD45.1 + CD45.2 + mice along with 2 × 105 CD45.1 + WBM cells (see also Fig. 2c). Total CD45.2 + PB chimerism 16 weeks post-transplant is indicated. Black dots represent individual engrafted recipients and red dots represent individual non-engrafted recipients. (b) LDA was applied to estimate number of repopulating units (RUs). The data fit well the LDA assumption (Pearson Chi-square and Deviance Chi-square >0.05). (c) Average Confetti labeling efficiency in adult PB of ROSA26+/Confetti + /Cre mice. ROSA26+/ConfettiE2a+/Cre (E2aCre, n = 13 mice), ROSA26+/ConfettiFlk1+/Cre (Flk1Cre, n = 7), ROSA26+/ConfettiVE-Cadherin+/Cre (VE-CadherinCre, n = 12), ROSA26+/ConfettiVav1+/Cre (Vav1Cre, n = 10), ROSA26+/ConfettiUbiquitin+/ERT2-Cre (UbiquitinERT2-Cre) treated at E7.5 (n = 5) or E8.5 (n = 6) and ROSA26+/Confetti Cdh5+/ERT2-Cre (Cdh5ERT2-Cre) treated at E8.5 (n = 5) or E9.5 (n = 7). Error bars indicate ±s.d. of mean. Individual data points are shown in red. (d) Log10(CV) of sample-to-sample variance in Confetti color distribution in CD45.2 + PB of recipients of 1.0EE AGM explant-derived cells at 16 weeks post-transplant. Variance calculated based on 7 mice. Source data are provided in Supplementary Table 1.

Supplementary Figure 3 Distribution of Confetti labeling and representative Confetti gating in +/Cre mice.

(a) Average Confetti color frequencies in adult PB of +/Cre mice at 10-16 weeks of age. Error bars denote s.d. of the mean among mice. (b) The average distribution of Confetti colors was similar in PB B-cells (B), T-cells (T), myeloid cells (M), and platelets (Plt) for all +/Cre mice examined. Error bars indicate s.d. of the mean among mice. For panels a and b ROSA26ERT2-Cre/Confetti (ROSA26ERT2-Cre, n = 7 mice) ROSA26+/Confetti E2a+/Cre (E2aCre, n = 13), ROSA26+/Confetti Flk1+/Cre (Flk1Cre, n = 7), ROSA26+/Confetti VE-Cadherin+/Cre (VE-CadherinCre, n = 12), ROSA26+/ConfettiVav1+/Cre mice (Vav1Cre, n = 10) (Supplementary Table 1). Individual data points are shown in black.

Supplementary Figure 4 Representative Confetti gating in +/Cre mice.

(a) Representative gating of Confetti colors in PB myeloid cells, B-cells, T-cells, and platelets. A ROSA26ERT2-Cre/Confetti mouse and a ROSA26+/Confetti mouse are shown. (b) Confetti labeling of PB B cells in five individual adult ROSA26+/ConfettiE2a+/Cre mice to show the high variability in Confetti color distribution between mice in this cohort. Note: Mouse #1 and Mouse #2 display largely only one Confetti color in their PB, reflective of activity of E2a-Cre early in development. (c,d) Confetti-labeling in tissues derived from all three germ layers are shown. Note, in this example, only YFP+ cells are detectable, reflecting early allele recombination in development.

Supplementary Figure 5 Intra-aortic cell clusters are polyclonal in origin.

Extended images of the same intra-aortic cell clusters shown Fig. 6. For better appreciation, all single colors are shown here.

Supplementary Figure 6 Analysis of Confetti fluorescence in intra-aortic cell clusters, CRE expression in VE-Cadherin+/Cre embryos and Confetti color stability in embryo-derived cells.

(a) Extended image of the same intra-aortic cell cluster shown in the second row of Fig. 5a and Supplemental Fig. 5 to illustrate non-specific GFP signal. Green arrow denotes true GFP+ cells while white arrow denotes non-specific GFP signal. (b) qRT-PCR for CRE expression in Confetti + and Confetti- VE-Cadherin + CD45- cells isolated from E8.5, E9.5, or E10.5 ROSA26+/ConfettiVE-Cadherin+/Cre and ROSA26+/ConfettiVE-Cadherin+/+ embryos. Here, iCCs were used as a positive control for CRE expression. mRNA relative expression levels were normalized to CRE expression in iCCs. Each bar represents an independent biological replicate. Each biological replicate was generated in an independent experiment where different embryonic tissues of the same time-point and genotype were analyzed together. mRNA extraction, cDNA generation and qRT-PCR were run at the same time for all samples. (c) Experimental schematic. YFP+, CFP+, RFP+ or Confetti- VE-Cadherin + CD45- cells were collected by FACS from E10.5 ROSA26+/ConfettiVE-Cadherin+/Cre embryos and then co-cultured with OP9 stromal cells for seven days. Cultures were then analyzed by flow cytometry for Confetti colors. (d) Distribution of Confetti colors in cultures of YFP+, CFP+, RFP+ or Confetti- VE-Cadherin + CD45- E10.5 ROSA26+/ConfettiVE-Cadherin+/Cre cells co-cultured for seven days on OP9 stroma. All source data for panels b and d are provided in Supplementary Table 1.

Supplementary Figure 7 Unprocessed scan related to gel on Figure 4c.

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Ganuza, M., Hall, T., Finkelstein, D. et al. Lifelong haematopoiesis is established by hundreds of precursors throughout mammalian ontogeny. Nat Cell Biol 19, 1153–1163 (2017). https://doi.org/10.1038/ncb3607

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