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Mast Cell Repopulating Ability Is Lost During the Transition From Pre-HSC to FL HSC

Yoshimoto, Momoko, Kosters, Astrid, Cornelius, Samuel, Valiente, Noemi, Cheng, Haizi, Latorre, Augusto, Nishida, Chika, Ghosn, Eliver E. B., Kobayashi, Michihiro·2022·Frontiers in Immunology
DOI 10.3389/fimmu.2022.896396PMC PMC9309215
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Abstract

Recent advances in developmental immunology have revealed a hematopoietic stem cell (HSC)-independent origin for various innate immune lineages, including mast cells (MCs). It is now established that adult bone marrow (BM) long-term HSCs do not regenerate MCs but, instead, the physiological production of MCs starts before the emergence of HSCs in the aorta-gonad-mesonephros (AGM) region and is mostly completed before birth. However, while the AGM region represents a major site of MC generation during ontogeny, whether the first emerging HSCs in the AGM or fetal liver (FL) possess the potential to regenerate MCs is unknown. Here, we combined three fate-mapping mouse models with detailed HSC transplantation assays to determine the potential of AGM and FL HSCs to produce MCs. We show that HSCs from E11.5 AGM and E12.5 FL efficiently repopulated MCs in recipients. In stark contrast, HSCs from ≥E14.5 FL failed to reconstitute MCs. An Endothelial (EC) fate-mapping study confirmed the EC origin of the majority of MCs. Additionally, our HSC-labeling showed that HSCs do not produce MCs in a physiological setting. Hence, although most MCs are generated and maintained via an HSC-independent pathway, the earliest HSCs to emerge in the AGM and seed the early FL can produce MCs, but only during a minimal time window. Our results challenge the stem cell theory in hematology and EC-derived mast cells may contribute to the pathogenesis of postnatal mast cell disorders.

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Figure 1 Efficient MC repopulation in neonatal NSG recipient mice. (A) Representative flow plots of recipient’s PerC cells transplanted with BM HSC cells. Sorted 100 adult BM HSCs or 3000 MPPs (B6; CD45.2) were transplanted into irradiated F1 B6/BoyJ (CD45.1+CD45.2+) mice together with 3x105 BoyJ BM MNCs (CD45.1). (B) Percentages of the donor, competitor, and recipient MC chimerism in the recipient’s PerC. (n=5 each) (C) A gating strategy for sorting of c-Kit+β7-integrin+ MC progenitor cells from E12.5 B6 FL (Top Panel). Representative gating for MC and macrophage populations in PerC of recipient NSG mice 2 months after transplant with 3500 of Kit+β7-integrin+ cells (bottom panel). (D) % reconstitution of MCs and Macrophages population in PerC of recipient NSG mice as in C(n=4).
Figure 1 Efficient MC repopulation in neonatal NSG recipient mice. (A) Representative flow plots of recipient’s PerC cells transplanted with BM HSC cells. Sorted 100 adult BM HSCs or 3000 MPPs (B6; CD45.2) were transplanted into irradiated F1 B6/BoyJ (CD45.1+CD45.2+) mice together with 3x105 BoyJ BM MNCs (CD45.1). (B) Percentages of the donor, competitor, and recipient MC chimerism in the recipient’s PerC. (n=5 each) (C) A gating strategy for sorting of c-Kit+β7-integrin+ MC progenitor cells from E12.5 B6 FL (Top Panel). Representative gating for MC and macrophage populations in PerC of recipient NSG mice 2 months after transplant with 3500 of Kit+β7-integrin+ cells (bottom panel). (D) % reconstitution of MCs and Macrophages population in PerC of recipient NSG mice as in C(n=4).CC BY · PubMed Central
Figure 2 AGM pre-HSC and FL HSC at E12.5 possess MC repopulating capacity, but not after E14.5. (A) Representative flow plots of MC, macrophage, and lymphoid reconstitutions from 15.5 FL, 12.5 FL HSC or E11.5 AGM pre-HSCs in PerC (gating strategy provided in S1B). (B) % Donor (CD45.2) contributions of MCs in PerC based on donor ages. (n=32 for 11.5, n=27 for E12.5, n=4 for E14.5, n=11 for E15.5, n=9 for adult BM). (C, D) Numbers of HSC transplanted and % donor (CD45.2) in the total host PerC MCs are shown for E11.5 AGM pre-HSCs (C) and E12.5 FL HSCs (D), (E) Repopulation of MCs in PerC of NSG recipients transplanted with E14.5 FL donor MNCs are shown (n=5 and 3 in independent experiment respectively).
Figure 2 AGM pre-HSC and FL HSC at E12.5 possess MC repopulating capacity, but not after E14.5. (A) Representative flow plots of MC, macrophage, and lymphoid reconstitutions from 15.5 FL, 12.5 FL HSC or E11.5 AGM pre-HSCs in PerC (gating strategy provided in S1B). (B) % Donor (CD45.2) contributions of MCs in PerC based on donor ages. (n=32 for 11.5, n=27 for E12.5, n=4 for E14.5, n=11 for E15.5, n=9 for adult BM). (C, D) Numbers of HSC transplanted and % donor (CD45.2) in the total host PerC MCs are shown for E11.5 AGM pre-HSCs (C) and E12.5 FL HSCs (D), (E) Repopulation of MCs in PerC of NSG recipients transplanted with E14.5 FL donor MNCs are shown (n=5 and 3 in independent experiment respectively).CC BY · PubMed Central
Figure 3 E12.5 FL HSCs are not exclusively labeled by iCdh5 nor iFgd5. (A) TAM injections into iCdh5 embryos at E12.5 were performed and %Tom was measured in various immune lineages after birth (n=5). (B) Experimental timeline is shown. (C) TAM was injected into iFgd5 mice at E12.5 and analyzed at E14.5 FL. %Tom in LT-HSC, MPP, and Kit+ are shown (n=7). (D) TAM was injected at E12.5 into iFgd5 embryo and analyzed FL at E14.5, then 4x105 FL MNCs from each cre (+) embryo were transplanted into adult NSG recipients, followed by lineage analysis at 18 weeks after transplant. %Tom of various fractions from recipients (post-transplant donor cells) are shown (*: p<0.05, n=5). (E) TAM E14.5 into iFgd5 was given and measured %TR at p0 (n=4). (F) %TR of LT-HSC, MPP, and c-Kit+ cells in the P0 neonatal BM when TAM was injected at E14.5. ns, not significant.
Figure 3 E12.5 FL HSCs are not exclusively labeled by iCdh5 nor iFgd5. (A) TAM injections into iCdh5 embryos at E12.5 were performed and %Tom was measured in various immune lineages after birth (n=5). (B) Experimental timeline is shown. (C) TAM was injected into iFgd5 mice at E12.5 and analyzed at E14.5 FL. %Tom in LT-HSC, MPP, and Kit+ are shown (n=7). (D) TAM was injected at E12.5 into iFgd5 embryo and analyzed FL at E14.5, then 4x105 FL MNCs from each cre (+) embryo were transplanted into adult NSG recipients, followed by lineage analysis at 18 weeks after transplant. %Tom of various fractions from recipients (post-transplant donor cells) are shown (*: p<0.05, n=5). (E) TAM E14.5 into iFgd5 was given and measured %TR at p0 (n=4). (F) %TR of LT-HSC, MPP, and c-Kit+ cells in the P0 neonatal BM when TAM was injected at E14.5. ns, not significant.CC BY · PubMed Central
Figure 4 Fate-mapping assays reveal an HSC-independent, but EC-dependent, origin for MCs. (A) Time points of TAM injection into iCdh5 or iFgd5 mice and various time points for analysis are depicted. (B) Representative flow plots for %Tom in BM HSCs, PerC, and skin MCs based on each TAM injection day (n=2-5 in each point). (C) Absolute percentages of Tom in PerC MCs were measured in iCdh5 mice. %Tom in various time points of analysis based on each embryonic day of TAM injection are plotted (n=3-7 in each point). (D) %TR of PerC MC, Macrophage (Mac), and Brain MG based on multiple TAM time points are plotted (n= 3-6 in each time point). (E) Kinetics of %TR of MC and Mac populations in PerC between early (<28 days) and late time points (>60 days) based on TAM injection day (n= 3-7 in each point). *: p<0.001(n=4). **: p<0.001 (n=3). (F) TAM was injected into p2 iFgd5 neonate and %TR of MC and Mac populations in PerC were plotted until one-year-old (n=3 in each point). ns, not significant.
Figure 4 Fate-mapping assays reveal an HSC-independent, but EC-dependent, origin for MCs. (A) Time points of TAM injection into iCdh5 or iFgd5 mice and various time points for analysis are depicted. (B) Representative flow plots for %Tom in BM HSCs, PerC, and skin MCs based on each TAM injection day (n=2-5 in each point). (C) Absolute percentages of Tom in PerC MCs were measured in iCdh5 mice. %Tom in various time points of analysis based on each embryonic day of TAM injection are plotted (n=3-7 in each point). (D) %TR of PerC MC, Macrophage (Mac), and Brain MG based on multiple TAM time points are plotted (n= 3-6 in each time point). (E) Kinetics of %TR of MC and Mac populations in PerC between early (<28 days) and late time points (>60 days) based on TAM injection day (n= 3-7 in each point). *: p<0.001(n=4). **: p<0.001 (n=3). (F) TAM was injected into p2 iFgd5 neonate and %TR of MC and Mac populations in PerC were plotted until one-year-old (n=3 in each point). ns, not significant.CC BY · PubMed Central
Figure 5 Diversification of HSC to the MC progenitor and HSC maturation. E10.5–11.5 pre-HSC in the AGM region contains a variety of cell populations including HSC with MC capacity (plus other innate lineages too), MPP, and other lineage-restricted progenitors. E12.5 FL contains at least 3 classes of MC repopulating cells; 1) HSCs (with reduced MC differentiation capacity), 2) MPPs with MC potential, and 3) Kit+β7-integrin+ MC progenitor cells. 1) is the consequence of E11.5 pre-HSC/HSC and 2) are derived from E9.5-10.5 AGM EC-derived production. 3) are derived from the early EC-derived wave and later AGM EC wave. In E14.5, HSCs had lost MC capacity, but MC progenitors still exist within MNCs, then distribute into general tissue and maintain long term in local.
Figure 5 Diversification of HSC to the MC progenitor and HSC maturation. E10.5–11.5 pre-HSC in the AGM region contains a variety of cell populations including HSC with MC capacity (plus other innate lineages too), MPP, and other lineage-restricted progenitors. E12.5 FL contains at least 3 classes of MC repopulating cells; 1) HSCs (with reduced MC differentiation capacity), 2) MPPs with MC potential, and 3) Kit+β7-integrin+ MC progenitor cells. 1) is the consequence of E11.5 pre-HSC/HSC and 2) are derived from E9.5-10.5 AGM EC-derived production. 3) are derived from the early EC-derived wave and later AGM EC wave. In E14.5, HSCs had lost MC capacity, but MC progenitors still exist within MNCs, then distribute into general tissue and maintain long term in local.CC BY · PubMed Central

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Metadata

Authors
Yoshimoto, M., Kosters, A., Cornelius, S., Valiente, N., Cheng, H., Latorre, A., Nishida, C., Ghosn, E. E. B., & Kobayashi, M.
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2022-07-08
Volume
13
ISSN
1664-3224
DOI
10.3389/fimmu.2022.896396
PMC
PMC9309215
Cited by
14
References
5
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
National Institute of Allergy and Infectious Diseases (R01AI121197, R01AI123126)

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