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Adiponectin receptors sustain haematopoietic stem cells throughout adulthood by protecting them from inflammation

Nature Cell Biology volume 24, pages 697–707 (2022)Cite this article

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Abstract

How are haematopoietic stem cells (HSCs) protected from inflammation, which increases with age and can deplete HSCs? Adiponectin, an anti-inflammatory factor that is not required for HSC function or haematopoiesis, promotes stem/progenitor cell proliferation after bacterial infection and myeloablation. Adiponectin binds two receptors, AdipoR1 and AdipoR2, which have ceramidase activity that increases upon adiponectin binding. Here we found that adiponectin receptors are non-cell-autonomously required in haematopoietic cells to promote HSC quiescence and self-renewal. Adiponectin receptor signalling suppresses inflammatory cytokine expression by myeloid cells and T cells, including interferon-γ and tumour necrosis factor. Without adiponectin receptors, the levels of these factors increase, chronically activating HSCs, reducing their self-renewal potential and depleting them during ageing. Pathogen infection accelerates this loss of HSC self-renewal potential. Blocking interferon-γ or tumour necrosis factor signalling partially rescues these effects. Adiponectin receptors are thus required in immune cells to sustain HSC quiescence and to prevent premature HSC depletion by reducing inflammation.

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Fig. 1: Adiponectin receptors promote HSC quiescence.
Fig. 2: Adiponectin receptors are required to sustain HSC function.
Fig. 3: Adiponectin receptors suppress the expression of inflammatory cytokines in bone marrow lymphocytes.
Fig. 4: Adiponectin receptors promote HSC function by reducing IFNγ signalling.
Fig. 5: Adiponectin receptors promote HSC function by reducing TNF signalling.
Fig. 6: Adiponectin receptors are required to sustain HSCs during ageing.

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Data availability

RNA-seq data associated with this paper are accessible in the NCBI Sequence Read Archive, BioProjects PRJNA699097 (associated with Fig. 1a–c), PRJNA729963 (associated with Fig. 3a) and PRJNA765672 (associated with Extended Data Fig. 4f). All other data supporting the findings of this study are available from the corresponding author on reasonable request. Source data are provided with this paper.

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Acknowledgements

S.J.M. is a Howard Hughes Medical Institute (HHMI) Investigator, the Mary McDermott Cook Chair in Pediatric Genetics, the Kathryn and Gene Bishop Distinguished Chair in Pediatric Research, the director of the Hamon Laboratory for Stem Cells and Cancer and a Cancer Prevention and Research Institute of Texas Scholar. This work was supported by the National Institutes of Health (DK118745), the Moody Medical Research Institute, the Josephine Hughes Sterling Foundation and the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation (all to S.J.M.). C.E.M. was supported by a Postdoctoral Fellowship from the American Cancer Society (PF-13-245-01-LIB). E.C.J. was supported by a Postdoctoral Fellowship from the Damon Runyon Cancer Research Foundation (2278-16). R.J.B. was supported by Ruth L. Kirschstein National Research Service Award Postdoctoral Fellowship from the National Heart, Lung, and Blood Institute (F32HL122095-01). Funding for the UT Dallas/UT Southwestern Green Fellows Program (C.D.S.) was supported, in part, by the Cecil and Ida Green Foundation. We thank G. Karsenty for providing the Adipor1fl/fl and Adipor2fl/fl mice, N. Loof, C. Cantu, T. Shih, G. Wilson and the Moody Foundation Flow Cytometry Facility, M. Mulkey for mouse colony management, and the BioHPC high-performance computing cloud at the University of Texas Southwestern Medical Center for providing computational resources.

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Authors and Affiliations

  1. Children’s Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Corbin E. Meacham, Elise C. Jeffery, Rebecca J. Burgess, Charukesi D. Sivakumar, Madison A. Arora, Anne Marie Stanley, Emily M. Colby, Zhiyu Zhao & Sean J. Morrison

  2. Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA

    Genevieve M. Crane

  3. Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX, USA

    Sean J. Morrison

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Contributions

C.E.M. and S.J.M. conceived the project, and designed and interpreted experiments. C.E.M. performed most of the experiments. E.C.J. and R.J.B. discussed experiments and helped interpret data. E.C.J. performed the stromal cell analysis. A.M.S. processed samples for flow cytometric analysis in Fig. 2. E.M.C. processed samples for flow cytometric analysis in Fig. 4. C.D.S. and M.A.A. performed ELISAs in Fig. 3 and processed samples for flow cytometric analysis in Fig. 6. A.M.S., E.M.C. and M.A.A. analysed blood samples from transplanted mice. G.M.C. performed histopathological analysis of spleen sections. Z.Z. performed bioinformatic and statistical analyses. C.E.M. and S.J.M. wrote the manuscript.

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Correspondence to Sean J. Morrison.

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Extended data

Extended Data Fig. 1 Adiponectin receptor deficient mice are born in normal numbers and are normal in size (related to Fig. 1).

a-c. Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl mice were born at the expected mendelian frequencies (a) and were grossly normal in size (b) and appearance (c) (n = 4 female and n = 8 male Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl mice and n = 10 female and n = 3 male control mice in one experiment (b)). d. The number of bone marrow cells in one femur and one tibia or in the spleen of 8-10-week-old Vav1-Cre and control mice (five mice per genotype in one experiment). e. White blood cell, red blood cell, and platelet counts in the blood of 8–10-week-old Vav1-Cre and control mice (five mice per genotype in one experiment). f-i. The frequencies of HSCs (f), MPPs (g), HPCs (h), CMPs, MEPs, and GMPs (i) in bone marrow from one femur and one tibia of Vav1-Cre and control mice (five mice per genotype in one experiment). j-m. The frequencies of HSCs (j), MPPs (k), HPCs (l), CMPs, MEPs, and GMPs (m) in splenocytes from Vav1-Cre and control mice (five mice per genotype in one experiment). All data represent mean ± standard deviation and each dot reflects a different mouse. Statistical significance was assessed using Mann-Whitney tests followed by Holm-Sidak’s multiple comparisons adjustments (b and d-e) or Student’s t-tests followed by Holm-Sidak’s multiple comparisons adjustments (f-m). All statistical tests were two-sided. Source numerical data are available in the source data files.

Source data

Extended Data Fig. 2 Flow cytometry gating strategy for the isolation of hematopoietic stem cells, progenitor cells, and differentiated cells (related to Figs. 1–6).

a-c. Representative flow cytometry gates used to identify hematopoietic stem and progenitor cells (a-b), NK cells, CD4 + T cells, and CD8 + T cells (c) in the bone marrow. The markers used to identify each of the cell populations characterized in this study are listed in Supplementary Table 1. d. Hematoxylin and Eosin stained sections from the spleens of Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl and control mice. In Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl mice the spleens were enlarged (Fig. 1d) and the red pulp was expanded throughout the spleen with increased numbers of myeloid, erythroid, and megakaryocytic cells. In control spleens there was limited extramedullary hematopoiesis confined to the subcapsular region. Representative images from three mice per genotype in one experiment are shown.

Extended Data Fig. 3 Adiponectin receptors are required to sustain HSC function (related to Fig. 2).

a-b. The percentages of HSCs that formed colonies (n = 6 mice per genotype in two independent experiments) (a) and colony size (n = 3 mice per genotype in one experiment) (b) from Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl and control mice. c. The percentage of whole bone marrow cells that formed CFU-GEMM, CFU-GM, CFU-G, CFU-M, and BFU-E colonies (n = 3 mice per genotype in one experiment). d. Donor CD45 + cells, T, B, and myeloid cells from the blood of mice competitively transplanted with donor bone marrow cells from Mx1-Cre; Adipor1fl/fl; Adipor2fl/fl (n = 27 recipients) or control (n = 25 recipients) mice (five donors per genotype in five independent experiments). e. Secondary recipients of bone marrow cells from the mice in (d) (n = 25 recipients from six Mx1-Cre; Adipor1fl/fl; Adipor2fl/fl donors and n = 24 recipients from five control donors in five independent experiments). All data represent mean ± standard deviation and each dot reflects a different mouse. Statistical significance was assessed using Mann-Whitney tests (d-e), a Student’s t-test (a), a multinomial logistic regression (b), and Student’s t-tests followed by Holm-Sidak’s multiple comparisons adjustments (c), or Mann-Whitney tests (d-e). All statistical tests were two-sided. Source numerical data are available in the source data files.

Source data

Extended Data Fig. 4 Adiponectin receptors suppress the production of inflammatory factors (related to Fig. 3).

a. ELISA analysis of inflammatory cytokines in spleen lysates from Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl and control mice (spleen lysates from 16 (IFNγ, TNF, IL6, and Il1β) or 13 (IFNα and IFNβ) Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl mice and 19 (IFNγ, TNF, IL6, and Il1β) or 14 (IFNα and IFNβ) control mice in two independent ELISAs per cytokine). b. qRT-PCR analysis of Tnf transcript levels in sorted bone marrow cells. Data are normalized to transcript levels in wildtype whole bone marrow (WBM) cells (cells sorted from six (WBM), three (HSC, HPC, CMP, MEP, GMP, T-cells, B-cells, and erythroid progenitors), or five (myeloid cells) Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl mice and from seven (WBM), three (HSC, HPC, CMP, MEP, GMP, and erythroid progenitors), or four (T-cells, B-cells, and myeloid cells) control mice in one experiment). c. qRT-PCR analysis of Tnf transcripts in sorted CD4 + T cells, CD8 + T cells, or NK cells from the bone marrow (cells sorted from three mice per genotype in one experiment). d. qRT-PCR analysis of Tnf transcripts in sorted macrophages, inflammatory monocytes, and neutrophils from the bone marrow. Data are normalized to transcript levels in wildtype WBM (cells sorted from seven mice per genotype in two independent experiments). e. The frequency of LepR+ stromal cells in bone marrow from 8-10 week old Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl and control mice (n = 7 mice per genotype in two independent experiments). f. RNAseq analysis of transcripts for Ifng and Tnf in LepR+ cells from 8-10 week old Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl and control mice (n = 3 mice per genotype one experiment). g. The frequencies of donor and competitor HSCs in the spleens of recipient mice co-transplanted with Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl or control donor cells and wildtype competitor cells 16 weeks after transplantation (n = 19 recipients from Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl donors and n = 20 recipients from control donors in four independent experiments). All data represent mean ± standard deviation and each dot reflects a different mouse. Statistical significance was assessed using Student’s t-tests followed by Holm-Sidak’s multiple comparisons adjustments (a-b and d), a matched samples two-way ANOVA followed by Sidak’s multiple comparisons adjustment (c), Student’s t-tests (e), or Mann-Whitney tests followed by Holm-Sidak’s multiple comparisons adjustments (a and g). All statistical tests were two-sided. Source numerical data are available in the source data files.

Source data

Extended Data Fig. 5 Adiponectin receptors promote HSC function by reducing IFNγ receptor signaling (related to Fig. 4).

a. Bone marrow (one femur and one tibia) and spleen cellularity in Vav1-Cre; Ifngr1fl/fl and control mice (n = 7 Vav1-Cre; Ifngrfl/fl mice and n = 6 control mice in three independent experiments). b-d. The frequencies of HSCs, MPPs, HPCs (b), CMPs, MEPs, GMPs (c), and differentiated T, B, myeloid, and erythroid cells (d) in the bone marrow of Vav1-Cre; Ifngr1fl/fl and control mice (n = 7 Vav1-Cre; Ifngrfl/fl mice and n = 6 control mice in three independent experiments). e−g. The frequencies of HSCs, MPPs, HPCs (e), CMPs, MEPs, GMPs (f), and differentiated cells (g) in the spleens of Vav1-Cre; Ifngr1fl/fl and control mice (n = 7 Vav1-Cre; Ifngrfl/fl mice and n = 6 control mice in three independent experiments). h. The percentage of HSCs that incorporated a 72 hour pulse of BrdU (n = 3 Vav1-Cre; Ifngrfl/fl mice and n = 4 control mice one experiment). i-o. The frequencies of HSCs (i), MPPs (j), HPCs (k), CMPs (l), MEPs (m), GMPs (n) and differentiated cells (o) in the bone marrow of control, Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl, and Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl; Ifngrfl/fl mice (n = 15 Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl mice, n = 13 Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl; Ifngrfl/f mice and n = 21 control mice in five independent experiments). All data represent mean ± standard deviation and each dot reflects a different mouse. Statistical significance was assessed using a matched samples two-way ANOVA followed by Sidak’s multiple comparisons adjustment (a), Mann-Whitney tests followed by Holm-Sidak’s multiple comparisons adjustments (b-g), a Student’s t-test (h), or one−way ANOVAs followed by Tukey’s multiple comparisons adjustments (i-o). All statistical tests were two-sided. Source numerical data are available in the source data files.

Source data

Extended Data Fig. 6 Adiponectin receptors promote HSC function by reducing TNF levels (related to Fig. 5).

a. Bone marrow (one femur and one tibia) and spleen cellularity in Tnf deficient and control mice (n = 5 Tnf-/- mice and n = 7 control mice in four independent experiments). b-d. The frequencies of HSCs, MPPs, HPCs (b), CMPs, MEPs, GMPs (c) and differentiated T, B, myeloid, and erythroid cells (d), in the bone marrow of Tnf deficient and control mice (n = 5 Tnf-/- mice and n = 7 control mice in four independent experiments). e-g. The frequencies of HSCs, MPPs, HPCs (e), CMPs, MEPs, GMPs (f) and differentiated cells (g), in the spleens of Tnf deficient and control mice (n = 5 (e and g) or n = 4 (f) Tnf-/- mice and n = 7 control mice in four independent experiments). h. The percentage of HSCs that incorporated a 72 hour pulse of BrdU (n = 4 Tnf-/- mice and n = 9 control mice in two independent experiments) i-o. The frequencies of HSCs (i), MPPs (j), HPCs (k), CMPs (l), MEPs (m), GMPs (n) and differentiated cells (o) in the bone marrow of control, Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl, and Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl; Tnf-/- mice (n = 12 Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl mice, n = 11 Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl; Tnf-/- mice and n = 12 control mice in five independent experiments). p-q. ELISA of TNF (p) or INFg (q) in blood plasma from Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl; Ifngrfl/fl (p), Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl; Tnf-/- (q), Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl and control mice (n = 6 Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl mice, n = 10 Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl; Ifngrfl/f mice and n = 17 control mice run in one ELISA per cytokine (p) and n = 13 Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl mice, n = 6 Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl; Tnf-/- mice and n = 12 control mice in one ELISA per cytokine (q)). All data represent mean ± standard deviation and each dot reflects a different mouse. Statistical significance was assessed using a matched samples two-way ANOVA followed by Sidak’s multiple comparisons adjustment (a), Student’s t-tests (b-h) followed by Holm-Sidak’s multiple comparisons adjustments (b-g), one-way ANOVAs followed by Tukey’s multiple comparisons adjustments (i-o and q), a Welch’s one-way ANOVA followed by Dunnett’s T3 multiple comparisons adjustment (o), or a Kruskal-Wallis test followed by Dunn’s multiple comparisons adjustment (o and p). All statistical tests were two-sided. Source numerical data are available in the source data files.

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Extended Data Fig. 7 Adiponectin receptor function reduces the frequencies of splenic myeloid cells in 5-6 and 19-24 month old mice (related to Fig. 6).

a-d. The frequencies of CMPs, MEPs, GMPs (a, c), differentiated T, B, myeloid, and erythroid cells (b, d) in the bone marrow from 5-6 month old (a-b) or 19-24 month old (c-d) Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl or control mice (n = 7 (a-b) or n = 5 (c-d) Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl mice and n = 10 (a-b) or n = 6 (c-d) control mice in two independent experiments per age group). e-n. The frequencies of HSCs (e, j), MPPs (f, k), HPCs (g, l), CMPs, MEPs, GMPs (h, m), and differentiated T, B, myeloid, and erythroid cells (i, n) in the spleens of 5–6-month-old (e-i) and 19-24 month-old (j-n) Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl or control mice (n = 7 (e-i) or n = 5 (j-n) Vav1-Cre; Adipor1fl/fl; Adipor2fl/fl mice and n = 10 (e-i) or n = 6 (j-n) control mice in two independent experiments per age group). All data represent mean ± standard deviation and each dot reflects a different mouse. Statistical significance was assessed using Mann-Whitney tests followed by Holm-Sidak’s multiple comparisons adjustments (a-n). All statistical tests were two-sided. Source numerical data are available in the source data files.

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Supplementary information

Reporting Summary

Peer Review File

Supplementary Table 1

Cell populations analysed by flow cytometry in this study.

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Meacham, C.E., Jeffery, E.C., Burgess, R.J. et al. Adiponectin receptors sustain haematopoietic stem cells throughout adulthood by protecting them from inflammation. Nat Cell Biol 24, 697–707 (2022). https://doi.org/10.1038/s41556-022-00909-9

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