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Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells

Nature Medicine volume 25, pages 1761–1771 (2019)Cite this article

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Abstract

A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte production. Here we show that voluntary running decreases hematopoietic activity in mice. Exercise protects mice and humans with atherosclerosis from chronic leukocytosis but does not compromise emergency hematopoiesis in mice. Mechanistically, exercise diminishes leptin production in adipose tissue, augmenting quiescence-promoting hematopoietic niche factors in leptin-receptor-positive stromal bone marrow cells. Induced deletion of the leptin receptor in Prrx1-creERT2; Leprfl/fl mice reveals that leptin’s effect on bone marrow niche cells regulates hematopoietic stem and progenitor cell (HSPC) proliferation and leukocyte production, as well as cardiovascular inflammation and outcomes. Whereas running wheel withdrawal quickly reverses leptin levels, the impact of exercise on leukocyte production and on the HSPC epigenome and transcriptome persists for several weeks. Together, these data show that physical activity alters HSPCs via modulation of their niche, reducing hematopoietic output of inflammatory leukocytes.

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Fig. 1: Exercise increases HSPC quiescence.
Fig. 2: Exercise dampens hematopoiesis by reducing adipose tissue leptin production.
Fig. 3: Voluntary running reduces LSK chromatin accessibility.
Fig. 4: Exercise augments emergency hematopoiesis and improves survival in sepsis.
Fig. 5: Disrupting leptin signaling reduces hematopoiesis and inflammation in acute MI.
Fig. 6: Sedentary lifestyle accelerates leukocyte supply in mice and humans with atherosclerosis.

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Data availability

All data are included in this published article and its supplementary information files. Raw sequencing data are available from Gene Expression Omnibus under accession numbers GSE110639 and GSE124799. Raw data other than sequencing data that support the findings of this study are available from the corresponding author upon reasonable request. Source data are available for Figs. 1–6.

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Acknowledgements

We thank M. Handley, E. Surette and A. Galvin of the HSCI-CRM Flow Cytometry Core Facility, Massachusetts General Hospital, for assistance with cell sorting, the Center for Skeletal Research Imaging and Biomechanical Testing Core (National Institutes of Health P30 AR066261), Massachusetts General Hospital, for bone histology and µCT imaging, the Bioanalytics Core at the Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, University of Louisville, for mass spectrometry analysis, the BPF Next-Gen Sequencing Core Facility at Harvard Medical School for their support for RNA-sequencing and K. Joyes for editing the manuscript. This work was funded in part by federal funds from the National Institutes of Health (HL142494, HL139598, HL131478, HL128264, AI07087, DK040561 and T32HL076136), the European Union’s Horizon 2020 research and innovation program (grant agreement no. 667837), the Deutsche Forschungsgemeinschaft (CR 603/1-1, HO 5279/1-2 and RO 5071/1-1) and a fellowship from the Netherlands Organisation for Scientific Research (Rubicon Grant: 835.15.014). We acknowledge Servier Medical Art (https://smart.servier.com) for providing images of mice and components of the cartoon.

Author information

Author notes

  1. These authors contributed equally: Vanessa Frodermann, David Rohde.

Authors and Affiliations

  1. Center for Systems Biology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Vanessa Frodermann, David Rohde, Gabriel Courties, Maximilian J. Schloss, Cameron S. McAlpine, Sebastian Cremer, Friedrich F. Hoyer, Fanny Herisson, Lisa Honold, Gustavo Santos Masson, Shuang Zhang, Jana Grune, Yoshiko Iwamoto, Stephen P. Schmidt, Gregory R. Wojtkiewicz, I-Hsiu Lee, Kamila Naxerova, Filip K. Swirski & Matthias Nahrendorf

  2. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA

    Nicolas Severe, Karin Gustafsson & David T. Scadden

  3. Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA, USA

    Nicolas Severe, Karin Gustafsson & David T. Scadden

  4. Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Hajera Amatullah & Kate L. Jeffrey

  5. Department of Genetics, Harvard Medical School, Boston, MA, USA

    Fei Ji

  6. Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA

    Fei Ji & Ruslan I. Sadreyev

  7. Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands

    Ian D. van Koeverden & Saskia C. A. de Jager

  8. Laboratory for Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands

    Gerard Pasterkamp

  9. Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands

    Saskia C. A. de Jager

  10. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Ruslan I. Sadreyev

  11. Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Jean MacFadyen, Peter Libby & Paul Ridker

  12. Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Matthias Nahrendorf

  13. Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany

    Matthias Nahrendorf

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  1. Vanessa Frodermann
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Contributions

V.F., D.R. and M.N. designed experiments. V.F., D.R., G.C., N.S., M.J.S., H.A., S.C., F.F.H., F.J., I.D.v.K., F.H., L.H., C.S.M., G.S.M., S.Z., J.G., Y.I., S.P.S., G.R.W., I.-H.L. and K.G. performed experiments and collected data. V.F., D.R., G.C., N.S., F.J., I.D.v.K., G.P., S.C.A.d.J., R.I.S., I.-H.L., J.M. and K.N. analyzed data. V.F., M.J.S., D.R., S.C., F.F.H. and G.S.M. performed surgeries. V.F., D.R., G.C., N.S., H.A., P.L., G.P., P.R., D.T.S., K.N., K.L.J., F.S. and M.N. discussed results and strategy. V.F., D.R. and M.N. wrote the manuscript, which was edited by all co-authors. M.N. supervised, directed and managed the study.

Corresponding author

Correspondence to Matthias Nahrendorf.

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Competing interests

The authors declare no competing interests.

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Peer review information Michael Basson was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Effects of 6 weeks of running.

(a) Mean distance run per hour (n = 24 animals). (b) Mean daily distance over the course of 6 weeks (n = 16 animals). (c) changes in sedentary (n = 12) and exercising mice (n = 17, **p = 0.0076, two-tailed U test) compared to initial six weeks prior. (d) Heart weight adjusted for tibia length (n = 9 animals per group). (e) Food consumption during the last week of exercise (***p = 0.0002, n = 9 animals per group, two-tailed Student’s t-test). (f) Flow cytometry gating strategy for leukocytes in skeletal muscle. (g) Total leukocytes, neutrophils, monocytes and macrophages per mg muscle tissue by flow cytometry (n = 7 animals for sedentary, n = 12 for exercise). (h) Representative microCT images of the proximal metaphysis and mid-diaphysis tibia of exercising and sedentary mice. (i) Parameters of bone microstructure, including trabecular and cortical thickness, bone mineral density and polar moment of inertia by µCT (n = 6 animals per group). (j) Representative Runx2 staining of tibial proximal metaphysis. Osteoblast surface per bone surface (Ob.S/BS, n = 6 animals per group). (k) Bone formation rate as observed by incorporation of calcein (20 mg/kg, 7 days prior) and alizarin red (30 mg/kg, 2 days prior to sacrifice) during bone mineralization at the diaphysis of femurs. Distance of fluorescent label indicated by the arrow demarcates the mineralization front at different times of administration. ‘#’ denotes medullary cavity and ‘##’ trabecular bone (n = 4 animals). Data are mean ± s.e.m. We acknowledge Servier Medical Art (https://smart.servier.com) for providing images of mice and components of the cartoon.

Extended Data Fig. 2 Increased stem and progenitor cell quiescence after 6 weeks of exercise.

Mice were given 5-bromo-2- deoxyuridine (BrdU) intraperitoneally (1 mg). BrdU incorporation in (a) long-term hematopoietic stem cells (LT-HSC), short-term HSC (ST-HSC), (b) common myeloid progenitors (CMP, ***p = 0.00026), megakaryocyte erythroid progenitors (MEP, ***p = 1.028 × 10−5), granulocyte macrophage progenitors (GMP, ***p = 4.17 × 10−4, all n = 14 animals for sedentary, n = 15 for exercise), macrophage and dendritic cell progenitors (MDP, **p = 0.0070, n = 7 animals per group) and B cell progenitors (B cell prog, **p = 0.0065, n = 6 animals per group) were analyzed 22 hours later (two-tailed U test for CMP, MDP and B cell prog; two-tailed Student’s for MEPs and GMPs). (c) Flow cytometry gating for hematopoietic progenitors and representative flow cytometry plots of BrdU gating. (d) Cell cycle analysis in LSK assessed by Ki-67/ DAPI staining. Representative flow cytometry dot plots of + LSK (*p = 0.038, n = 7 animals for sedentary, n = 12 for exercise, 2 independent experiments, two-tailed U test). (e) Experimental outline for BrdU pulse-chase experiment. Mice received BrdU in drinking water for 3 weeks (baseline, n = 3 animals) prior to 3 weeks of exercise. (f) BrdU incorporation into LT-HSC, ST-HSC, multipotent progenitors (MPP, **p = 0.0074), CMP (p = 0.14), MEP (*p = 0.034) and GMP (p = 0.07, n = 9 animals for sedentary, n = 4 for exercise, two-tailed U test comparing sedentary and exercise). (g) Representative images of granulocyte macrophage colonies from sedentary and running mice. (h) Bone marrow unit assay (CFU) of bone marrow mononuclear cells (BMNCs) for complete colonies (*p = 0.036, n = 6 animals per group, 2 independent experiments, two-tailed U-test). (i) Number of HSPC per femur in sedentary and exercising mice (n = 15 animals per group). (j) Number of marrow leukocytes at Zeitgeber 13: B cells (**p = 0.0089), CD4 T cells, CD8 T cells (*p = 0.048), neutrophils (*p = 0.044), monocytes (*p = 0.041), eosinophils (*p = 0.019, n = 5 animals for sedentary, n = 6 for exercise) and NK cells (**p = 0.00099, n = 3 per group, two-tailed U test). (k) Numbers of platelets (*p = 0.016, two-tailed Student’s), red blood cells (RBC), hemoglobin (HGB) and hematocrit (HCT, n = 12 animals for sedentary and n = 11 for exercise, 4 independent experiments). Data are mean ± s.e.m.We acknowledge Servier Medical Art (https://smart.servier.com) for providing images of mice and components of the cartoon.

Extended Data Fig. 3 Neutral running effects on bone marrow neurotransmitters, corticosterone and selected hematopoietic niche cells.

(a) Mass spectrometry of norepinephrine and acetylcholine in the bone marrow after 6 weeks of exercise (n = 5 animals per group). (b) Choline acetyltransferase (ChAT) expression by bone marrow CD45+ leukocytes (n = 3 animals per group). (c) Experimental outline, administration of a competitive antagonist of the muscarinic acetylcholine receptors (atropine) during 3 weeks exercise. Leukocytes in circulation (n = 5 animals for Sed-Saline, n = 3 for Ex-Saline, n = 2 for Ex-Atropine). (d) Plasma corticosterone at Zeitgeber time (ZG 1 (n = 11 animals for sedentary, n = 8 for exercise), ZG 7 (n = 8 sedentary, n = 11 exercise), ZG 13 (n = 6 sedentary, n = 9 exercise) after exercise for 6 weeks. (e) Nestin+ stromal cells (n = 6 animals for sedentary, n = 8 for exercise, 3 independent experiments), (f) OCN+ osteoblasts, (n = 9 animals per group, 4 independent experiments) (g) endothelial cells (n = 8 animals for sedentary, n = 10 for exercise, 6 independent experiments) and (h) bone marrow macrophages (n = 5 animals per group, 2 independent experiments) were isolated by fluorescence-activated cell sorting. GFP stromal reporter mice either had access to exercise wheels for 6 weeks or remained sedentary. Representative dot plots are shown. Expression of Cxcl12, Vcam1, Kitl and Angpt1 was assessed by qPCR, ND: not detectable. (i) Numbers of stromal niche cells in sedentary and exercising mice (n = 9 and n = 8 for LepR+, n = 6 and n = 8 for Nestin+, n = 9 and n = 9 for OCN+, n = 8 and n = 10 for CD31high, n = 5 and n = 5 animals for sedentary and exercise, respectively). (j) Gene expression of several niche factors in total bone marrow by qPCR (n = 8 animals for sedentary for Ccl2 and Pf4, n = 12 for sedentary for Tgfb, Csf1, n = 16 for sedentary for Il7, Csf2, Csf3, n = 13 for exercise for Ccl2, Tgfb, n = 19 for exercise for Il7, Csf1, Csf2, Csf3, 4 independent experiments). (k) Markers for osteolineage cells (Sp7,Bglap, Runx2) and adipocytes (Lpl, Fabp4) by qPCR in total bone marrow (n = 8 animals per group, 2 independent experiments). All mRNA levels were normalized to Actb Ct values. Data are mean ± s.e.m., where appropriate. We acknowledge Servier Medical Art (https://smart.servier.com) for providing images of mice and components of the cartoon.

Extended Data Fig. 4 Exercise reduces visceral adipose tissue macrophages.

(a) Visceral adipose tissue (VAT) per mouse adjusted for (BW; ***p = 0.00069, n = 9 animals for sedentary, n = 7 for exercise, 2 independent experiments, two-tailed U test). (b) Cytokine production by visceral adipose tissue by qPCR (*p = 0.034, **p = 0.0087, n = 6 animals per group, 2 independent experiments, two-tailed U test). (c) Macrophages per mg VAT. Representative dot plots are shown (*p = 0.016, n = 5 animals for sedentary, n = 4 for exercise, two-tailed U test). (d) Experimental outline for e. Mice received BrdU in drinking water for 3 weeks (baseline, n = 4 animals) prior to 3 weeks of exercise. (e) BrdU incorporation into VAT macrophages (*p = 0.045, n = 9 animals for sedentary, n = 7 for exercise, 2 independent experiments, two-tailed U test comparing sedentary and exercise). Representative dot plots are shown. (f) Longitudinal sections of tibias were stained by perilipin (red) and counterstained by DAPI (blue). (g) Quantification of adipocyte numbers and size in the proximal metaphysis of tibias (**p = 0.0055, n = 8 animals for sedentary, n = 9 for exercise, 3 independent experiments, two-tailed U-test). (h) In vitro adipocyte differentiation assay of bone marrow stromal cells from all long bones and pelvic bones. Representative images with 100x magnification are shown (n = 4 animals per group). (i,j) Visualization of marrow adipose tissue in tibias by osmium stain by μCT and marrow adipose tissue (MAT) per marrow volume (MV) (n = 3 animals per group). (k) Leptin expression by qPCR in visceral adipose tissue (VAT; **p = 0.0022, n = 6 animals per group, two-tailed U test) and bone marrow (BM; n = 3 animals for sedentary, n = 6 for exercise). mRNA levels were normalized to Actb Ct values. Data are mean ± s.e.m. (l) Lack of correlation between tibial adipocyte size and leptin concentration (R2 = 0.0002, P = 0.96, n = 17 animals, linear regression analysis). We acknowledge Servier Medical Art (https://smart.servier.com) for providing images of mice and components of the cartoon.

Extended Data Fig. 5 Leptin supplementation and antibody neutralization.

(a) Leptin levels in blood (*p = 0.19 for both sed-leptin vs ex-saline and ex-saline vs ex-leptin, one-way analysis of variance with Sidak’s post hoc test) and bone marrow (*p = 0.013 sed-leptin vs ex-saline, *p = 0.042 sed-saline vs ex-saline, **p = 0.0038 ex-saline versus ex-leptin, n = 12 animals for sed-saline and ex-saline, n = 10 for sed-leptin, n = 13 for ex-leptin, 5 independent experiments, with Dunn’s post hoc test) as measured by ELISA. (b) LSK proliferation 22 h after intraperitoneal injection of BrdU (*p = 0.047 sed-saline versus ex-sal, P = 0.05 ex-saline versus ex-leptin, ***p = 0.00031 sed-leptin versus ex-sal, n = 12 animals for sed-saline and ex-saline, n = 10 for sed-leptin, n = 13 for ex-leptin, 5 independent experiments, one-way analysis of variance with Sidak’s post hoc test), LSK numbers and (c) expression of hematopoietic factors in bone marrow of exercising and sedentary mice implanted with osmotic minipumps as described in Fig. 2h (*p = 0.016 and **p = 0.0026 for Cxcl12, *p = 0.025 sed-saline versus ex-saline and *p = 0.046 ex-saline versus ex-leptin for Vcam1, ***p = 0.00074 ex-saline versus ex-leptin and p = 0.09 sed-saline versus ex-saline for Angpt1, n = 12 animals for sed-saline and ex-saline, n = 10 for sed-leptin, n = 13 for Ex-Leptin). (d) Running distance with either saline or leptin and access to exercise wheels for 6 weeks. Mean distance run per hour (n = 4 animals per group). (e) Injection of antibody or leptin into sedentary mice. Circulating leukocytes levels at Zeitgeber time 7 (*p = 0.010 IgG versus αLep, **p = 0.0072 αLep versus leptin) and LSK proliferation 22 h after intraperitoneal injection (**p = 0.0038 IgG versus αLep, ***p = 1.52 × 10−5, n = 6 animals for IgG, n = 7 for α-Lep, n = 4 for Leptin, 2 independent experiments, one-way analysis of variance with Sidak’s post hoc test). Data are mean ± s.e.m. We acknowledge Servier Medical Art (https://smart.servier.com) for providing images of mice and components of the cartoon.

Extended Data Fig. 6 Leptin receptor expression in the bone marrow.

(a) Representative flow cytometry dot plots of leptin receptor (LepR) expression in B cells, myeloid cells, T cells, (b) bone marrow long-term hematopoietic stem cells (LT-HSC), short-term HSC (ST-HSC), multipotent progenitors (MPP), common myeloid progenitors (CMP), megakaryocyte erythroid progenitors (MEP), granulocyte macrophage progenitors (GMP) and (c) stromal bone marrow cells (n = 3 independent experiments with similar results). (d) Bone marrow unit assay (CFU) for complete colonies (n = 4 donor animals). Bone marrow mononuclear cells (BMNCs) were plated with increasing concentrations of leptin. (e) Experimental outline for bone marrow transplantation; data shown in panel f-i. Total bone marrow was isolated from db/db donor mice and transplanted into wild type recipients. After an 8-week recovery period, mice exercised for 6 weeks or remained sedentary. (f) Leptin levels in serum by ELISA (**p = 0.0059, n = 11 animals for sedentary, n = 10 for exercise, 2 independent experiments, two-tailed Student’s t-test). (g) Circulating leukocyte levels at Zeitgeber time 7 (**p = 0.0042, n = 11 for animals sedentary, n = 10 for exercise, 2 independent experiments, two-tailed Student’s t-test). (h) BrdU incorporation into LSK 22 h after intraperitoneal injection (*p = 0.045, n = 10 animals sedentary, n = 9 for exercise, 2 independent experiments, two-tailed Student’s t-test). (i) Gene expression by qPCR in total bone marrow of Cxcl12 (*p = 0.042), Vcam1 (*p = 0.03), Kitl (*p = 0.014) and Angpt1 (* p = 0.0168, n = 11 animals for sedentary, n = 10 for exercise, 2 independent experiments, two-tailed U test for Cxcl12 and two-tailed Student’s t-test for Vcam1, Kitl, Angpt1). mRNA levels were normalized to Actb Ct values. (j) Leptin levels in blood of Leprfl/f and Prrx1-creERT2:Leprfl/fl mice measured by ELISA (n = 8 animals for Leprfl/fl and n = 11 for Prrx1-creERT2:Leprfl/fl). (k) Representative microCT images of the proximal metaphysis and mid-diaphysis tibia of Prrx1-creERT2:Leprfl/fl mice and their Leprfl/fl littermates. (b) Parameters of bone microstructure, including trabecular and cortical thickness, bone mineral density and polar moment of inertia by µCT (n = 3 animals per group). Data are mean ± s.e.m. We acknowledge Servier Medical Art (https://smart.servier.com) for providing images of mice and components of the cartoon.

Extended Data Fig. 7 Exercise effects wane after 6 sedentary weeks.

(a) Experimental outline for b-c. (b) Blood (*p = 0.012, ***p = 8.89 × 10−5) and tibial (**p = 0.0053, ***p = 0.00079) leptin concentrations measured by ELISA (n = 9 animals for sedentary and exercise, n = 13 animals for post-exercise-sedentary, 3 independent experiments, with Dunn’s post hoc test). (c) Gene expression of niche factors Cxcl12 (*p = 0.015), Vcam1 (*p = 0.038), Kitl (**p = 0.0037 sedentary versus exercise, **p = 0.0035 exercise versus post-exercise-sedentary) and Angpt1 (*p = 0.027) in whole bone marrow by qPCR (n = 9 animals for sedentary and exercise, n = 13 animals for post-exercise-sedentary, 3 independent experiments, one-way analysis of variance with Sidak’s post hoc test). mRNA levels were normalized to Actb Ct values. (d) Experimental outline for e. The post-exercise-sedentary group had access to exercise wheels for 6 weeks after which the wheels were removed for the following 6 weeks. Sedentary controls had no access, while the exercise group had access to wheels during the last 6 weeks before sacrifice. (e) Circulating leukocyte levels at Zeitgeber time 7 (*p = 0.028 sedentary versus exercise, *p = 0.045 exercise versus post-exercise sedentary) and BrdU incorporation into LSK 22 h after intraperitoneal injection (*p = 0.045 sedentary versus exercise, *p = 0.014 exercise versus post-exercise-sedentary, n = 6 animals per group, with Dunn’s post hoc test). (f) Outline of the competitive bone marrow transplantation experiments. LSK were isolated from CD45.2 donors that either exercised for 6 weeks or were sedentary. These were transplanted in a 1:1 ratio into CD45.1 recipients together with LSK isolated from Ubc-GFP mice that exercised for 6 weeks and had a 3-week post-exercise-sedentary period. Blood chimerism 8 weeks after transplantation (n = 4 animals per group, p = 0.12 for exercise versus post-exercise-sedentary donor chimerism, Wilcoxon matched-pairs signed rank test). Data are mean ± s.e.m. We acknowledge Servier Medical Art (https://smart.servier.com) for providing images of mice and components of the cartoon.

Extended Data Fig. 8 Background ATAC-seq signals are similar, while peaks are higher in LSK of sedentary mice.

(a) Average profiles of ATAC-seq tag density among randomly shuffled regions of the same size as the actual ATAC-seq peaks. These profiles are similar among different conditions, suggesting the absence of background shift between ATAC-seq signals. (b) Tracks of normalized ATAC-seq tag density for the loci of additional genes in the top ten significant genes in the cell cycle category as determined by DAVID in Fig. 3n. (c) Scatter plot of normalized tag density at ATAC-seq peaks shows comparison between LSK from sedentary versus post-exercise-sedentary cohorts. Peaks with significantly lower and higher tag density in post-running mice are highlighted in orange and black, respectively (FDR < 0.01). The top ten significant genes in the cell cycle pathway determined by DAVID (refer to d) and Mki67 are indicated; see Supplementary Table 1 for all genes. (d) Functional categories enriched among genes with differential chromatin accessibility in LSK from sedentary versus post-exercise-sedentary mice as determined by DAVID. (e) Tracks of normalized ATAC-seq tag density for the loci of the top ten significant genes in the cell cycle category as determined by DAVID in d.

Extended Data Fig. 9 Leptin in acute MI.

(a) Experimental outline for b-e. (b) Leptin blood levels on day 6 after MI (n = 5 animals for Sed-Saline and Ex-Saline, n = 6 for Ex-Leptin, 3 independent experiments). (c) Infarct CD45+ leukocyte levels on day 6 after MI (*p = 0.025, n = 5 animals for Sed-Saline and Ex-Saline, n = 6 for Ex-Leptin, 3 independent experiments, with Dunn’s post hoc test). (d) Flow cytometry gating and quantification of neutrophils (*p = 0.039 Sed-Saline versus Ex-Leptin, *p = 0.021 Ex-Saline versus Ex-Leptin), monocytes (*p = 0.018 Sed-Saline versus Ex-Leptin, *p = 0.015 Ex-Saline versus Ex-Leptin), macrophages and lymphocytes in the infarct in respective cohorts (n = 5 animals for Sed-Saline and Ex-Saline, n = 6 for Ex-Leptin, 3 independent experiments, with Dunn’s post hoc test). (e) Cardiac magnetic resonance imaging on day 21 after MI. Ejection fraction (EF), enddiastolic volume (EDV), endsystolic volume (ESV) and left ventricular (LV) mass were determined (n = 7 animals for Sed-Saline, n = 5 for Ex-Saline, n = 8 for Ex-Leptin, 3 independent experiments). (f) Experimental outline for panels g-j. (g) Circulating leukocytes at Zeitgeber 7 (**p = 0.0017, n = 8 animals for IgG and n = 10 for αLep, 3 independent experiments, two-tailed Student’s). (h) BrdU incorporation into granulocyte macrophage progenitors (GMP) 3 days after MI (p = 0.05, n = 8 animals for IgG and n = 10 for αLep, 3 independent experiments, two-tailed Student’s t-test). (i) Bone marrow unit assay (CFU) of bone marrow mononuclear cells (BMNCs) for complete colonies (***p = 0.00041, n = 7 animals for IgG and n = 10 for αLep, 3 independent experiments, two-tailed U test). (j) Neutrophils and monocytes per mg infarct tissue (*p = 0.03, n = 5 animals for IgG, n = 6 for αLep, two-tailed U test). (k) Experimental outline for l. (l) Representative immunohistochemical stainings and quantification of myeloid cells (CD11b), collagen deposition (Collagen I), and myofibroblasts (alpha smooth muscle actin) in the infarct border zone (*p = 0.026 for CD11b and Collagen I, n = 6 animals per group, two-tailed U test). Data are mean ± s.e.m. We acknowledge Servier Medical Art (https://smart.servier.com) for providing images of mice and components of the cartoon.

Extended Data Fig. 10 Stromal leptin receptor deletion attenuates atherosclerosis, inflammation and hematopoiesis.

(a) Experimental outline for b-h. Leprfl/fl mice and Prrx1-creERT2:Leprfl/fl littermates were injected with tamoxifen and received a single IV injection of AAV-PCSK9 followed by a high fat diet for 12 weeks. (b) Representative cross sections of aortic roots stained with Oil red O and assessment of lesion size (*p = 0.042, n = 8 animals per group, two-tailed Student’s t-test). (c) Flow cytometry enumeration of myeloid cells in aortas of Leprfl/fl and Prrx1-creERT2:Leprfl/fl mice (*p = 0.023, n = 8 animals per group, two-tailed Student’s t-test). (d) CD68 histological staining of aortic root lesions. Percentage of positive staining per plaque (*p = 0.029, n = 6 animals for Leprfl/fl, n = 8 for Prrx1-creERT2:Leprfl/fl, two-tailed U test). (e) Representative flow plots and statistical analysis of long-term hematopoietic stem cells (LT-HSC) in femur bone marrow (*p = 0.046, n = 9 animals per group, two-tailed Student’s t-test). (f) Bone marrow unit assay for complete colonies (CFU-C) of bone marrow mononuclear cells (BMNCs) (*p = 0.036, n = 9 animals per group, two-tailed Student’s t-test). (g) BrdU incorporation assay 22 hours after intraperitoneal injection for LT-HSC and progenitors (GMP) proliferation (*p = 0.027 for LT-HSC, *p = 0.017 for GMP, n = 9 animals per group, two-tailed Student’s t-test). (h) Circulating myeloid cells at Zeitgeber time 7 (*p = 0.014 for neutrophils, *p = 0.046 for monocytes, n = 10 animals for Leprfl/fl, n = 9 for Prrx1-creERT2:Leprfl/fl, two-tailed Student’s t-test). Data are mean ± s.e.m. (i) Athero-express cohort. The illustrates inclusion criteria for patients and separation into sedentary lifestyle and exercise groups. We acknowledge Servier Medical Art (https://smart.servier.com) for providing images of mice and components of the cartoon.

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Frodermann, V., Rohde, D., Courties, G. et al. Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells. Nat Med 25, 1761–1771 (2019). https://doi.org/10.1038/s41591-019-0633-x

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