Lyve1+ macrophages of murine peritoneal mesothelium promote omentum-independent ovarian tumor growth

Nan Zhang; Seung Hyeon Kim; Anastasiia Gainullina; Emma C. Erlich; Emily J. Onufer; Jiseon Kim; Rafael S. Czepielewski; Beth A. Helmink; Joseph R. Dominguez; Brian T. Saunders; Jie Ding; Jesse W. Williams; Jean X. Jiang; Brahm H. Segal; Bernd H. Zinselmeyer; Gwendalyn J. Randolph; Ki Wook Kim

doi:10.1084/jem.20210924

Lyve1⁺ macrophages of murine peritoneal mesothelium promote omentum-independent ovarian tumor growth

Nan Zhang, Seung Hyeon Kim, Anastasiia Gainullina, Emma C. Erlich, Emily J. Onufer, Jiseon Kim, Rafael S. Czepielewski, Beth A. Helmink, Joseph R. Dominguez, Brian T. Saunders, Jie Ding, Jesse W. Williams, Jean X. Jiang, Brahm H. Segal, Bernd H. Zinselmeyer, Gwendalyn J. Randolph, Ki Wook Kim

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

Two resident macrophage subsets reside in peritoneal fluid. Macrophages also reside within mesothelial membranes lining the peritoneal cavity, but they remain poorly characterized. Here, we identified two macrophage populations (LYVE1^hi MHC II^lo-hi CX₃CR1gfp^lo/− and LYVE1^lo/− MHC II^hi CX₃CR1gfp^hi subsets) in the mesenteric and parietal mesothelial linings of the peritoneum. These macrophages resembled LYVE1⁺ macrophages within surface membranes of numerous organs. Fatemapping approaches and analysis of newborn mice showed that LYVE1^hi macrophages predominantly originated from embryonic-derived progenitors and were controlled by CSF1 made by Wt1⁺ stromal cells. Their gene expression profile closely overlapped with ovarian tumor-associated macrophages previously described in the omentum. Indeed, syngeneic epithelial ovarian tumor growth was strongly reduced following in vivo ablation of LYVE1^hi macrophages, including in mice that received omentectomy to dissociate the role from omental macrophages. These data reveal that the peritoneal compartment contains at least four resident macrophage populations and that LYVE1^hi mesothelial macrophages drive tumor growth independently of the omentum.

Original language	English (US)
Article number	e20210924
Journal	Journal of Experimental Medicine
Volume	218
Issue number	12
DOIs	https://doi.org/10.1084/jem.20210924
State	Published - Dec 6 2021
Externally published	Yes

Bibliographical note

Funding Information:
We thank Dr. Steffen Jung (Weizmann Institute of Science, Israel) and Charles Harris (WUSM) for providing mouse strains. We also thank all the members of the Randolph laboratory at WUSM and the Kim laboratory at UIC for helpful discussion or reading the manuscript. We thank Christophe Benoist and colleagues at ImmGen for collecting samples and generating data from ULI-RNAseq. We also thank WUSM and UIC Flow Cytometry Core. We are grateful for technical support from Julie Prior and Kathleen Duncan from the Molecular Imaging Center at WUSM. This study was supported by National Institutes of Health grants R37 AI049653 (to G.J. Randolph); R01DK119147, DP1DK126190, and R01DK126753 (to K-W. Kim); R01AG045040 (to J.X. Jiang); R01CA188900 (to B.H. Segal); R00HL138163 (to J.W. Williams); T32DK077653 (to E.C. Erlich and E.J. Onufer); P50CA094056 (to WUSM Molecular Imaging Center); P30AR0737752 (to WUSM Rheumatic Disease Research Center); and P30CA091842 (to WUSM Siteman Cancer Center Small Animal Cancer Imaging shared resource); and Welch Foundation grant AQ-1507 (to J.X. Jiang).

Funding Information:
Disclosures: J.W. Williams reported grants from American Heart Association and grants from NIH NHLBI outside the submitted work. No other disclosures were reported.

Funding Information:
This study was supported by National Institutes of Health grants R37 AI049653 (to G.J. Randolph); R01DK119147, DP1DK126190, and R01DK126753 (to K-W. Kim); R01AG045040 (to J.X. Jiang); R01CA188900 (to B.H. Segal); R00HL138163 (to J.W. Williams); T32DK077653 (to E.C. Erlich and E.J. Onufer); P50CA094056 (to WUSM Molecular Imaging Center); P30AR0737752 (to WUSM Rheumatic Disease Research Center); and P30CA091842 (to WUSM Siteman Cancer Center Small Animal Cancer Imaging shared resource); and Welch Foundation grant AQ-1507 (to J.X. Jiang). R.S. Czepielewski received support from the Lawrence C. Pakula, MD, IBD Research Fellowship (FA-2020-01-IBD-1).

Publisher Copyright:
© 2021 Zhang et al.

Publisher link

10.1084/jem.20210924

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Zhang, N., Kim, S. H., Gainullina, A., Erlich, E. C., Onufer, E. J., Kim, J., Czepielewski, R. S., Helmink, B. A., Dominguez, J. R., Saunders, B. T., Ding, J., Williams, J. W., Jiang, J. X., Segal, B. H., Zinselmeyer, B. H., Randolph, G. J., & Kim, K. W. (2021). Lyve1⁺ macrophages of murine peritoneal mesothelium promote omentum-independent ovarian tumor growth. Journal of Experimental Medicine, 218(12), Article e20210924. https://doi.org/10.1084/jem.20210924

Zhang, N, Kim, SH, Gainullina, A, Erlich, EC, Onufer, EJ, Kim, J, Czepielewski, RS, Helmink, BA, Dominguez, JR, Saunders, BT, Ding, J, Williams, JW, Jiang, JX, Segal, BH, Zinselmeyer, BH, Randolph, GJ & Kim, KW 2021, 'Lyve1⁺ macrophages of murine peritoneal mesothelium promote omentum-independent ovarian tumor growth', Journal of Experimental Medicine, vol. 218, no. 12, e20210924. https://doi.org/10.1084/jem.20210924

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title = "Lyve1+ macrophages of murine peritoneal mesothelium promote omentum-independent ovarian tumor growth",

abstract = "Two resident macrophage subsets reside in peritoneal fluid. Macrophages also reside within mesothelial membranes lining the peritoneal cavity, but they remain poorly characterized. Here, we identified two macrophage populations (LYVE1hi MHC IIlo-hi CX3CR1gfplo/− and LYVE1lo/− MHC IIhi CX3CR1gfphi subsets) in the mesenteric and parietal mesothelial linings of the peritoneum. These macrophages resembled LYVE1+ macrophages within surface membranes of numerous organs. Fatemapping approaches and analysis of newborn mice showed that LYVE1hi macrophages predominantly originated from embryonic-derived progenitors and were controlled by CSF1 made by Wt1+ stromal cells. Their gene expression profile closely overlapped with ovarian tumor-associated macrophages previously described in the omentum. Indeed, syngeneic epithelial ovarian tumor growth was strongly reduced following in vivo ablation of LYVE1hi macrophages, including in mice that received omentectomy to dissociate the role from omental macrophages. These data reveal that the peritoneal compartment contains at least four resident macrophage populations and that LYVE1hi mesothelial macrophages drive tumor growth independently of the omentum.",

author = "Nan Zhang and Kim, {Seung Hyeon} and Anastasiia Gainullina and Erlich, {Emma C.} and Onufer, {Emily J.} and Jiseon Kim and Czepielewski, {Rafael S.} and Helmink, {Beth A.} and Dominguez, {Joseph R.} and Saunders, {Brian T.} and Jie Ding and Williams, {Jesse W.} and Jiang, {Jean X.} and Segal, {Brahm H.} and Zinselmeyer, {Bernd H.} and Randolph, {Gwendalyn J.} and Kim, {Ki Wook}",

note = "Funding Information: We thank Dr. Steffen Jung (Weizmann Institute of Science, Israel) and Charles Harris (WUSM) for providing mouse strains. We also thank all the members of the Randolph laboratory at WUSM and the Kim laboratory at UIC for helpful discussion or reading the manuscript. We thank Christophe Benoist and colleagues at ImmGen for collecting samples and generating data from ULI-RNAseq. We also thank WUSM and UIC Flow Cytometry Core. We are grateful for technical support from Julie Prior and Kathleen Duncan from the Molecular Imaging Center at WUSM. This study was supported by National Institutes of Health grants R37 AI049653 (to G.J. Randolph); R01DK119147, DP1DK126190, and R01DK126753 (to K-W. Kim); R01AG045040 (to J.X. Jiang); R01CA188900 (to B.H. Segal); R00HL138163 (to J.W. Williams); T32DK077653 (to E.C. Erlich and E.J. Onufer); P50CA094056 (to WUSM Molecular Imaging Center); P30AR0737752 (to WUSM Rheumatic Disease Research Center); and P30CA091842 (to WUSM Siteman Cancer Center Small Animal Cancer Imaging shared resource); and Welch Foundation grant AQ-1507 (to J.X. Jiang). Funding Information: Disclosures: J.W. Williams reported grants from American Heart Association and grants from NIH NHLBI outside the submitted work. No other disclosures were reported. Funding Information: This study was supported by National Institutes of Health grants R37 AI049653 (to G.J. Randolph); R01DK119147, DP1DK126190, and R01DK126753 (to K-W. Kim); R01AG045040 (to J.X. Jiang); R01CA188900 (to B.H. Segal); R00HL138163 (to J.W. Williams); T32DK077653 (to E.C. Erlich and E.J. Onufer); P50CA094056 (to WUSM Molecular Imaging Center); P30AR0737752 (to WUSM Rheumatic Disease Research Center); and P30CA091842 (to WUSM Siteman Cancer Center Small Animal Cancer Imaging shared resource); and Welch Foundation grant AQ-1507 (to J.X. Jiang). R.S. Czepielewski received support from the Lawrence C. Pakula, MD, IBD Research Fellowship (FA-2020-01-IBD-1). Publisher Copyright: {\textcopyright} 2021 Zhang et al.",

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T1 - Lyve1+ macrophages of murine peritoneal mesothelium promote omentum-independent ovarian tumor growth

AU - Zhang, Nan

AU - Kim, Seung Hyeon

AU - Gainullina, Anastasiia

AU - Erlich, Emma C.

AU - Onufer, Emily J.

AU - Kim, Jiseon

AU - Czepielewski, Rafael S.

AU - Helmink, Beth A.

AU - Dominguez, Joseph R.

AU - Saunders, Brian T.

AU - Ding, Jie

AU - Williams, Jesse W.

AU - Jiang, Jean X.

AU - Segal, Brahm H.

AU - Zinselmeyer, Bernd H.

AU - Randolph, Gwendalyn J.

AU - Kim, Ki Wook

N1 - Funding Information: We thank Dr. Steffen Jung (Weizmann Institute of Science, Israel) and Charles Harris (WUSM) for providing mouse strains. We also thank all the members of the Randolph laboratory at WUSM and the Kim laboratory at UIC for helpful discussion or reading the manuscript. We thank Christophe Benoist and colleagues at ImmGen for collecting samples and generating data from ULI-RNAseq. We also thank WUSM and UIC Flow Cytometry Core. We are grateful for technical support from Julie Prior and Kathleen Duncan from the Molecular Imaging Center at WUSM. This study was supported by National Institutes of Health grants R37 AI049653 (to G.J. Randolph); R01DK119147, DP1DK126190, and R01DK126753 (to K-W. Kim); R01AG045040 (to J.X. Jiang); R01CA188900 (to B.H. Segal); R00HL138163 (to J.W. Williams); T32DK077653 (to E.C. Erlich and E.J. Onufer); P50CA094056 (to WUSM Molecular Imaging Center); P30AR0737752 (to WUSM Rheumatic Disease Research Center); and P30CA091842 (to WUSM Siteman Cancer Center Small Animal Cancer Imaging shared resource); and Welch Foundation grant AQ-1507 (to J.X. Jiang). Funding Information: Disclosures: J.W. Williams reported grants from American Heart Association and grants from NIH NHLBI outside the submitted work. No other disclosures were reported. Funding Information: This study was supported by National Institutes of Health grants R37 AI049653 (to G.J. Randolph); R01DK119147, DP1DK126190, and R01DK126753 (to K-W. Kim); R01AG045040 (to J.X. Jiang); R01CA188900 (to B.H. Segal); R00HL138163 (to J.W. Williams); T32DK077653 (to E.C. Erlich and E.J. Onufer); P50CA094056 (to WUSM Molecular Imaging Center); P30AR0737752 (to WUSM Rheumatic Disease Research Center); and P30CA091842 (to WUSM Siteman Cancer Center Small Animal Cancer Imaging shared resource); and Welch Foundation grant AQ-1507 (to J.X. Jiang). R.S. Czepielewski received support from the Lawrence C. Pakula, MD, IBD Research Fellowship (FA-2020-01-IBD-1). Publisher Copyright: © 2021 Zhang et al.

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N2 - Two resident macrophage subsets reside in peritoneal fluid. Macrophages also reside within mesothelial membranes lining the peritoneal cavity, but they remain poorly characterized. Here, we identified two macrophage populations (LYVE1hi MHC IIlo-hi CX3CR1gfplo/− and LYVE1lo/− MHC IIhi CX3CR1gfphi subsets) in the mesenteric and parietal mesothelial linings of the peritoneum. These macrophages resembled LYVE1+ macrophages within surface membranes of numerous organs. Fatemapping approaches and analysis of newborn mice showed that LYVE1hi macrophages predominantly originated from embryonic-derived progenitors and were controlled by CSF1 made by Wt1+ stromal cells. Their gene expression profile closely overlapped with ovarian tumor-associated macrophages previously described in the omentum. Indeed, syngeneic epithelial ovarian tumor growth was strongly reduced following in vivo ablation of LYVE1hi macrophages, including in mice that received omentectomy to dissociate the role from omental macrophages. These data reveal that the peritoneal compartment contains at least four resident macrophage populations and that LYVE1hi mesothelial macrophages drive tumor growth independently of the omentum.

AB - Two resident macrophage subsets reside in peritoneal fluid. Macrophages also reside within mesothelial membranes lining the peritoneal cavity, but they remain poorly characterized. Here, we identified two macrophage populations (LYVE1hi MHC IIlo-hi CX3CR1gfplo/− and LYVE1lo/− MHC IIhi CX3CR1gfphi subsets) in the mesenteric and parietal mesothelial linings of the peritoneum. These macrophages resembled LYVE1+ macrophages within surface membranes of numerous organs. Fatemapping approaches and analysis of newborn mice showed that LYVE1hi macrophages predominantly originated from embryonic-derived progenitors and were controlled by CSF1 made by Wt1+ stromal cells. Their gene expression profile closely overlapped with ovarian tumor-associated macrophages previously described in the omentum. Indeed, syngeneic epithelial ovarian tumor growth was strongly reduced following in vivo ablation of LYVE1hi macrophages, including in mice that received omentectomy to dissociate the role from omental macrophages. These data reveal that the peritoneal compartment contains at least four resident macrophage populations and that LYVE1hi mesothelial macrophages drive tumor growth independently of the omentum.

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