Hypoxia-mediated chemotaxis and residence of macrophage in decidua by secreting VEGFA and CCL2 during normal pregnancy

in Reproduction
Authors:
Xue-Yun QinLaboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China
NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, People’s Republic of China

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Hui-Hui ShenLaboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China
NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, People’s Republic of China

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Xin-Yan ZhangLaboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

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Xing ZhangLaboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

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Feng XieCenter for Diagnosis and Treatment of Cervical and Uterine Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

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Wen-Jun WangLaboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

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Yu XiongDepartment of Obstetrics, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, People’s Republic of China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

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Jie MeiReproductive Medicine Center, Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medicine School, Nanjing, People’s Republic of China

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Ming-Qing LiLaboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China
NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, People’s Republic of China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

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https://orcid.org/0000-0002-9276-0722
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Correspondence should be addressed to M-Q Li or W Wang or Y Xiong or J Mei; Email: mqli@fudan.edu.cn or wangwenjun985@fckyy.org.cn or xiongyu1535@fckyy.org.cn or meijie560@163.com

*(X-Y Qin, H-H Shen and X-Y Zhang contributed equally to this work)

DOI:
https://doi.org/10.1530/REP-22-0473
Volume/Issue:
Volume 165: Issue 5
Page Range:
543–555
Article Type:
Research Article
Online Publication Date:
29 Mar 2023
Copyright:
© Society for Reproduction and Fertility 2023
Restricted access

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In brief

Hypoxia is vital for the establishment of the maternal–fetal interface during early pregnancy. This study shows that decidual macrophages (dMφ) could be recruited and reside in decidua under the regulation of hypoxia/VEGFA-CCL2 axis.

Abstract

Infiltration and residence of decidual macrophages (dMφ) are of great significance to pregnancy maintenance for their role in angiogenesis, placental development, and inducing immune tolerance. Besides, hypoxia has now been acknowledged as an important biological event at maternal–fetal interface in the first trimester. However, whether and how hypoxia regulates biofunctions of dMφ remain elusive. Herein, we observed increased expression of C–C motif chemokine ligand 2 (CCL2) and residence of macrophages in decidua compared to secretory-phase endometrium. Moreover, hypoxia treatment on stromal cells improved the migration and adhesion of dMφ. Mechanistically, these effects might be mediated by upregulated CCL2 and adhesion molecules (especially ICAM2 and ICAM5) on stromal cells in the presence of endogenous vascular endothelial growth factor-A (VEGFA) in hypoxia. These findings were also verified by recombinant VEGFA and indirect coculture, indicating that the interaction between stromal cells and dMφ in hypoxia condition may facilitate dMφ recruitment and residence. In conclusion, VEGFA derived from a hypoxic environment may manipulate CCL2/CCR2 and adhesion molecules to enhance the interactions between dMφ and stromal cells and thus contribute to the enrichment of macrophages in decidua early during normal pregnancy.

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Sept 2018 onwards Past Year Past 30 Days
Full Text Views 67 67 11
PDF Downloads 85 85 12

 

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Print ISSN:
1470-1626
Online ISSN:
1741-7899

  • Abu El-Asrar AM, Ahmad A, Siddiquei MM, De Zutter A, Allegaert E, Gikandi PW, De Hertogh G, Van Damme J, Opdenakker G & & Struyf S 2019 The proinflammatory and proangiogenic macrophage migration inhibitory factor is a potential regulator in proliferative diabetic retinopathy. Frontiers in Immunology 10 2752. (https://doi.org/10.3389/fimmu.2019.02752)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Andraweera PH, Dekker GA & & Roberts CT 2012 The vascular endothelial growth factor family in adverse pregnancy outcomes. Human Reproduction Update 18 436–457. (https://doi.org/10.1093/humupd/dms011)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bartoszewska S, Kochan K, Piotrowski A, Kamysz W, Ochocka RJ, Collawn JF & & Bartoszewski R 2015 The hypoxia-inducible miR-429 regulates hypoxia-inducible factor-1α expression in human endothelial cells through a negative feedback loop. FASEB Journal 29 1467–1479. (https://doi.org/10.1096/fj.14-267054)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chen X, Liu J, He B, Li Y, Liu S, Wu B, Wang S, Zhang S, Xu X & & Wang J 2015 Vascular endothelial growth factor (VEGF) regulation by hypoxia inducible factor-1 alpha (HIF1A) starts and peaks during endometrial breakdown, not repair, in a mouse menstrual-like model. Human Reproduction 30 2160–2170. (https://doi.org/10.1093/humrep/dev156)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, D'amore PA, Dana MR, Wiegand SJ & & Streilein JW 2004 VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. Journal of Clinical Investigation 113 1040–1050. (https://doi.org/10.1172/JCI20465)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Díaz-Bulnes P, Saiz ML, López-Larrea C & & Rodríguez RM 2019. Crosstalk Between Hypoxia and ER Stress Response: A Key Regulator of Macrophage Polarization. Frontiers in Immunology 10 2951. (https://doi.org/10.3389/fimmu.2019.02951)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Erlebacher A 2013 Immunology of the maternal-fetal interface. Annual Review of Immunology 31 387–411. (https://doi.org/10.1146/annurev-immunol-032712-100003)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Felsenstein M, Blank A, Bungert AD, Mueller A, Ghori A, Kremenetskaia I, Rung O, Broggini T, Turkowski K & Scherschinski L et al.2020 CCR2 of Tumor Microenvironmental Cells Is a Relevant Modulator of Glioma Biology. Cancers (Basel) 12 1882. (https://doi.org/10.3390/cancers12071882)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Flores CT, Wildes TJ, Drake JA, Moore GL, Dean BD, Abraham RS & & Mitchell DA 2018 Lin(-)CCR2(+) hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade. Nature Communications 9 4313. (https://doi.org/10.1038/s41467-018-06182-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fu OY, Chang HW, Lin YD, Chuang LY, Hou MF & & Yang CH 2016 Breast cancer-associated high-order SNP-SNP interaction of CXCL12/CXCR4-related genes by an improved multifactor dimensionality reduction (MDR-ER). Oncology Reports 36 1739–1747. (https://doi.org/10.3892/or.2016.4956)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Genbacev O, Joslin R, Damsky CH, Polliotti BM & & Fisher SJ 1996 Hypoxia alters early gestation human cytotrophoblast differentiation/invasion in vitro and models the placental defects that occur in preeclampsia. Journal of Clinical Investigation 97 540–550. (https://doi.org/10.1172/JCI118447)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hao Q, Vadgama JV & & Wang P 2020 CCL2/CCR2 signaling in cancer pathogenesis. Cell Communication and Signaling 18 82. (https://doi.org/10.1186/s12964-020-00589-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • He YY, Du MR, Guo PF, He XJ, Zhou WH, Zhu XY & & Li DJ 2007 Regulation of C-C motif chemokine ligand 2 and its receptor in human decidual stromal cells by pregnancy-associated hormones in early gestation. Human Reproduction 22 2733–2742. (https://doi.org/10.1093/humrep/dem208)

    • Search Google Scholar
    • Export Citation

  • Hu WT, Li MQ, Liu W, Jin LP, Li DJ & & Zhu XY 2014 IL-33 enhances proliferation and invasiveness of decidual stromal cells by up-regulation of CCL2/CCR2 via NF-κB and ERK1/2 signaling. Molecular Human Reproduction 20 358–372. (https://doi.org/10.1093/molehr/gat094)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • James JL, Stone PR & & Chamley LW 2006 The regulation of trophoblast differentiation by oxygen in the first trimester of pregnancy. Human Reproduction Update 12 137–144. (https://doi.org/10.1093/humupd/dmi043)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kashyap S, Osman M, Ferguson CM, Nath MC, Roy B, Lien KR, Nath KA, Garovic VD, Lerman LO & & Grande JP 2018 Ccl2 deficiency protects against chronic renal injury in murine renovascular hypertension. Scientific Reports 8 8598. (https://doi.org/10.1038/s41598-018-26870-y)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Koelwyn GJ, Corr EM, Erbay E & & Moore KJ 2018 Regulation of macrophage immunometabolism in atherosclerosis. Nature Immunology 19 526–537. (https://doi.org/10.1038/s41590-018-0113-3)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lash GE, Pitman H, Morgan HL, Innes BA, Agwu CN & & Bulmer JN 2016 Decidual macrophages: key regulators of vascular remodeling in human pregnancy. Journal of Leukocyte Biology 100 315–325. (https://doi.org/10.1189/jlb.1A0815-351R)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li M, Wu ZM, Yang H & & Huang SJ 2011 NFκB and JNK/MAPK activation mediates the production of major macrophage- or dendritic cell-recruiting chemokine in human first trimester decidual cells in response to proinflammatory stimuli. Journal of Clinical Endocrinology and Metabolism 96 2502–2511. (https://doi.org/10.1210/jc.2011-0055)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li W, Kohara H, Uchida Y, James JM, Soneji K, Cronshaw DG, Zou YR, Nagasawa T & & Mukouyama YS 2013 Peripheral nerve-derived CXCL12 and VEGF-A regulate the patterning of arterial vessel branching in developing limb skin. Developmental Cell 24 359–371. (https://doi.org/10.1016/j.devcel.2013.01.009)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liang X, Arullampalam P, Yang Z & & Ming XF 2019 Hypoxia enhances endothelial intercellular adhesion molecule 1 protein level through upregulation of arginase Type II and mitochondrial oxidative stress. Frontiers in Physiology 10 1003. (https://doi.org/10.3389/fphys.2019.01003)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Linde N, Casanova-Acebes M, Sosa MS, Mortha A, Rahman A, Farias E, Harper K, Tardio E, Reyes Torres I & Jones J et al.2018 Macrophages orchestrate breast cancer early dissemination and metastasis. Nature Communications 9 21. (https://doi.org/10.1038/s41467-017-02481-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Linde N, Lederle W, Depner S, Van Rooijen N, Gutschalk CM & & Mueller MM 2012 Vascular endothelial growth factor-induced skin carcinogenesis depends on recruitment and alternative activation of macrophages. Journal of Pathology 227 17–28. (https://doi.org/10.1002/path.3989)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu XT, Sun HT, Zhang ZF, Shi RX, Liu LB, Yu JJ, Zhou WJ, Gu CJ, Yang SL & Liu YK et al.,2018 Indoleamine 2,3-dioxygenase suppresses the cytotoxicity of 1 NK cells in response to ectopic endometrial stromal cells in endometriosis. Reproduction 156 397–404. (https://doi.org/10.1530/REP-18-0112)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lu H, Yang HL, Zhou WJ, Lai ZZ, Qiu XM, Fu Q, Zhao JY, Wang J, Li DJ & & Li MQ 2021 Rapamycin prevents spontaneous abortion by triggering decidual stromal cell autophagy-mediated NK cell residence. Autophagy 17 2511–2527. (https://doi.org/10.1080/15548627.2020.1833515)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Morrison AR, Yarovinsky TO, Young BD, Moraes F, Ross TD, Ceneri N, Zhang J, Zhuang ZW, Sinusas AJ & Pardi R et al.2014 Chemokine-coupled β2 integrin-induced macrophage Rac2-myosin IIA interaction regulates VEGF-A mRNA stability and arteriogenesis. Journal of Experimental Medicine 211 1957–1968. (https://doi.org/10.1084/jem.20132130)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ning F, Liu H & & Lash GE 2016 The role of decidual macrophages during normal and pathological pregnancy. American Journal of Reproductive Immunology 75 298–309. (https://doi.org/10.1111/aji.12477)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pringle KG, Kind KL, Sferruzzi-Perri AN, Thompson JG & & Roberts CT 2010 Beyond oxygen: complex regulation and activity of hypoxia inducible factors in pregnancy. Human Reproduction Update 16 415–431. (https://doi.org/10.1093/humupd/dmp046)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rehn M, Olsson A, Reckzeh K, Diffner E, Carmeliet P, Landberg G & & Cammenga J 2011 Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche. Blood 118 1534–1543. (https://doi.org/10.1182/blood-2011-01-332890)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ruytinx P, Proost P, Van Damme J & & Struyf S 2018 Chemokine-induced macrophage polarization in inflammatory conditions. Frontiers in Immunology 9 1930. (https://doi.org/10.3389/fimmu.2018.01930)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sajjadi MS, Ghandil P, Shahbazian N & & Saberi A 2020 Association of vascular endothelial growth factor A polymorphisms and aberrant expression of connexin 43 and VEGFA with idiopathic recurrent spontaneous miscarriage. Journal of Obstetrics and Gynaecology Research 46 369–375. (https://doi.org/10.1111/jog.14192)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sánchez-Navarro A, Pérez-Villalva R, Murillo-De-Ozores AR, Martínez-Rojas M, Rodríguez-Aguilera JR, González N, Castañeda-Bueno M, Gamba G, Recillas-Targa F & & Bobadilla NA 2021 Vegfa promoter gene hypermethylation at HIF1α binding site is an early contributor to CKD progression after renal ischemia. Scientific Reports 11 8769. (https://doi.org/10.1038/s41598-021-88000-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Semenza GL 2003 Targeting HIF-1 for cancer therapy. Nature Reviews. Cancer 3 721–732. (https://doi.org/10.1038/nrc1187)

  • Semenza GL 2013 HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. Journal of Clinical Investigation 123 3664–3671. (https://doi.org/10.1172/JCI67230)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shen HH, Wang CJ, Zhang XY, Sheng YR, Yang SL, Zheng ZM, Shi JL, Qiu XM, Xie F & & Li MQ 2021 HIF1A-induced heme oxygenase 1 promotes the survival of decidual stromal cells against excess heme-mediated oxidative stress. Reproduction 163 33–43. (https://doi.org/10.1530/REP-21-0314)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Su MT, Lin SH, Chen YC & & Kuo PL 2014 Gene-gene interactions and gene polymorphisms of VEGFA and EG-VEGF gene systems in recurrent pregnancy loss. Journal of Assisted Reproduction and Genetics 31 699–705. (https://doi.org/10.1007/s10815-014-0223-2)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wei CY, Li MQ, Zhu XY & & Li DJ 2021 Immune status of decidual macrophages is dependent on the CCL2/CCR2/JAK2 pathway during early pregnancy. American Journal of Reproductive Immunology 86 e13480. (https://doi.org/10.1111/aji.13480)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wei H, Xu Z, Chen L, Wei Q, Huang Z, Liu G, Li W, Wang J, Tang Q & & Pu J 2022 Long non-coding RNA PAARH promotes hepatocellular carcinoma progression and angiogenesis via upregulating HOTTIP and activating HIF-1α/VEGF signaling. Cell Death and Disease 13 102. (https://doi.org/10.1038/s41419-022-04505-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wheeler KC, Jena MK, Pradhan BS, Nayak N, Das S, Hsu CD, Wheeler DS, Chen K & & Nayak NR 2018 VEGF may contribute to macrophage recruitment and M2 polarization in the decidua. PLoS One 13 e0191040. (https://doi.org/10.1371/journal.pone.0191040)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Willenborg S, Lucas T, Van Loo G, Knipper JA, Krieg T, Haase I, Brachvogel B, Hammerschmidt M, Nagy A & Ferrara N et al.2012 CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood 120 613–625. (https://doi.org/10.1182/blood-2012-01-403386)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wolf M, Clay SM, Zheng S, Pan P & & Chan MF 2019 MMP12 inhibits corneal neovascularization and inflammation through regulation of CCL2. Scientific Reports 9 11579. (https://doi.org/10.1038/s41598-019-47831-z)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wyatt MA, Baumgarten SC, Weaver AL, Van Oort CC, Fedyshyn B, Ruano R, Shenoy CC & & Enninga EAL 2021 Evaluating markers of immune tolerance and angiogenesis in maternal blood for an association with risk of pregnancy loss. Journal of Clinical Medicine 10 3579. (https://doi.org/10.3390/jcm10163579)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yamada K, Maishi N, Akiyama K, Towfik Alam M, Ohga N, Kawamoto T, Shindoh M, Takahashi N, Kamiyama T & Hida Y et al.2015 CXCL12-CXCR7 axis is important for tumor endothelial cell angiogenic property. International Journal of Cancer 137 2825–2836. (https://doi.org/10.1002/ijc.29655)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yamanaka-Tatematsu M, Nakashima A, Fujita N, Shima T, Yoshimori T & & Saito S 2013 Autophagy induced by HIF1α overexpression supports trophoblast invasion by supplying cellular energy. PLoS One 8 e76605. (https://doi.org/10.1371/journal.pone.0076605)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yang HL, Lai ZZ, Shi JW, Zhou WJ, Mei J, Ye JF, Zhang T, Wang J, Zhao JY & Li DJ et al.2022 A defective lysophosphatidic acid-autophagy axis increases miscarriage risk by restricting decidual macrophage residence. Autophagy 18 2459–2480. (https://doi.org/10.1080/15548627.2022.2039000)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yang HL, Zhou WJ, Lu H, Lei ST, Ha SY, Lai ZZ, Zheng ZM, Ruan LY, He YY & Li DJ et al.2019 Decidual stromal cells promote the differentiation of CD56(bright) CD16(-) NK cells by secreting IL-24 in early pregnancy. American Journal of Reproductive Immunology 81 e13110. (https://doi.org/10.1111/aji.13110)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yang J, Yan J & & Liu B 2018 Targeting VEGF/VEGFR to modulate antitumor immunity. Frontiers in Immunology 9 978. (https://doi.org/10.3389/fimmu.2018.00978)

  • Yu N, Wu JL, Xiao J, Fan L, Chen SH & & Li W 2019 HIF-1α regulates angiogenesis via Notch1/STAT3/ETBR pathway in trophoblastic cells. Cell Cycle 18 3502–3512. (https://doi.org/10.1080/15384101.2019.1689481)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhao H, Wong RJ & & Stevenson DK 2021 The impact of hypoxia in early pregnancy on placental cells. International Journal of Molecular Sciences 22 9675. (https://doi.org/10.3390/ijms22189675)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhou WJ, Yang HL, Mei J, Chang KK, Lu H, Lai ZZ, Shi JW, Wang XH, Wu K & Zhang T et al.2022 Fructose-1,6-bisphosphate prevents pregnancy loss by inducing decidual COX-2(+) macrophage differentiation. Science Advances 8 eabj2488. (https://doi.org/10.1126/sciadv.abj2488)

    • PubMed
    • Search Google Scholar
    • Export Citation