Perivascular localized cells commit erythropoiesis in PDGF-B-expressing solid tumors  

作　　者：Kayoko Hosaka Chenchen Wang Shiyue Zhang Xue Lv Takahiro Seki Yin Zhang Xu Jing Jieyu Wu Qiqiao Du Xingkang He Yulong Fan Xuan Li Makoto Kondo Masahito Yoshihara Hong Qian Lihong Shi Ping Zhu Yuanfu Xu Yunlong Yang Tao Cheng Yihai Cao 

机构地区：[1]Department of Microbiology,Tumor and Cell Biology,Karolinska Institute,Stockholm,Sweden [2]State Key Laboratory of Experimental Hematology,National Clinical Research Center for Blood Diseases,Haihe Laboratory of Cell Ecosystem,Institute of Hematology&Blood Diseases Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College,Tianjin,P.R.China [3]Tianjin Institutes of Health Science,Tianjin,P.R.China [4]School of Pharmacology,Binzhou Medical University,Yantai,Shandong,P.R.China [5]Department of Clinical Laboratory,the Second Hospital of Shandong University,Jinan,Shandong,P.R.China [6]Department of Gastroenterology,Sir Run Run Shaw Hospital,Zhejiang University Medical School,Hangzhou,Zhejiang,P.R.China [7]Center for Hematology and Regenerative Medicine,Department of Medicine,Karolinska Institute,Karolinska University Hospital,Stockholm,Sweden [8]Department of Biosciences and Nutrition,Karolinska Institute,Huddinge,Sweden [9]Department of Cellular and Genetic Medicine,School of Basic Medical Sciences,Fudan University,Shanghai,P.R.China

出　　处：《Cancer Communications》2023年第6期637-660,共24页癌症通讯（英文）

基　　金：CAMS Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-017;National Natural Science Foundation of China,Grant/Award Number:81970107;State Key Laboratory of Experimental Hematology Research,Grant/Award Number:Z22-02;Tianjin“131”Science Fund for Creative Research Groups,Grant/Award Number:2021;Swedish Research Council,Grant/Award Numbers:2016-02215,2019-01502,2020-06121,2021-06122;National Key R&D Program of China,Grant/Award Number:2020YFC0846600;Hong Kong Centre for Cerebro-cardiovascular Health Engineering;Swedish Cancer Foundation,Grant/Award Number:200734PjF;Swedish Children’s Cancer Foundation,Grant/Award Number:PR2018-0107;Strategic Research Areas(SFO)-Stem Cell and Regenerative Medicine Foundation;Karolinska Institute distinguished professor award;Karolinska Institute Foundation;Scandinavia-Japan Sasakawa Foundation,Grant/Award Number:81801163;Doctor Fund of Shandong Natural Science Foundation,Grant/Award Number:ZR201807060846;Japan Society for the Promotion of Science(JSPS)Overseas Research Fellowships。

摘　　要：Background:Tumors possess incessant growth features,and expansion of their masses demands sufficient oxygen supply by red blood cells(RBCs).In adult mammals,the bone marrow(BM)is the main organ regulating hematopoiesis with dedicated manners.Other than BM,extramedullary hematopoiesis is discovered in various pathophysiological settings.However,whether tumors can contribute to hematopoiesis is completely unknown.Accumulating evidence shows that,in the tumor microenvironment(TME),perivascular localized cells retain progenitor cell properties and can differentiate into other cells.Here,we sought to better understand whether and how perivascular localized pericytes in tumors manipulate hematopoiesis.Methods:To test if vascular cells can differentiate into RBCs,genome-wide expression profiling was performed using mouse-derived pericytes.Genetic tracing of perivascular localized cells employing NG2-CreERT2:R26R-tdTomato mouse strain was used to validate the findings in vivo.Fluorescence-activated cell sorting(FACS),single-cell sequencing,and colony formation assays were applied for biological studies.The production of erythroid differentiationspecific cytokine,erythropoietin(EPO),in TME was checked using quantitative polymerase chain reaction(qPCR),enzyme-linked immunosorbent assay(ELISA,magnetic-activated cell sorting and immunohistochemistry.To investigate BM function in tumor erythropoiesis,BM transplantation mouse models were employed.Results:Genome-wide expression profiling showed that in response to plateletderived growth factor subunit B(PDGF-B),neural/glial antigen 2(NG2)+perivascular localized cells exhibited hematopoietic stem and progenitor-like features and underwent differentiation towards the erythroid lineage.PDGF-B simultaneously targeted cancer-associated fibroblasts to produce high levels of EPO,a crucial hormone that necessitates erythropoiesis.FACS analysis using genetic tracing of NG2+cells in tumors defined the perivascular localized cell-derived subpopulation of hematopoietic cells.Single-cell se

关 键 词：cancer HEMATOPOIESIS PDGF-B perivascular localized cell stem cell tumor vasculature 

分 类 号：R730[医药卫生—肿瘤]