期刊论文详细信息
Cancer Communications
Perivascular localized cells commit erythropoiesis in PDGF-B-expressing solid tumors
article
Lihong Shi1  Ping Zhu1  Yuanfu Xu1  Yunlong Yang3  Tao Cheng1  Yihai Cao4  Kayoko Hosaka4  Chenchen Wang1  Shiyue Zhang1  Xue Lv1  Takahiro Seki4  Yin Zhang4  Xu Jing4  Jieyu Wu4  Qiqiao Du4  Xingkang He4  Yulong Fan1  Xuan Li1  Makoto Kondo8  Masahito Yoshihara9  Hong Qian8 
[1] 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 Institutes of Health Science;Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University;Department of Microbiology, Tumor and Cell Biology, Karolinska Institute;School of Pharmacology, Binzhou Medical University;Department of Clinical Laboratory, the Second Hospital of Shandong University;Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University Medical School;Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital;Department of Biosciences and Nutrition, Karolinska Institute
关键词: cancer;    hematopoiesis;    PDGF-B;    perivascular localized cell;    stem cell;    tumor vasculature;   
DOI  :  10.1002/cac2.12423
学科分类:社会科学、人文和艺术(综合)
来源: Springer
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【 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 differentiation-specific 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 platelet-derived 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 sequencing and colony formation assays validated the fact that, upon PDGF-B stimulation, NG2+ cells isolated from tumors acted as erythroblast progenitor cells, which were distinctive from the canonical BM hematopoietic stem cells.Conclusions Our data provide a new concept of hematopoiesis within tumor tissues and novel mechanistic insights into perivascular localized cell-derived erythroid cells within TME. Targeting tumor hematopoiesis is a novel therapeutic concept for treating various cancers that may have profound impacts on cancer therapy.

【 授权许可】

CC BY|CC BY-NC-ND   

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