共培养策略在类器官研究中的应用进展

芦瑜; 席雨梦; 何晓明; 杨少坤; 张佳; 王雷; 何朝星; 向柏

doi:10.19401/j.cnki.1007-3639.2023.03.014

您当前的位置：

首页 >

文章列表页 >

共培养策略在类器官研究中的应用进展

综述 | 更新时间：2025-12-31

- 共培养策略在类器官研究中的应用进展
- Advances in the application of co-culture strategies in organoids
- 中国癌症杂志 2023年33卷第3期页码：293-302
- 作者机构：
  
  1. 河北医科大学药学院，河北石家庄 050017
  2. 石家庄市第四医院药剂科，河北石家庄 050035
  3. 河北医科大学第四医院胸外科，河北石家庄 050011
- 作者简介：
  
  [ "芦瑜（ORCID: 0000-0002-0200-7973），硕士在读。" ]
  何朝星（ORCID: 0000-0001-8019-0622），硕士，高级实验师；
  向柏（ORCID: 0000-0002-4789-641X），博士，教授，河北医科大学药学院药剂学教研室主任。
- 基金信息：
  
  国家自然科学基金(81973251)
- DOI：10.19401/j.cnki.1007-3639.2023.03.014
  中图分类号： R73-35+1
- 收稿：2022-05-13，
  
  修回：2022-08-05，
  
  纸质出版：2023-03-30
- 稿件说明：
移动端阅览
芦瑜, 席雨梦, 何晓明, 等. 共培养策略在类器官研究中的应用进展[J]. 中国癌症杂志, 2023,33(3):293-302.

Yu LU, Yumeng XI, Xiaoming HE, et al. Advances in the application of co-culture strategies in organoids[J]. China Oncology, 2023, 33(3): 293-302.
芦瑜, 席雨梦, 何晓明, 等. 共培养策略在类器官研究中的应用进展[J]. 中国癌症杂志, 2023,33(3):293-302. DOI： 10.19401/j.cnki.1007-3639.2023.03.014.

Yu LU, Yumeng XI, Xiaoming HE, et al. Advances in the application of co-culture strategies in organoids[J]. China Oncology, 2023, 33(3): 293-302. DOI： 10.19401/j.cnki.1007-3639.2023.03.014.

摘要

类器官作为一种良好的体外研究模型，在生物医学领域中的应用越来越广泛。通过采用各种组织培养技术开发自组装的3D结构，类器官可重现器官固有结构中细胞的高度复杂性，因此被广泛用于研究调节机体发育和疾病的机制、高通量药物筛选及个性化治疗等。为更好地重现微环境内细胞间的相互作用，共培养策略已经扩展到更多的细胞类型，共培养策略的迅速发展使类器官技术的应用前景更加广阔，并为治疗人类疾病和再生医学开辟了新的道路。本文阐述共培养策略在类器官生成中的作用，并重点介绍不同细胞成分及微生物组与类器官共培养的应用，以期为构建开发具有更高体内模拟程度的类器官提供参考和帮助。

Abstract

As a good in vitro research model

organoids are more and more widely used in the biomedical field. By developing self-assembled 3D structures using various tissue culture techniques

organoids can rebuild the high complexity of cells in the inherent structure of the organ

and are therefore unanimously used to study mechanisms regulating body development and disease

high-throughput drug screening

and personalized treatment and so on. To better reca

pitulate cell-to-cell interactions within the microenvironment

co-culture strategies have been extended to more cell types

and their rapid development offers broader prospects for organoids and paves the way for the treatment of human diseases and regenerative medicine. This review discussed the role of co-culture strategies in organoid generation

and focused on the application of various cellular components and microorganisms in organoid construction

thereby providing reference and help for scholars to construct and develop organoids with a higher degree of

in vivo

simulation.

关键词

Keywords

references

PRIOR N , INACIO P , HUCH M . Liver organoids: from basic research to therapeutic applications [J ] . Gut , 2019 , 68 ( 12 ): 2228 - 2237 . DOI: 10.1136/gutjnl-2019-319256 http://doi.org/10.1136/gutjnl-2019-319256

LAU H C H , KRANENBURG O , XIAO H P , et al . Organoid models of gastrointestinal cancers in basic and translational research [J ] . Nat Rev Gastroenterol Hepatol , 2020 , 17 ( 4 ): 203 - 222 . DOI: 10.1038/s41575-019-0255-2 http://doi.org/10.1038/s41575-019-0255-2

Models for immuno-oncology research [J ] . Cancer Cell , 2020 , 38 ( 2 ): 145 - 147 . DOI: S1535-6108(20)30371-8 http://doi.org/S1535-6108(20)30371-8

SMOLAR J , HORST M , SALEMI S , et al . Predifferentiated smooth muscle-like adipose-derived stem cells for bladder engineering [J ] . Tissue Eng Part A , 2020 , 26 ( 17/18 ): 979 - 992 . DOI: 10.1089/ten.tea.2019.0216 http://doi.org/10.1089/ten.tea.2019.0216 https://www.liebertpub.com/doi/10.1089/ten.tea.2019.0216 https://www.liebertpub.com/doi/10.1089/ten.tea.2019.0216

YUKI K , CHENG N , NAKANO M , et al . Organoid models of tumor immunology [J ] . Trends Immunol , 2020 , 41 ( 8 ): 652 - 664 . DOI: S1471-4906(20)30134-4 http://doi.org/S1471-4906(20)30134-4

HOFER M , LUTOLF M P . Engineering organoids [J ] . Nat Rev Mater , 2021 , 6 ( 5 ): 402 - 420 . DOI: 10.1038/s41578-021-00279-y http://doi.org/10.1038/s41578-021-00279-y

SAHIN U . Studying tumor-reactive T cells: a personalized organoid model [J ] . Cell Stem Cell , 2018 , 23 ( 3 ): 318 - 319 . DOI: S1934-5909(18)30400-4 http://doi.org/S1934-5909(18)30400-4

CHAKRABARTI J , KOH V , SO J , et al . A preclinical human-derived autologous gastric cancer organoid/immune cell co-culture model to predict the efficacy of targeted therapies [J ] . J Vis Exp , 2021 , ( 173 ).

HOLOKAI L , CHAKRABARTI J , LUNDY J , et al . Murine- and human-derived autologous organoid/immune cell co-cultures as pre-clinical models of pancreatic ductal adenocarcinoma [J ] . Cancers , 2020 , 12 ( 12 ): 3816 . DOI: 10.3390/cancers12123816 http://doi.org/10.3390/cancers12123816 https://www.mdpi.com/2072-6694/12/12/3816 https://www.mdpi.com/2072-6694/12/12/3816

CHAKRABARTI J , HOLOKAI L , SYU L , et al . Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer [J ] . Oncotarget , 2018 , 9 ( 100 ): 37439 - 37457 . DOI: 10.18632/oncotarget.26473 http://doi.org/10.18632/oncotarget.26473

TEIJEIRA A , MIGUELIZ I , GARASA S , et al . Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagers [J ] . Theranostics , 2022 , 12 ( 3 ): 1373 - 1387 . DOI: 10.7150/thno.63359 http://doi.org/10.7150/thno.63359

OU L L , WANG H S , LIU Q , et al . Dichotomous and stable gamma delta T-cell number and function in healthy individuals [J ] . J Immunother Cancer , 2021 , 9 ( 5 ): e002274.

FERREIRA R O , GRANHA I , FERREIRA R S , et al . Effect of serial systemic and intratumoral injections of oncolytic ZIKV BR in mice bearing embryonal CNS tumors [J ] . Viruses , 2021 , 13 ( 10 ): 2103 . DOI: 10.3390/v13102103 http://doi.org/10.3390/v13102103 https://www.mdpi.com/1999-4915/13/10/2103 https://www.mdpi.com/1999-4915/13/10/2103

HUANG L X , RONG Y , TANG X , et al . Engineered exosomes as an in situ DC-primed vaccine to boost antitumor immunity in breast cancer [J ] . Mol Cancer , 2022 , 21 ( 1 ): 45 . DOI: 10.1186/s12943-022-01515-x http://doi.org/10.1186/s12943-022-01515-x

WHELAN K A , MUIR A B , NAKAGAWA H . Esophageal 3D culture systems as modeling tools in esophageal epithelial pathobiology and personalized medicine [J ] . Cell Mol Gastroenterol Hepatol , 2018 , 5 ( 4 ): 461 - 478 . DOI: 10.1016/j.jcmgh.2018.01.011 http://doi.org/10.1016/j.jcmgh.2018.01.011

PATNAUDE L , MAYO M , MARIO R , et al . Mechanisms and regulation of IL-22-mediated intestinal epithelial homeostasis and repair [J ] . Life Sci , 2021 , 271 : 119195.

SCHREURS R R C E , BAUMDICK M E , SAGEBIEL A F , et al . Human fetal TNF-α-cytokine-producing CD4 + effector memory T cells promote intestinal development and mediate inflammation early in life [J ] . Immunity , 2019 , 50 ( 2 ): 462 - 476 .e8. DOI: 10.1016/j.immuni.2018.12.010 http://doi.org/10.1016/j.immuni.2018.12.010 https://linkinghub.elsevier.com/retrieve/pii/S1074761318305363 https://linkinghub.elsevier.com/retrieve/pii/S1074761318305363

GRETEN F R , GRIVENNIKOV S I . Inflammation and cancer: triggers, mechanisms, and consequences [J ] . Immunity , 2019 , 51 ( 1 ): 27 - 41 . DOI: S1074-7613(19)30295-X http://doi.org/S1074-7613(19)30295-X

JOWETT G M , NORMAN M D A , YU T T L , et al . ILC1 drive intestinal epithelial and matrix remodelling [J ] . Nat Mater , 2021 , 20 ( 2 ): 250 - 259 . DOI: 10.1038/s41563-020-0783-8 http://doi.org/10.1038/s41563-020-0783-8

YE W R , LUO C , LI C L , et al . Organoids to study immune functions, immunological diseases and immunotherapy [J ] . Cancer Lett , 2020 , 477 : 31 - 40 . DOI: S0304-3835(20)30096-3 http://doi.org/S0304-3835(20)30096-3

XIANG Z , ZHOU Z J , SONG S Z , et al . Dexamethasone suppresses immune evasion by inducing GR/STAT3 mediated downregulation of PD-L1 and IDO1 pathways [J ] . Oncogene , 2021 , 40 ( 31 ): 5002 - 5012 . DOI: 10.1038/s41388-021-01897-0 http://doi.org/10.1038/s41388-021-01897-0

CATTANEO C M , DIJKSTRA K K , FANCHI L F , et al . Tumor organoid-T-cell coculture systems [J ] . Nat Protoc , 2020 , 15 ( 1 ): 15 - 39 . DOI: 10.1038/s41596-019-0232-9 http://doi.org/10.1038/s41596-019-0232-9

BAR-EPHRAIM Y E , KRETZSCHMAR K , CLEVERS H . Organoids in immunological research [J ] . Nat Rev Immunol , 2020 , 20 ( 5 ): 279 - 293 . DOI: 10.1038/s41577-019-0248-y http://doi.org/10.1038/s41577-019-0248-y

CHERNE M D , SIDAR B , SEBRELL T A , et al . A synthetic hydrogel, VitroGel ® ORGANOID-3, improves immune cell-epithelial interactions in a tissue chip co-culture model of human gastric organoids and dendritic cells [J ] . Front Pharmacol , 2021 , 12 : 707891.

MORIKAWA R , NEMOTO Y , YONEMOTO Y , et al . Intraepithelial lymphocytes suppress intestinal tumor growth by cell-to-cell contact via CD103/E-cadherin signal [J ] . Cell Mol Gastroenterol Hepatol , 2021 , 11 ( 5 ): 1483 - 1503 . DOI: 10.1016/j.jcmgh.2021.01.014 http://doi.org/10.1016/j.jcmgh.2021.01.014

DAVIDSON S , COLES M , THOMAS T , et al . Fibroblasts as immune regulators in infection, inflammation and cancer [J ] . Nat Rev Immunol , 2021 , 21 ( 11 ): 704 - 717 . DOI: 10.1038/s41577-021-00540-z http://doi.org/10.1038/s41577-021-00540-z

SAHAI E , ASTSATUROV I , CUKIERMAN E , et al . A framework for advancing our understanding of cancer-associated fibroblasts [J ] . Nat Rev Cancer , 2020 , 20 ( 3 ): 174 - 186 . DOI: 10.1038/s41568-019-0238-1 http://doi.org/10.1038/s41568-019-0238-1

SAINI H , NIKKHAH M . Fabrication method of a high-density co-culture tumor-stroma platform to study cancer progression [J ] . Methods Mol Biol , 2021 , 2258 : 241 - 255 . DOI: 10.1007/978-1-0716-1174-6_16 http://doi.org/10.1007/978-1-0716-1174-6_16

JANG I , BENINGO K A . Integrins, CAFs and mechanical forces in the progression of cancer [J ] . Cancers , 2019 , 11 ( 5 ): 721 . DOI: 10.3390/cancers11050721 http://doi.org/10.3390/cancers11050721 https://www.mdpi.com/2072-6694/11/5/721 https://www.mdpi.com/2072-6694/11/5/721

NARUSE M , OCHIAI M , SEKINE S , et al . Re-expression of REG family and DUOXs genes in CRC organoids by co-culturing with CAFs [J ] . Sci Rep , 2021 , 11 ( 1 ): 2077 . DOI: 10.1038/s41598-021-81475-2 http://doi.org/10.1038/s41598-021-81475-2

LUO X B , FONG E L S , ZHU C J , et al . Hydrogel-based colorectal cancer organoid co-culture models [J ] . Acta Biomater , 2021 , 132 : 461 - 472 . DOI: 10.1016/j.actbio.2020.12.037 http://doi.org/10.1016/j.actbio.2020.12.037

LIU J Y , LI P F , WANG L , et al . Cancer-associated fibroblasts provide a stromal niche for liver cancer organoids that confers trophic effects and therapy resistance [J ] . Cell Mol Gastroenterol Hepatol , 2021 , 11 ( 2 ): 407 - 431 . DOI: 10.1016/j.jcmgh.2020.09.003 http://doi.org/10.1016/j.jcmgh.2020.09.003

DAWSON J C , SERRELS A , STUPACK D G , et al . Targeting FAK in anticancer combination therapies [J ] . Nat Rev Cancer , 2021 , 21 ( 5 ): 313 - 324 . DOI: 10.1038/s41568-021-00340-6 http://doi.org/10.1038/s41568-021-00340-6

CHEN X , LI R , ZHAO H , et al . Phenotype transition of fibroblasts incorporated into patient-derived oral carcinoma organoids [J ] . Oral Dis , 2021 : 2021Nov5.

MIURA A , YAMADA D , NAKAMURA M , et al . Oncogenic potential of human pluripotent stem cell-derived lung organoids with HER2 overexpression [J ] . Int J Cancer , 2021 , 149 ( 8 ): 1593 - 1604 . DOI: 10.1002/ijc.33713 http://doi.org/10.1002/ijc.33713

CHEN H , DU L , LI J , et al . Modeling cancer metastasis using acoustically bio-printed patient-derived 3D tumor microtissues [J ] . J Mater Chem B , 2022 , 10 ( 11 ): 1843 - 1852 . DOI: 10.1039/D1TB02789A http://doi.org/10.1039/D1TB02789A http://xlink.rsc.org/?DOI=D1TB02789A http://xlink.rsc.org/?DOI=D1TB02789A

SHINKAWA T , OHUCHIDA K , MOCHIDA Y , et al . Subtypes in pancreatic ductal adenocarcinoma based on niche factor dependency show distinct drug treatment responses [J ] . J Exp Clin Cancer Res , 2022 , 41 ( 1 ): 89 . DOI: 10.1186/s13046-022-02301-9 http://doi.org/10.1186/s13046-022-02301-9

CHENG Q S , JABBARI K , WINKELMAIER G , et al . Overexpression of CD36 in mammary fibroblasts suppresses colony growth in breast cancer cell lines [J ] . Biochem Biophys Res Commun , 2020 , 526 ( 1 ): 41 - 47 . DOI: 10.1016/j.bbrc.2020.03.061 http://doi.org/10.1016/j.bbrc.2020.03.061 https://linkinghub.elsevier.com/retrieve/pii/S0006291X20305465 https://linkinghub.elsevier.com/retrieve/pii/S0006291X20305465

FIORINI E , VEGHINI L , CORBO V . Modeling cell communication in cancer with organoids: making the complex simple [J ] . Front Cell Dev Biol , 2020 , 8 : 166 . DOI: 10.3389/fcell.2020.00166 http://doi.org/10.3389/fcell.2020.00166

FELDMANN K , MAURER C , PESCHKE K , et al . Mesenchymal plasticity regulated by Prrx1 drives aggressive pancreatic cancer biology [J ] . Gastroenterology , 2021 , 160 ( 1 ): 346 - 361 .e24. DOI: 10.1053/j.gastro.2020.09.010 http://doi.org/10.1053/j.gastro.2020.09.010

CHEN X M , SONG E W . Turning foes to friends: targeting cancer-associated fibroblasts [J ] . Nat Rev Drug Discov , 2019 , 18 ( 2 ): 99 - 115 . DOI: 10.1038/s41573-018-0004-1 http://doi.org/10.1038/s41573-018-0004-1

DI DONATO M , ZAMAGNI A , GALASSO G , et al . The androgen receptor/filamin A complex as a target in prostate cancer microenvironment [J ] . Cell Death Dis , 2021 , 12 ( 1 ): 127 . DOI: 10.1038/s41419-021-03402-7 http://doi.org/10.1038/s41419-021-03402-7

NAKAMURA H , SUGANO M , MIYASHITA T , et al . Organoid culture containing cancer cells and stromal cells reveals that podoplanin-positive cancer-associated fibroblasts enhance proliferation of lung cancer cells [J ] . Lung Cancer , 2019 , 134 : 100 - 107 . DOI: S0169-5002(19)30394-0 http://doi.org/S0169-5002(19)30394-0

JORGENSEN M , RAMESH P , TORO M , et al . Alginate hydrogel microtubes for salivary gland cell organization and cavitation [J ] . Bioengineering (Basel) , 2022 , 9 ( 1 ): 38 .

YANG H , FENG R , FU Q , et al . Human induced pluripotent stem cell-derived mesenchymal stem cells promote healing via TNF-α-stimulated gene-6 in inflammatory bowel disease models [J ] . Cell Death Dis , 2019 , 10 ( 10 ): 718 . DOI: 10.1038/s41419-019-1957-7 http://doi.org/10.1038/s41419-019-1957-7

MOUSSA L , LAPIÈRE A , SQUIBAN C , et al . BMP antagonists secreted by mesenchymal stromal cells improve colonic organoid formation: application for the treatment of radiation-induced injury [J ] . Cell Transplant , 2020 , 29 : 963689720929683.

CORDERO-ESPINOZA L , DOWBAJ A M , KOHLER T N , et al . Dynamic cell contacts between periportal mesenchyme and ductal epithelium act as a rheostat for liver cell proliferation [J ] . Cell Stem Cell , 2021 , 28 ( 11 ): 1907 - 1921.e8 . DOI: 10.1016/j.stem.2021.07.002 http://doi.org/10.1016/j.stem.2021.07.002 https://linkinghub.elsevier.com/retrieve/pii/S1934590921002873 https://linkinghub.elsevier.com/retrieve/pii/S1934590921002873

TANAKA C , FURIHATA K , NAGANUMA S , et al . Establishment of a mouse model of pancreatic cancer using human pancreatic cancer cell line S2-013-derived organoid [J ] . Hum Cell , 2022 , 35 ( 2 ): 735 - 744 . DOI: 10.1007/s13577-022-00684-7 http://doi.org/10.1007/s13577-022-00684-7

ADELSON R P , PALIKUQI B , WEISS Z , et al . Morphological characterization of Etv2 vascular explants using fractal analysis and atomic force microscopy [J ] . Microvasc Res , 2021 , 138 : 104205.

PALIKUQI B , NGUYEN D H T , LI G , et al . Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis [J ] . Nature , 2020 , 585 ( 7825 ): 426 - 432 . DOI: 10.1038/s41586-020-2712-z http://doi.org/10.1038/s41586-020-2712-z

SALMON I , GREBENYUK S , ABDEL FATTAH A R , et al . Engineering neurovascular organoids with 3D printed microfluidic chips [J ] . Lab Chip , 2022 , 22 ( 8 ): 1615 - 1629 . DOI: 10.1039/D1LC00535A http://doi.org/10.1039/D1LC00535A http://xlink.rsc.org/?DOI=D1LC00535A http://xlink.rsc.org/?DOI=D1LC00535A

AHN Y , AN J H , YANG H J , et al . Human blood vessel organoids penetrate human cerebral organoids and form a vessel-like system [J ] . Cells , 2021 , 10 ( 8 ): 2036 . DOI: 10.3390/cells10082036 http://doi.org/10.3390/cells10082036 https://www.mdpi.com/2073-4409/10/8/2036 https://www.mdpi.com/2073-4409/10/8/2036

PRADHAN S , WEISS A A . Probiotic properties of escherichia coli nissle in human intestinal organoids [J ] . mBio , 2020 , 11 ( 4 ): e01470-e01420.

PUSCHHOF J , PLEGUEZUELOS-MANZANO C , CLEVERS H . Organoids and organs-on-chips: Insights into human gut-microbe interactions [J ] . Cell Host Microbe , 2021 , 29 ( 6 ): 867 - 878 . DOI: 10.1016/j.chom.2021.04.002 http://doi.org/10.1016/j.chom.2021.04.002

NAKAMOTO N , SASAKI N , AOKI R , et al . Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis [J ] . Nat Microbiol , 2019 , 4 ( 3 ): 492 - 503 . DOI: 10.1038/s41564-018-0333-1 http://doi.org/10.1038/s41564-018-0333-1

NATARAJAN V , SIMONEAU C R , ERICKSON A L , et al . Modelling T-cell immunity against hepatitis C virus with liver organoids in a microfluidic coculture system [J ] . Open Biol , 2022 , 12 ( 3 ): 210320.

LEE D , KIM Y , CHUNG C . Scientific validation and clinical application of lung cancer organoids [J ] . Cells , 2021 , 10 ( 11 ): 3012 . DOI: 10.3390/cells10113012 http://doi.org/10.3390/cells10113012 https://www.mdpi.com/2073-4409/10/11/3012 https://www.mdpi.com/2073-4409/10/11/3012

HAN Y L , DUAN X H , YANG L L , et al . Identification of SARS-CoV-2 inhibitors using lung and colonic organoids [J ] . Nature , 2021 , 589 ( 7841 ): 270 - 275 . DOI: 10.1038/s41586-020-2901-9 http://doi.org/10.1038/s41586-020-2901-9

HUANG J , HUME A J , ABO K M , et al . SARS-CoV-2 infection of pluripotent stem cell-derived human lung alveolar type 2 cells elicits a rapid epithelial-intrinsic inflammatory response [J ] . Cell Stem Cell , 2020 , 27 ( 6 ): 962 - 973.e7 . DOI: 10.1016/j.stem.2020.09.013 http://doi.org/10.1016/j.stem.2020.09.013

SHEK D , CHEN D S , READ S A , et al . Examining the gut-liver axis in liver cancer using organoid models [J ] . Cancer Lett , 2021 , 510 : 48 - 58 . DOI: 10.1016/j.canlet.2021.04.008 http://doi.org/10.1016/j.canlet.2021.04.008

HOLOKAI L , CHAKRABARTI J , BRODA T , et al . Increased programmed death-ligand 1 is an early epithelial cell response to helicobacter pylori infection [J ] . PLoS Pathog , 2019 , 15 ( 1 ): e1007468.

SAYED I M , SAHAN A Z , VENKOVA T , et al . Helicobacter pylori infection downregulates the DNA glycosylase NEIL2, resulting in increased genome damage and inflammation in gastric epithelial cells [J ] . J Biol Chem , 2020 , 295 ( 32 ): 11082 - 11098 . DOI: 10.1074/jbc.RA119.009981 http://doi.org/10.1074/jbc.RA119.009981

XU R , ZHOU X T , WANG S K , et al . Tumor organoid models in precision medicine and investigating cancer-stromal interactions [J ] . Pharmacol Ther , 2021 , 218 : 107668.

浏览量

5157

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

肿瘤类器官研究现状与展望

类器官在肿瘤转化医学中的应用和进展

食管鳞癌肿瘤微环境相关研究进展