Defense of COVID-19 by Human Organoids

Springer Science and Business Media LLC - Tập 1 - Trang 113-128 - 2021
Ting Lv1,2, Fanlu Meng3, Meng Yu1, Haihui Huang2, Xinhua Lin1, Bing Zhao1
1State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China
2Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China
3Shandong Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University, Dezhou, China

Tóm tắt

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has created an immense menace to public health worldwide, exerting huge effects on global economic and political conditions. Understanding the biology and pathogenesis mechanisms of this novel virus, in large parts, relies on optimal physiological models that allow replication and propagation of SARS-CoV-2. Human organoids, derived from stem cells, are three-dimensional cell cultures that recapitulate the cellular organization, transcriptional and epigenetic signatures of their counterpart organs. Recent studies have indicated their great values as experimental virology platforms, making human organoid an ideal tool for investigating host–pathogen interactions. Here, we summarize research developments for SARS-CoV-2 infection of various human organoids involved in multiple systems, including lung, liver, brain, intestine, kidney and blood vessel organoids. These studies help us reveal the pathogenesis mechanism of COVID-19, and facilitate the development of effective vaccines and drugs as well as other therapeutic regimes.

Tài liệu tham khảo

Aurora M, Spence JR (2016) hPSC-derived lung and intestinal organoids as models of human fetal tissue. Dev Biol 420(2):230–238. https://doi.org/10.1016/j.ydbio.2016.06.006 Bagley JA, Reumann D, Bian S, Levi-Strauss J, Knoblich JA (2017) Fused cerebral organoids model interactions between brain regions. Nat Methods 14(7):743–751. https://doi.org/10.1038/nmeth.4304 Bao L, Deng W, Huang B, Gao H, Liu J, Ren L et al (2020) The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature 583(7818):830–833. https://doi.org/10.1038/s41586-020-2312-y Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR, Stripp BR et al (2013) Type 2 alveolar cells are stem cells in adult lung. J Clin Invest 123(7):3025–3036. https://doi.org/10.1172/JCI68782 Barkauskas CE, Chung MI, Fioret B, Gao X, Katsura H, Hogan BL (2017) Lung organoids: current uses and future promise. Development 144(6):986–997. https://doi.org/10.1242/dev.140103 Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH et al (2010) Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6(1):25–36. https://doi.org/10.1016/j.stem.2009.11.013 Birey F, Andersen J, Makinson CD, Islam S, Wei W, Huber N et al (2017) Assembly of functionally integrated human forebrain spheroids. Nature 545(7652):54–59. https://doi.org/10.1038/nature22330 Bozzo CP, Nchioua R, Volcic M, Krüger J, Heller S, Stürzel CM et al (2020) IFITM proteins promote SARS-CoV-2 infection of human lung cells. bioRxiv. https://doi.org/10.1101/2020.08.18.255935 Bullen CK, Hogberg HT, Bahadirli-Talbott A, Bishai WR, Hartung T, Keuthan C et al (2020) Infectability of human BrainSphere neurons suggests neurotropism of SARS-CoV-2. Altex 37(4):665–671. https://doi.org/10.14573/altex.2006111 Burgueno JF, Reich A, Hazime H, Quintero MA, Fernandez I, Fritsch J et al (2020) Expression of SARS-CoV-2 entry molecules ACE2 and TMPRSS2 in the gut of patients with IBD. Inflamm Bowel Dis 26(6):797–808. https://doi.org/10.1093/ibd/izaa085 Butler CR, Hynds RE, Gowers KH, Lee Ddo H, Brown JM, Crowley C et al (2016) Rapid expansion of human epithelial stem cells suitable for airway tissue engineering. Am J Respir Crit Care Med 194(2):156–168. https://doi.org/10.1164/rccm.201507-1414OC Chekani-Azar S, Gharib Mombeni E, Birhan M (2020) CRISPR/Cas9 gene editing technology and its application to the coronavirus disease (COVID-19), a review. J World’s Poult Res 10(1):01–09. https://doi.org/10.36380/scil.2020.jlsb1 Chen YW, Huang SX, de Carvalho A, Ho SH, Islam MN, Volpi S et al (2017) A three-dimensional model of human lung development and disease from pluripotent stem cells. Nat Cell Biol 19(5):542–549. https://doi.org/10.1038/ncb3510 Claude-Rosny E (2020) COVID-19 therapy and prevention. Discoveries (craiova) 8(3):e113. https://doi.org/10.15190/d.2020.10 Colmenero I, Santonja C, Alonso-Riano M, Noguera-Morel L, Hernandez-Martin A, Andina D et al (2020) SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases. Br J Dermatol 183(4):729–737. https://doi.org/10.1111/bjd.19327 Dai W, Xu X, Leng Z, Yu W, Lin H, Li H, Lin J, Qiu Z, Dai Y (2020) Clinical characteristics of asymptomatic patients with SARS-CoV-2 in zhejiang an imperceptible source of infection. Can Respir J. https://doi.org/10.1155/2020/2045341 Dedhia PH, Bertaux-Skeirik N, Zavros Y, Spence JR (2016) Organoid models of human gastrointestinal development and disease. Gastroenterology 150(5):1098–1112. https://doi.org/10.1053/j.gastro.2015.12.042 Duan X, Han Y, Yang L, Nilsson-Payant BE, Wang P, Zhang T et al (2020) Identification of drugs blocking SARS-CoV-2 infection using human pluripotent stem cell-derived colonic organoids. bioRxiv. https://doi.org/10.1101/2020.05.02.073320 Dutta D, Heo I, Clevers H (2017) Disease modeling in stem cell-derived 3D organoid systems. Trends Mol Med 23(5):393–410. https://doi.org/10.1016/j.molmed.2017.02.007 Eiraku M, Takata N, Ishibashi H, Kawada M, Sakakura E, Okuda S et al (2011) Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472(7341):51–56. https://doi.org/10.1038/nature09941 Fan Z, Chen L, Li J, Cheng X, Yang J, Tian C et al (2020) Clinical features of COVID-19-related liver functional abnormality. Clin Gastroenterol Hepatol 18(7):1561–1566. https://doi.org/10.1016/j.cgh.2020.04.002 Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R, Agrawal V et al (2015) Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat Commun 6:8715. https://doi.org/10.1038/ncomms9715 Gao J, Zhang S, Zhou K, Zhao X, Liu J, Pu Z (2020) Epidemiological and clinical characteristics of patients with COVID-19 from a designated hospital in Hangzhou City: a retrospective observational study. Hong Kong Med J. https://doi.org/10.12809/hkmj208693 Germain ND, Banda EC, Becker S, Naegele JR, Grabel LB (2013) Derivation and isolation of NKX2.1-positive basal forebrain progenitors from human embryonic stem cells. Stem Cells Dev 22(10):1477–1489. https://doi.org/10.1089/scd.2012.0264 Geurts MH, van der Vaart J, Beumer J, Clevers H (2021) The organoid platform: promises and challenges as tools in the fight against COVID-19. Stem Cell Rep 16(3):412–418. https://doi.org/10.1016/j.stemcr.2020.11.009 Gonzalez RF, Allen L, Gonzales L, Ballard PL, Dobbs LG (2010) HTII-280, a biomarker specific to the apical plasma membrane of human lung alveolar type II cells. J Histochem Cytochem 58(10):891–901. https://doi.org/10.1369/jhc.2010.956433 Grassi L, Alfonsi R, Francescangeli F, Signore M, De Angelis ML, Addario A et al (2019) Organoids as a new model for improving regenerative medicine and cancer personalized therapy in renal diseases. Cell Death Dis 10(3):201. https://doi.org/10.1038/s41419-019-1453-0 Han Y, Duan X, Yang L, Nilsson-Payant BE, Wang P, Duan F et al (2021) Identification of SARS-CoV-2 inhibitors using lung and colonic organoids. Nature 589(7841):270–275. https://doi.org/10.1038/s41586-020-2901-9 Hofer M, Lutolf MP (2021) Engineering organoids. Nat Rev Mater. https://doi.org/10.1038/s41578-021-00279-y Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S et al (2020) SARS-CoV-2 Cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181(2):271-280e8. https://doi.org/10.1016/j.cell.2020.02.052 Hou YJ, Okuda K, Edwards CE, Martinez DR, Asakura T, Dinnon KH 3rd et al (2020) SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract. Cell 182(2):429-446e14. https://doi.org/10.1016/j.cell.2020.05.042 Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y et al (2020a) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395(10223):497–506. https://doi.org/10.1016/s0140-6736(20)30183-5 Huang J, Hume AJ, Abo KM, Werder RB, Villacorta-Martin C, Alysandratos KD et al (2020b) SARS-CoV-2 infection of pluripotent stem cell-derived human lung alveolar type 2 cells elicits a rapid epithelial-intrinsic inflammatory response. Cell Stem Cell 27(6):962–973. https://doi.org/10.1016/j.stem.2020.09.013 Huang KY, Lin MS, Kuo TC, Chen CL, Lin CC, Chou YC et al (2021) Humanized COVID-19 decoy antibody effectively blocks viral entry and prevents SARS-CoV-2 infection. EMBO Mol Med 13(1):e12828. https://doi.org/10.15252/emmm.202012828 Huch M, Dorrell C, Boj SF, van Es JH, Li VS, van de Wetering M et al (2013) In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494(7436):247–250. https://doi.org/10.1038/nature11826 Huch M, Gehart H, van Boxtel R, Hamer K, Blokzijl F, Verstegen MM et al (2015) Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160(1–2):299–312. https://doi.org/10.1016/j.cell.2014.11.050 Jacob F, Pather SR, Huang WK, Zhang F, Wong SZH, Zhou H et al (2020) Human pluripotent stem cell-derived neural cells and brain organoids reveal SARS-CoV-2 neurotropism predominates in choroid plexus epithelium. Cell Stem Cell 27(6):937-950e9. https://doi.org/10.1016/j.stem.2020.09.016 Jo J, Xiao Y, Sun AX, Cukuroglu E, Tran HD, Goke J et al (2016) Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell 19(2):248–257. https://doi.org/10.1016/j.stem.2016.07.005 Johansen MD, Irving A, Montagutelli X, Tate MD, Rudloff I, Nold MF et al (2020) Animal and translational models of SARS-CoV-2 infection and COVID-19. Mucosal Immunol 13(6):877–891. https://doi.org/10.1038/s41385-020-00340-z.PubMedPMID:32820248;PubMedCentralPMCID:PMCPMC7439637 Kadoshima T, Sakaguchi H, Nakano T, Soen M, Ando S, Eiraku M et al (2013) Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci USA 110(50):20284–20289. https://doi.org/10.1073/pnas.1315710110 Katsura H, Sontake V, Tata A, Kobayashi Y, Edwards CE, Heaton BE et al (2020) Human lung stem cell-based alveolospheres provide insights into SARS-CoV-2-mediated interferon responses and pneumocyte dysfunction. Cell Stem Cell 27(6):890–904. https://doi.org/10.1016/j.stem.2020.10.005 Kim H, Park HJ, Choi H, Chang Y, Park H, Shin J et al (2019) Modeling G2019S-LRRK2 saporadic Parkinson’s disease in 3D midbrain organoids. Stem Cell Rep 12(3):518–531. https://doi.org/10.1016/j.stemcr.2019.01.020 Kim HK, Kim H, Lee MK, Choi WH, Jang Y, Shin JS et al (2020b) Generation of tonsil organoids as an ex vivo model for SARS-CoV-2 infection. bioRxiv. https://doi.org/10.1101/2020.08.06.239574 Kim J, Koo BK, Knoblich JA (2020a) Human organoids: model systems for human biology and medicine. Nat Rev Mol Cell Biol 21(10):571–584. https://doi.org/10.1038/s41580-020-0259-3 Kipkorir V, Cheruiyot I, Ngure B, Misiani M, Munguti J (2020) Prolonged SARS-CoV-2 RNA detection in anal/rectal swabs and stool specimens in COVID-19 patients after negative conversion in nasopharyngeal RT-PCR test. J Med Virol 92(11):2328–2331. https://doi.org/10.1002/jmv.26007 Kruger J, Gross R, Conzelmann C, Muller JA, Koepke L, Sparrer KMJ et al (2020) Drug Inhibition of SARS-CoV-2 Replication in Human Pluripotent Stem Cell-Derived Intestinal Organoids. Cell Mol Gastroenterol Hepatol 11(4):935–948. https://doi.org/10.1016/j.jcmgh.2020.11.003 Lamers M, JoepJelte BV, Kelvin K, Jens P et al (2020) SARS-CoV-2 productively infects human gut enterocytes. Science 369(6499):50–54. https://doi.org/10.1126/science.abc1669 Lamers MM, van der Vaart J, Knoops K, Riesebosch S, Breugem TI, Mykytyn AZ et al (2021) An organoid-derived bronchioalveolar model for SARS-CoV-2 infection of human alveolar type II-like cells. EMBO J 40(5):e105912. https://doi.org/10.15252/embj.2020105912 Lancaster MA, Knoblich JA (2014) Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc 9(10):2329–2340. https://doi.org/10.1038/nprot.2014.158 Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME et al (2013) Cerebral organoids model human brain development and microcephaly. Nature 501(7467):373–379. https://doi.org/10.1038/nature12517 Li F, Han M, Dai P, Xu W, He J, Tao X et al (2020) Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide. bioRxiv. https://doi.org/10.1101/2020.09.11.293035 Ling XC, Kang EY, Lin JY, Chen HC, Lai CC, Ma DH et al (2020) Ocular manifestation, comorbidities, and detection of severe acute respiratory syndrome-coronavirus 2 from conjunctiva in coronavirus disease 2019: a systematic review and meta-analysis. Taiwan J Ophthalmol 10(3):153–166. https://doi.org/10.4103/tjo.tjo_53_20 Little MH, McMahon AP (2012) Mammalian kidney development: principles, progress, and projections. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a008300 Liu Y, Liu H, Sauvey C, Yao L, Zarnowska ED, Zhang SC (2013) Directed differentiation of forebrain GABA interneurons from human pluripotent stem cells. Nat Protoc 8(9):1670–1679. https://doi.org/10.1038/nprot.2013.106 Lopez-Robles J, de la Hera I, Pardo-Sanchez J, Ruiz-Martinez J, Cutillas-Marco E (2020) Chilblain-like lesions: a case series of 41 patients during the COVID-19 pandemic. Clin Exp Dermatol 45(7):891–892. https://doi.org/10.1111/ced.14275 Lu R, Zhao X, Li J, Niu P, Yang B, Wu H et al (2020) Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 395(10224):565–574. https://doi.org/10.1016/s0140-6736(20)30251-8 Luo S, Zhang X, Xu H (2020) Don’t overlook digestive symptoms in patients with 2019 novel coronavirus disease (COVID-19). Clin Gastroenterol Hepatol 18(7):1636–1637. https://doi.org/10.1016/j.cgh.2020.03.043 Mae SI, Shono A, Shiota F, Yasuno T, Kajiwara M, Gotoda-Nishimura N et al (2013) Monitoring and robust induction of nephrogenic intermediate mesoderm from human pluripotent stem cells. Nat Commun 4:1367. https://doi.org/10.1038/ncomms2378 Mahalingam R, Dharmalingam P, Santhanam A, Kotla S, Davuluri G, Karmouty-Quintana H et al (2021) Single-cell RNA sequencing analysis of SARS-CoV-2 entry receptors in human organoids. J Cell Physiol 236(4):2950–2958. https://doi.org/10.1002/jcp.30054 Makovoz B, Rasmus M, Eriksen AZ, tenOever BR, Blenkinsop TA (2020) SARS-CoV-2 infection of ocular cells from human adult donor eyes and hESC-derived eye organoids. SSRN. https://doi.org/10.2139/ssrn.3650574 MaL L, Michael H, Hess CP (2020) More on neurologic features in severe SARS-CoV-2 infection. New Engl J Med. https://doi.org/10.1056/NEJMc2015132 Mao L, Jin H, Wang M, Hu Y, Chen S, He Q et al (2020) Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan,China. JAMA Neurol 77(6):683–690. https://doi.org/10.1001/jamaneurol.2020.1127 Mariani J, Coppola G, Zhang P, Abyzov A, Provini L, Tomasini L et al (2015) FOXG1-dependent dysregulation of GABA/Glutamate neuron differentiation in autism spectrum disorders. Cell 162(2):375–390. https://doi.org/10.1016/j.cell.2015.06.034 McQualter JL, Yuen K, Williams B, Bertoncello I (2010) Evidence of an epithelial stem/progenitor cell hierarchy in the adult mouse lung. Proc Natl Acad Sci USA 107(4):1414–1419. https://doi.org/10.1073/pnas.0909207107 Melley LE, Bress E, Polan E (2020) Hypogeusia as the initial presenting symptom of COVID-19. BMJ Case Rep. https://doi.org/10.1136/bcr-2020-236080 Meng X, Lou QY, Yang WY, Chen R, Xu WH, Yang Y et al (2021) Gordian Knot: gastrointestinal lesions caused by three highly pathogenic coronaviruses from SARS-CoV and MERS-CoV to SARS-CoV-2. Eur J Pharmacol 890:173659. https://doi.org/10.1016/j.ejphar.2020.173659 Mesci P, Macia A, Saleh A, Martin-Sancho L, Yin X, Snethlage C et al (2020) Sofosbuvir protects human brain organoids against SARS-CoV-2. bioRxiv. https://doi.org/10.1101/2020.05.30.125856 Mich JK, Close JL, Levi BP (2017) Putting two heads together to build a better brain. Cell Stem Cell 21(3):289–290. https://doi.org/10.1016/j.stem.2017.08.017 Michels B, Mohammed H, Barbara I, Tian Z, Constantin M et al (2020) Pooled in vitro and in vivo CRISPR-Cas9 screening identifies tumor suppressors in human colon organoids. Cell Stem Cell 26(5):782–792. https://doi.org/10.1016/j.stem.2020.04.003 Miyajima A, Tanaka M, Itoh T (2014) Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell Stem Cell 14(5):561–574. https://doi.org/10.1016/j.stem.2014.04.010 Monteil V, Kwon H, Prado P, Hagelkruys A, Wimmer RA, Stahl M et al (2020) Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell 181(4):905-913e7. https://doi.org/10.1016/j.cell.2020.04.004 Monteil V, Dyczynski M, Lauschke VM, Kwon H, Wirnsberger G, Youhanna S et al (2021) Human soluble ACE2 improves the effect of remdesivir in SARS-CoV-2 infection. EMBO Mol Med 13(1):e13426. https://doi.org/10.15252/emmm.202013426 Morawska L, Cao J (2020) Airborne transmission of SARS-CoV-2: the world should face the reality. Environ Int 139:105730. https://doi.org/10.1016/j.envint.2020.105730 Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J et al (2020) A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis 94:55–58. https://doi.org/10.1016/j.ijid.2020.03.062 Morizane R, Bonventre JV (2017) Kidney organoids: a translational journey. Trends Mol Med 23(3):246–263. https://doi.org/10.1016/j.molmed.2017.01.001 Mou H, Vinarsky V, Tata PR, Brazauskas K, Choi SH, Crooke AK et al (2016) Dual SMAD signaling inhibition enables long-term expansion of diverse epithelial basal cells. Cell Stem Cell 19(2):217–231. https://doi.org/10.1016/j.stem.2016.05.012 Mulay A, Konda B, Garcia G, Yao C, Beil S, Sen C et al (2020) SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery. bioRxiv. https://doi.org/10.1101/2020.06.29.174623 Mykytyn AZ, Breugem TI, Riesebosch S, Schipper D, van den Doel PB, Rottier RJ et al (2020) The SARS-CoV-2 multibasic cleavage site facilitates early serine protease2 mediated entry into organoid-derived human airway cells. bioRxiv. https://doi.org/10.1101/2020.09.07.286120 Nakamura T, Sato T (2018) Advancing intestinal organoid technology toward regenerative medicine. Cell Mol Gastroenterol Hepatol 5(1):51–60. https://doi.org/10.1016/j.jcmgh.2017.10.006 Nakano T, Ando S, Takata N, Kawada M, Muguruma K, Sekiguchi K et al (2012) Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10(6):771–785. https://doi.org/10.1016/j.stem.2012.05.009 Nikolic MZ, Rawlins EL (2017) Lung organoids and their use to study cell-cell interaction. Curr Pathobiol Rep 5(2):223–231. https://doi.org/10.1007/s40139-017-0137-7 Norma F, Raul S (2020) Origin, structural characteristics, prevention measures, diagnosis and potential drugs to prevent and COVID-19. Medwave 20(8):e8037. https://doi.org/10.5867/medwave.2020.08.8037 Ochs M, Nyengaard JR, Jung A, Knudsen L, Voigt M, Wahlers T et al (2004) The number of alveoli in the human lung. Am J Respir Crit Care Med 169(1):120–124. https://doi.org/10.1164/rccm.200308-1107OC Ogawa M, Ogawa S, Bear CE, Ahmadi S, Chin S, Li B et al (2015) Directed differentiation of cholangiocytes from human pluripotent stem cells. Nat Biotechnol 33(8):853–861. https://doi.org/10.1038/nbt.3294 Pasca AM, Sloan SA, Clarke LE, Tian Y, Makinson CD, Huber N et al (2015) Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods 12(7):671–678. https://doi.org/10.1038/nmeth.3415 Pei R, Feng J, Zhang Y, Sun H, Li L, Yang X et al (2020) Host metabolism dysregulation and cell tropism identification in human airway and alveolar organoids upon SARS-CoV-2 infection. Protein Cell. https://doi.org/10.1007/s13238-020-00811-w Pellegrini L, Albecka A, Mallery DL, Kellner MJ, Paul D, Carter AP et al (2020) SARS-CoV-2 infects the brain choroid plexus and disrupts the blood-CSF barrier in human brain organoids. Cell Stem Cell 27(6):951-961e5. https://doi.org/10.1016/j.stem.2020.10.001 Qi F, Qian S, Zhang S, Zhang Z (2020) Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun 526(1):135–140. https://doi.org/10.1016/j.bbrc.2020.03.044 Qian X, Song H, Ming GL (2019) Brain organoids: advances, applications and challenges. Development. https://doi.org/10.1242/dev.166074 Ramani S, Crawford SE, Blutt SE, Estes MK (2018) Human organoid cultures: transformative new tools for human virus studies. Curr Opin Virol 29:79–86. https://doi.org/10.1016/j.coviro.2018.04.001 Ramani A, Muller L, Ostermann PN, Gabriel E, Abida-Islam P, Muller-Schiffmann A et al (2020) SARS-CoV-2 targets neurons of 3D human brain organoids. EMBO J 39(20):e106230. https://doi.org/10.15252/embj.2020106230 Randhawa GS, Soltysiak MPM, El Roz H, de Souza CPE, Hill KA, Kari L (2020) Machine learning using intrinsic genomic signatures for rapid classification of novel pathogens: COVID-19 case study. PLoS ONE 15(4):e0232391. https://doi.org/10.1371/journal.pone.0232391 Rawlins EL, Okubo T, Xue Y, Brass DM, Auten RL, Hasegawa H et al (2009) The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell 4(6):525–534. https://doi.org/10.1016/j.stem.2009.04.002 Ringel T, Frey N, Ringnalda F, Janjuha S, Cherkaoui S, Butz S et al (2020) Genome-scale CRISPR screening in human intestinal organoids identifies drivers of TGF-beta resistance. Cell Stem Cell 26(3):431-440e8. https://doi.org/10.1016/j.stem.2020.02.007 Rock JR, Onaitis MW, Rawlins EL, Lu Y, Clark CP, Xue Y et al (2009) Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc Natl Acad Sci USA 106(31):12771–12775. https://doi.org/10.1073/pnas.0906850106 Sachs N, Papaspyropoulos A, Zomer-van Ommen DD, Heo I, Bottinger L, Klay D et al (2019) Long-term expanding human airway organoids for disease modeling. EMBO J. https://doi.org/10.15252/embj.2018100300 Sakaguchi H, Kadoshima T, Soen M, Narii N, Ishida Y, Ohgushi M et al (2015) Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat Commun 6:8896. https://doi.org/10.1038/ncomms9896 Salahudeen AA, Choi SS, Rustagi A, Zhu J, de la OS, Flynn RA, et al (2020) Progenitor identification and SARS-CoV-2 infection in long-term human distal lung organoid cultures. bioRxiv. https://doi.org/10.1101/2020.07.27.212076 Sampaziotis F, de Brito MC, Madrigal P, Bertero A, Saeb-Parsy K, Soares FAC et al (2015) Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nat Biotechnol 33(8):845–852. https://doi.org/10.1038/nbt.3275 Sampaziotis F, Muraro D, Tysoe OC, Sawiak S, Beach TE, Godfrey EM, Upponi Sara S, Brevini T, Wesley BT, Garcia-Bernardo J et al (2021) Cholangiocyte organoids can repair bile ducts after transplantation in the human liver. Science 371(6531):839–846. https://doi.org/10.1126/science.aaz6964 Samuel RM, Majd H, Richter MN, Ghazizadeh Z, Zekavat SM, Navickas A et al (2020) Androgen signaling regulates SARS-CoV-2 receptor levels and is associated with severe COVID-19 symptoms in men. Cell Stem Cell 27(6):876-889e12. https://doi.org/10.1016/j.stem.2020.11.009 Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE et al (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459(7244):262–265. https://doi.org/10.1038/nature07935 Sato T, Stange DE, Ferrante M, Vries RG, Van Es JH, Van den Brink S et al (2011) Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 141(5):1762–1772. https://doi.org/10.1053/j.gastro.2011.07.050 Shi J, Wen Z, Zhong G, Yang H, Wang C, Huang B, Liu R, He X, Shuai L, Sun Z et al (2020) Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus-2. Science 368:1016–1020 Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S (2020) Neuroinvasion of SARS-CoV-2 in human and mouse brain. bioRxiv. https://doi.org/10.1101/2020.06.25.169946 Sperati C (2020) Coronavirus: kidney damage caused by COVID-19. Johns Hopkins University School of Medicine, Baltimore Stanifer ML, Kee C, Cortese M, Zumaran CM, Triana S, Mukenhirn M et al (2020) Critical role of type III interferon in controlling SARS-CoV-2 infection in human intestinal epithelial cells. Cell Rep 32(1):107863. https://doi.org/10.1016/j.celrep.2020.107863 Stelzner M, Helmrath M, Dunn JC, Henning SJ, Houchen CW, Kuo C et al (2012) A nomenclature for intestinal in vitro cultures. Am J Physiol Gastrointest Liver Physiol 302(12):G1359–G1363. https://doi.org/10.1152/ajpgi.00493.2011 Strikoudis A, Cieslak A, Loffredo L, Chen YW, Patel N, Saqi A et al (2019) Modeling of fibrotic lung disease using 3D organoids derived from human pluripotent stem cells. Cell Rep 27(12):3709-3723e5. https://doi.org/10.1016/j.celrep.2019.05.077 Tadokoro T, Wang Y, Barak LS, Bai Y, Randell SH, Hogan BL (2014) IL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells. Proc Natl Acad Sci USA 111(35):E3641–E3649. https://doi.org/10.1073/pnas.1409781111 Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ, Ferguson C et al (2015) Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526(7574):564–568. https://doi.org/10.1038/nature15695 Takayama K (2020) In vitro and animal models for SARS-CoV-2 research. Trends Pharmacol Sci 41(8):513–517 Takebe T, Sekine K, Enomura M, Koike H, Kimura M, Ogaeri T et al (2013) Vascularized and functional human liver from an PSC-derived organ bud transplant. Nature 499(7459):481–484. https://doi.org/10.1038/nature12271 Tata PR, Mou H, Pardo-Saganta A, Zhao R, Prabhu M, Law BM et al (2013) Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 503(7475):218–223. https://doi.org/10.1038/nature12777 Teisanu RM, Chen H, Matsumoto K, McQualter JL, Potts E, Foster WM et al (2011) Functional analysis of two distinct bronchiolar progenitors during lung injury and repair. Am J Respir Cell Mol Biol 44(6):794–803. https://doi.org/10.1165/rcmb.2010-0098OC Tindle C, Fuller M, Fonseca A, Taheri S, Ibeawuchi SR, Beutler N et al (2020) Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19. bbioRxiv. https://doi.org/10.1101/2020.10.17.344002 Tiwari SK, Wang S, Smith D, Carlin AF, Rana TM (2021) Revealing tissue-specific SARS-CoV-2 infection and host responses using human stem cell-derived lung and cerebral organoids. Stem Cell Rep 16(3):437–445. https://doi.org/10.1016/j.stemcr.2021.02.005 Tsujimoto H, Kasahara T, Sueta SI, Araoka T, Sakamoto S, Okada C et al (2020) A modular differentiation system maps multiple human kidney lineages from pluripotent stem cells. Cell Rep 31(1):107476. https://doi.org/10.1016/j.celrep.2020.03.040 Wang F, Wang H, Fan J, Zhang Y, Wang H, Zhao Q (2020c) Pancreatic injury patterns in patients with coronavirus disease 19 pneumonia. Gastroenterology 159(1):367–370. https://doi.org/10.1053/j.gastro.2020.03.055 Wang M, Yan W, Qi W, Wu D, Zhu L, Li W et al (2020a) Clinical characteristics and risk factors of liver injury in COVID-19: a retrospective cohort study from Wuhan, China. China Hepatol Int 14(5):723–732. https://doi.org/10.1007/s12072-020-10075-5 Wang S, Li W, Hui H, Tiwari SK, Zhang Q, Croker BA et al (2020b) Cholesterol 25-Hydroxylase inhibits SARS-CoV-2 and other coronaviruses by depleting membrane cholesterol. EMBO J 39(21):e106057. https://doi.org/10.15252/embj.2020106057 Wataya T, Ando S, Muguruma K, Ikeda H, Watanabe K, Eiraku M et al (2008) Minimization of exogenous signals in ES cell culture induces rostral hypothalamic differentiation. Proc Natl Acad Sci USA 105(33):11796–11801. https://doi.org/10.1073/pnas.0803078105 Wei XS, Wang X, Niu YR, Ye LL, Peng WB, Wang ZH et al (2020) Diarrhea is associated with prolonged symptoms and viral carriage in corona virus disease 2019. Clin Gastroenterol Hepatol 18(8):1753-1759e2. https://doi.org/10.1016/j.cgh.2020.04.030 Weibel ER (1963) Morphometry of the human lung. Bull Eur Physiopathol Respir 15:999–1013 Whitsett JA, Alenghat T (2015) Respiratory epithelial cells orchestrate pulmonary innate immunity. Nat Immunol 16(1):27–35. https://doi.org/10.1038/ni.3045 WHO (2020) Weekly epidemiological update on COVID-19 - 11 May 2021. https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---11-may-2021 Williamson IA, Arnold JW, Samsa LA, Gaynor L, DiSalvo M, Cocchiaro JL et al (2018) A high-throughput organoid microinjection platform to study gastrointestinal microbiota and luminal physiology. Cell Mol Gastroenterol Hepatol 6(3):301–319. https://doi.org/10.1016/j.jcmgh.2018.05.004 Wimmer RA, Leopoldi A, Aichinger M, Wick N, Hantusch B, Novatchkova M et al (2019a) Human blood vessel organoids as a model of diabetic vasculopathy. Nature 565(7740):505–510. https://doi.org/10.1038/s41586-018-0858-8 Wimmer R, Alexandra L, Martin A, Dontscho K, Josef M (2019b) Generation of blood vessel organoids from human pluripotent stem cells. Nat Protoc 14(11):3082–3100. https://doi.org/10.1038/s41596-019-0213-z Wolfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Muller MA et al (2020) Virological assessment of hospitalized patients with COVID-2019. Nature 581(7809):465–469. https://doi.org/10.1038/s41586-020-2196-x XaJ M, WeiLin J (2020) iPSCs-derived platform: a feasible tool for probing the neurotropism of SARS-CoV-2. ACS Chem Neurosci 11(17):2489–2491. https://doi.org/10.1021/acschemneuro.0c00512 Xiang Y, Tanaka Y, Patterson B, Kang YJ, Govindaiah G, Roselaar N et al (2017) Fusion of regionally specified hPSC-derived organoids models human brain development and interneuron migration. Cell Stem Cell 21(3):383–398. https://doi.org/10.1016/j.stem.2017.07.007 Xiang Y, Yoshiaki T, Patterson B, Cakir B, Kim KY, Cho YS et al (2018) Generation and fusion of human cortical and medial ganglionic eminence brain organoids. Curr Protoc Stem Cell Biol. https://doi.org/10.1002/cpsc.61 Xiang Y, Tanaka Y, Cakir B, Patterson B, Kim KY, Sun P et al (2019) hESC-derived thalamic organoids form reciprocal projections when fused with cortical organoids. Cell Stem Cell 4(3):487-497e7. https://doi.org/10.1016/j.stem.2018.12.015 Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H (2020) Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 158(6):1831-1833e3. https://doi.org/10.1053/j.gastro.2020.02.055 Xiong S, Liu L, Lin F, Shi J, Han L, Liu H et al (2020) Clinical characteristics of 116 hospitalized patients with COVID-19 in Wuhan, China: a single-centered, retrospective, observational study. BMC Infect Dis 20(1):787. https://doi.org/10.1186/s12879-020-05452-2 Yang X, Yu Y, Xu J, Shu H, Ja X, Liu H et al (2020a) Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 8(5):475–481. https://doi.org/10.1016/s2213-2600(20)30079-5 Yang L, Han Y, Nilsson-Payant BE, Gupta V, Wang P, Duan X et al (2020b) A human pluripotent stem cell-based platform to study SARS-CoV-2 tropism and model virus infection in human cells and organoids. Cell Stem Cell 27(1):125–136. https://doi.org/10.1016/j.stem.2020.06.015 Yi J, Bergstrom K, Fu J, Shan X, McDaniel JM, McGee S et al (2019) Dclk1 in tuft cells promotes inflammation-driven epithelial restitution and mitigates chronic colitis. Cell Death Differ 26(9):1656–1669. https://doi.org/10.1038/s41418-018-0237-x Yoon SJ, Elahi LS, Pasca AM, Marton RM, Gordon A, Revah O et al (2019) Reliability of human cortical organoid generation. Nat Methods 16(1):75–78. https://doi.org/10.1038/s41592-018-0255-0 Zang R, Gomez M, Broc T, Qiru PR, Naomi W et al (2020) TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci Immunol. https://doi.org/10.1126/sciimmunol.abc3582 Zhang BZ, Chu H, Han S, Shuai H, Deng J, Hu YF et al (2020) SARS-CoV-2 infects human neural progenitor cells and brain organoids. Cell Res 30(10):928–931. https://doi.org/10.1038/s41422-020-0390-x Zhao B, Ni C, Gao R, Wang Y, Yang L, Wei J et al (2020) Recapitulation of SARS-CoV-2 infection and cholangiocyte damage with human liver ductal organoids. Protein Cell 11(10):771–775. https://doi.org/10.1007/s13238-020-00718-6 Zhou J, Li C, Liu X, Chiu MC, Zhao X, Wang D et al (2020) Infection of bat and human intestinal organoids by SARS-CoV-2. Nat Med 26(7):1077–1083. https://doi.org/10.1038/s41591-020-0912-6 Zhu N, Zhang D, Wang W, Li X, Yang B, Song J et al (2020) A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 382(8):727–733. https://doi.org/10.1056/NEJMoa2001017