Parallel use of human stem cell lung and heart models provide insights for SARS-CoV-2 treatment

Rajeev Rudraraju; Matthew J. Gartner; Jessica A. Neil; Elizabeth S. Stout; Joseph Chen; Elise J. Needham; Michael See; Charley Mackenzie-Kludas; Leo Yi Yang Lee; Mingyang Wang; Hayley Pointer; Kathy Karavendzas; Dad Abu-Bonsrah; Damien Drew; Yu Bo Yang Sun; Jia Ping Tan; Guizhi Sun; Adrian Salavaty; Natalie Charitakis; Hieu T. Nim; Peter D. Currie; Wai Hong Tham; Enzo Porrello; Jose M. Polo; Sean J. Humphrey; Mirana Ramialison; David A. Elliott; Kanta Subbarao

doi:10.1016/j.stemcr.2023.05.007

Parallel use of human stem cell lung and heart models provide insights for SARS-CoV-2 treatment

Rajeev Rudraraju, Matthew J. Gartner, Jessica A. Neil, Elizabeth S. Stout, Joseph Chen, Elise J. Needham, Michael See, Charley Mackenzie-Kludas, Leo Yi Yang Lee, Mingyang Wang, Hayley Pointer, Kathy Karavendzas, Dad Abu-Bonsrah, Damien Drew, Yu Bo Yang Sun, Jia Ping Tan, Guizhi Sun, Adrian Salavaty, Natalie Charitakis, Hieu T. NimPeter D. Currie, Wai Hong Tham, Enzo Porrello^*, Jose M. Polo^*, Sean J. Humphrey^*, Mirana Ramialison^*, David A. Elliott^*, Kanta Subbarao^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

8 Citations (SciVal)

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe coronavirus disease 2019 (COVID-19). To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures infected with SARS-CoV-2. With CRISPR-Cas9-mediated knockout of ACE2, we demonstrated that angiotensin-converting enzyme 2 (ACE2) was essential for SARS-CoV-2 infection of both cell types but that further processing in lung cells required TMPRSS2, while cardiac cells required the endosomal pathway. Host responses were significantly different; transcriptome profiling and phosphoproteomics responses depended strongly on the cell type. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational drug combinations for effective treatment of a virus that affects multiple organ systems.

Original language	English
Pages (from-to)	1308-1324
Number of pages	17
Journal	Stem Cell Reports
Volume	18
Issue number	6
DOIs	https://doi.org/10.1016/j.stemcr.2023.05.007
Publication status	Published - 13 Jun 2023
Externally published	Yes

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Rudraraju, R., Gartner, M. J., Neil, J. A., Stout, E. S., Chen, J., Needham, E. J., See, M., Mackenzie-Kludas, C., Yang Lee, L. Y., Wang, M., Pointer, H., Karavendzas, K., Abu-Bonsrah, D., Drew, D., Yang Sun, Y. B., Tan, J. P., Sun, G., Salavaty, A., Charitakis, N., ... Subbarao, K. (2023). Parallel use of human stem cell lung and heart models provide insights for SARS-CoV-2 treatment. Stem Cell Reports, 18(6), 1308-1324. https://doi.org/10.1016/j.stemcr.2023.05.007

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title = "Parallel use of human stem cell lung and heart models provide insights for SARS-CoV-2 treatment",

abstract = "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe coronavirus disease 2019 (COVID-19). To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures infected with SARS-CoV-2. With CRISPR-Cas9-mediated knockout of ACE2, we demonstrated that angiotensin-converting enzyme 2 (ACE2) was essential for SARS-CoV-2 infection of both cell types but that further processing in lung cells required TMPRSS2, while cardiac cells required the endosomal pathway. Host responses were significantly different; transcriptome profiling and phosphoproteomics responses depended strongly on the cell type. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational drug combinations for effective treatment of a virus that affects multiple organ systems.",

keywords = "antiviral drugs, COVID-19, human stem cell-derived lung and heart models, SARS-CoV-2",

author = "Rajeev Rudraraju and Gartner, \{Matthew J.\} and Neil, \{Jessica A.\} and Stout, \{Elizabeth S.\} and Joseph Chen and Needham, \{Elise J.\} and Michael See and Charley Mackenzie-Kludas and \{Yang Lee\}, \{Leo Yi\} and Mingyang Wang and Hayley Pointer and Kathy Karavendzas and Dad Abu-Bonsrah and Damien Drew and \{Yang Sun\}, \{Yu Bo\} and Tan, \{Jia Ping\} and Guizhi Sun and Adrian Salavaty and Natalie Charitakis and Nim, \{Hieu T.\} and Currie, \{Peter D.\} and Tham, \{Wai Hong\} and Enzo Porrello and Polo, \{Jose M.\} and Humphrey, \{Sean J.\} and Mirana Ramialison and Elliott, \{David A.\} and Kanta Subbarao",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = jun,

day = "13",

doi = "10.1016/j.stemcr.2023.05.007",

language = "English",

volume = "18",

pages = "1308--1324",

journal = "Stem Cell Reports",

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Rudraraju, R, Gartner, MJ, Neil, JA, Stout, ES, Chen, J, Needham, EJ, See, M, Mackenzie-Kludas, C, Yang Lee, LY, Wang, M, Pointer, H, Karavendzas, K, Abu-Bonsrah, D, Drew, D, Yang Sun, YB, Tan, JP, Sun, G, Salavaty, A, Charitakis, N, Nim, HT, Currie, PD, Tham, WH, Porrello, E, Polo, JM, Humphrey, SJ, Ramialison, M, Elliott, DA & Subbarao, K 2023, 'Parallel use of human stem cell lung and heart models provide insights for SARS-CoV-2 treatment', Stem Cell Reports, vol. 18, no. 6, pp. 1308-1324. https://doi.org/10.1016/j.stemcr.2023.05.007

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T1 - Parallel use of human stem cell lung and heart models provide insights for SARS-CoV-2 treatment

AU - Rudraraju, Rajeev

AU - Gartner, Matthew J.

AU - Neil, Jessica A.

AU - Stout, Elizabeth S.

AU - Chen, Joseph

AU - Needham, Elise J.

AU - See, Michael

AU - Mackenzie-Kludas, Charley

AU - Yang Lee, Leo Yi

AU - Wang, Mingyang

AU - Pointer, Hayley

AU - Karavendzas, Kathy

AU - Abu-Bonsrah, Dad

AU - Drew, Damien

AU - Yang Sun, Yu Bo

AU - Tan, Jia Ping

AU - Sun, Guizhi

AU - Salavaty, Adrian

AU - Charitakis, Natalie

AU - Nim, Hieu T.

AU - Currie, Peter D.

AU - Tham, Wai Hong

AU - Porrello, Enzo

AU - Polo, Jose M.

AU - Humphrey, Sean J.

AU - Ramialison, Mirana

AU - Elliott, David A.

AU - Subbarao, Kanta

PY - 2023/6/13

Y1 - 2023/6/13

N2 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe coronavirus disease 2019 (COVID-19). To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures infected with SARS-CoV-2. With CRISPR-Cas9-mediated knockout of ACE2, we demonstrated that angiotensin-converting enzyme 2 (ACE2) was essential for SARS-CoV-2 infection of both cell types but that further processing in lung cells required TMPRSS2, while cardiac cells required the endosomal pathway. Host responses were significantly different; transcriptome profiling and phosphoproteomics responses depended strongly on the cell type. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational drug combinations for effective treatment of a virus that affects multiple organ systems.

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KW - antiviral drugs

KW - COVID-19

KW - human stem cell-derived lung and heart models

KW - SARS-CoV-2

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U2 - 10.1016/j.stemcr.2023.05.007

DO - 10.1016/j.stemcr.2023.05.007

M3 - Article

C2 - 37315523

AN - SCOPUS:85161265126

SN - 2213-6711

VL - 18

SP - 1308

EP - 1324

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 6

ER -

Parallel use of human stem cell lung and heart models provide insights for SARS-CoV-2 treatment

Abstract

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