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  3. Drug Discovery Platform Targeting M. tuberculosis with Human Embryonic Stem Cell-Derived Macrophages

Drug Discovery Platform Targeting M. tuberculosis with Human Embryonic Stem Cell-Derived Macrophages

  • Stem Cell Reports. 2019 Dec 10;13(6):980-991. doi: 10.1016/j.stemcr.2019.10.002.
Hyo-Won Han 1,  Hyang-Hee Seo 1,  Hye-Yeong Jo 1,  Hyeong-Jun Han 2,  Virgínia C A Falcão 3,  Vincent Delorme 3,  Jinyeong Heo 4,  David Shum 4,  Jang-Hoon Choi 5,  Jin-Moo Lee 5,  Seung Hun Lee 6,  Hye-Ryeon Heo 7,  Seok-Ho Hong 7,  Mi-Hyun Park 1,  Rajesh K Thimmulappa 8,  Jung-Hyun Kim 9
Affiliations

Affiliations

  • 1 Division of Intractable Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, Cheongju 28159, Republic of Korea; National Stem Cell Bank of Korea, Korea Institute of Health, Cheongju 28160, Republic of Korea.
  • 2 Division of Intractable Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, Cheongju 28159, Republic of Korea.
  • 3 Tuberculosis Research Laboratory, Discovery Biology, Institute Pasteur Korea, Seongnam 13488, Republic of Korea.
  • 4 Screening Discovery Platform, Screening Sciences and Novel Assay Technologies, Institute Pasteur Korea, Seongnam 13488, Republic of Korea.
  • 5 Division of Viral Disease Research, Center for Infectious Diseases Research, National Institute of Health, Korea Centers for Disease Control and Prevention, Cheongju 28159, Republic of Korea.
  • 6 Division of Bacterial Disease Research, Center for Infectious Disease Research, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, Cheongju 28159, Republic of Korea.
  • 7 Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon 24341, Republic of Korea.
  • 8 Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru 570015, India.
  • 9 Division of Intractable Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, Cheongju 28159, Republic of Korea; National Stem Cell Bank of Korea, Korea Institute of Health, Cheongju 28160, Republic of Korea. Electronic address: kjhcorea@korea.kr.
PMID: 31680058 DOI: 10.1016/j.stemcr.2019.10.002
Abstract

A major limitation in anti-tuberculosis drug screening is the lack of reliable and scalable models for homogeneous human primary macrophage cells of non-cancer origin. Here we report a modified protocol for generating homogeneous populations of macrophage-like cells from human embryonic stem cells. The induced macrophages, referred to as iMACs, presented similar transcriptomic profiles and characteristic immunological features of classical macrophages and were permissive to viral and Bacterial infection, in particular Mycobacterium tuberculosis (Mtb). More importantly, iMAC production was amenable to scale up. To evaluate iMAC efficiency in high-throughput anti-tuberculosis drug screening, we performed a phenotypic screening against intracellular Mtb, involving a library of 3,716 compounds that included FDA-approved drugs and other bioactive compounds. Our primary screen identified 120 hits, which were validated in a secondary screen by dose-intracellular and -extracellular Mtb assays. Our confirmatory studies identified a novel anti-Mtb compound, 10-DEBC, also showing activity against drug-resistant strains.

Keywords

Mycobacterium tuberculosis (Mtb); anti-tuberculosis compound; drug discovery platform; human embryonic stem cell-derived induced macrophage-like cells (iMACs).

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