Stem Cell Reports, 2019. 13, 1-12, DOI: https://doi.org/10.1016/j.stemcr.2019.10.002

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

Hyo-Won Han, Hyang-Hee Seo;Hye-Yeong Jo; Hyeong-jun Han; Virginia C.A. Falcao; Vincent Delorme; Jinyeong Heo; David Shum; Jang-Hoon Choi; Jin-Moo Lee; Seung Hun Lee; Hye-Ryeon Heo; Seok-Ho Hong; Mi-Hyun Park; Rajesh K. Thimmulappa; Jung-Hyun Kim

Highlights

ㆍ Methods for large-scale production of hPSC-derived macrophage-like cells (iMACs)

ㆍ iMACs recapitulate immune response of human monocyte in M. tuberculosis infection

ㆍ High-throughput screening of 3,716 compounds using iMACs identified novel anti-tuberculosis compounds

ㆍ 10-DEBC inhibited intra- and extracellular growth of drug-resistant M. tuberculosis

Summary

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 tranomic 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.

• DOI: https://doi.org/10.1016/j.stemcr.2019.10.002
• ISBN or ISSN: 2213-6711

• 본 연구는 질병관리본부 연구개발과제연구비를 지원받아 수행되었습니다.
• This research was supported by a fund by Research of Korea Centers for Disease Control and Prevention.