Ciclopirox Ethanolamine Preserves the Immature State of Human HSCs by Mediating Intracellular Iron Content

• Published in: Blood advances Vol. 7; no. 24; pp. 7407 - 7417
• Main Authors: Safaee Talkhoncheh, Mehrnaz, Baudet, Aurélie, Ek, Fredrik, Subramaniam, Agatheeswaran, Kao, Yun-Ruei, Miharada, Natsumi, Karlsson, Christine, Oburoglu, Leal, Rydström, Anna, Zemaitis, Kristijonas, Alattar, Abdul Ghani, Rak, Justyna, Pietras, Kristian, Olsson, Roger, Will, Britta, Larsson, Jonas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.12.2023; The American Society of Hematology
• Subjects: Antigens, CD34 - metabolism; Basic Medicine; Cell and Molecular Biology; Cell- och molekylärbiologi; Ciclopirox - metabolism; Ciclopirox - pharmacology; Ethanolamines - metabolism; Ethanolamines - pharmacology; Hematopoiesis and Stem Cells; Hematopoietic Stem Cells - metabolism; Humans; Iron - metabolism; Medical and Health Sciences; Medical Biotechnology; Medicin och hälsovetenskap; Medicinsk bioteknologi; Medicinska och farmaceutiska grundvetenskaper
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2023009844

•Ciclopirox Ethanolamine (CPX) is a regulator of HSCs and preserves the stem cell state in culture.•CPX-induced HSC maintenance is mediated by intracellular iron chelation, which restricts respiratory capacity and proliferation. Culture conditions in which hematopoietic stem cells (HSCs) can be expanded for clinical benefit are highly sought after. To elucidate regulatory mechanisms governing the maintenance and propagation of human HSCs ex vivo, we screened libraries of annotated small molecules in human cord blood (CB) cells using an optimized assay for detection of functional HSCs during culture. We found that the antifungal agent ciclopirox ethanolamine (CPX) selectively supported immature CD34+CD90+ cells during culture and enhanced their long-term in vivo repopulation capacity. Purified HSCs treated with CPX showed a reduced cell division rate and an enrichment of HSC-specific gene expression patterns. Mechanistically, we found that the HSC stimulating effect of CPX was directly mediated by chelation of the intracellular iron pool, which in turn affected iron-dependent proteins and enzymes mediating cellular metabolism and respiration. Our findings unveil a significant impact of iron homeostasis in regulation of human HSCs, with important implications for both basic HSC biology and clinical hematology.