Ciclopirox Ethanolamine Preserves the Immature State of Human HSCs by Mediating Intracellular Iron Content
(2023) In Blood Advances 7(24). p.7407-7417- Abstract
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... (More)
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.
(Less)
- author
- organization
-
- LUCC: Lund University Cancer Centre
- Experimental oncology (research group)
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- LU Profile Area: Light and Materials
- LTH Profile Area: Nanoscience and Semiconductor Technology
- NanoLund: Centre for Nanoscience
- Chemical Biology and Therapeutics (research group)
- MultiPark: Multidisciplinary research focused on Parkinson´s disease
- Hematogenomics (research group)
- Hematopoietic Stem Cell Development (research group)
- Transfusion Medicine (research group)
- Stem Cells to Red Blood Cells (research group)
- Division of Molecular Medicine and Gene Therapy
- Clinical Physiology and Nuclear Medicine, Malmö (research group)
- publishing date
- 2023-07-24
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Blood Advances
- volume
- 7
- issue
- 24
- pages
- 7407 - 7417
- publisher
- American Society of Hematology
- external identifiers
-
- scopus:85181044148
- pmid:37487020
- ISSN
- 2473-9529
- DOI
- 10.1182/bloodadvances.2023009844
- language
- English
- LU publication?
- yes
- additional info
- Copyright © 2023 American Society of Hematology.
- id
- caee1641-aed6-4db3-9fb0-58c1bddf11fa
- date added to LUP
- 2023-09-01 08:43:47
- date last changed
- 2024-08-12 09:16:18
@article{caee1641-aed6-4db3-9fb0-58c1bddf11fa, abstract = {{<p>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.</p>}}, author = {{Safaee Talkhoncheh, Mehrnaz and Baudet, Aurélie and Ek, Fredrik and Subramaniam, Agatheeswaran and Kao, Yun-Ruei and Miharada, Natsumi and Karlsson, Christine and Oburoglu, Leal and Rydström, Anna and Žemaitis, Kristijonas and Alattar, Abdul Ghani and Rak, Justyna and Pietras, Kristian and Olsson, Roger and Will, Britta and Larsson, Jonas}}, issn = {{2473-9529}}, language = {{eng}}, month = {{07}}, number = {{24}}, pages = {{7407--7417}}, publisher = {{American Society of Hematology}}, series = {{Blood Advances}}, title = {{Ciclopirox Ethanolamine Preserves the Immature State of Human HSCs by Mediating Intracellular Iron Content}}, url = {{http://dx.doi.org/10.1182/bloodadvances.2023009844}}, doi = {{10.1182/bloodadvances.2023009844}}, volume = {{7}}, year = {{2023}}, }