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Development of a novel and synthetic HematoMiR technology that broadly modulates quiescence of stem cells and enhances HSC expansion

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Abstract

Hematopoietic stem cell (HSCs) transplantation is the primary therapeutic modality used to treat hematopoietic disorders. It centers on the capability of a small quantity of HSCs to repopulate whole blood lineages. Along with limited availability of suitable donors, the need for sufficient number of donor HSCs is still challenging in clinical relevance. This has been addressed by ex vivo HSC expansion albeit with partial success, and thus development of an alternative strategy that could improve HSC expansion is required. To that end, we aimed to build HematoMiR, an oligo-based technology that broadly targets HSC quiescence factors. Here, we show that HematoMiRs and their combinations targeting over 50 factors involved in HSC quiescence could induce robust ex vivo murine and human HSC expansion. In particular, HematoMiR-5 treatment enhanced cell cycle through down-regulation of negative cell cycle regulators in HSCs. HematoMiR-5 treated HSPCs had reduced DNA damage during the course of ex vivo expansion. Moreover, HematoMiR-5 treatment led to sustained HSC self-renewal ability and a low apoptosis rate. In addition, HematoMiR-5 expanded HSCs demonstrated successful engraftment and repopulation capacity in the recipient animals. Furthermore, combinatorial treatments of HematoMiR-2 and 5 allowed vigorous ex vivo HSC expansion. These findings demonstrate that novel and synthetic HematoMiR technology is feasible for HSC ex vivo expansion through the sequence-dependent modulation of numerous HSC quiescence modulators.

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The data that supports the findings of this study are available in the supplementary material of this article.

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Acknowledgements

We like to thank Dr. Emrah Nikerel for initial automations. We would like to thank to Dr. Esra Albayrak and Dr. Rukset Attar (UCB sample collection), Dr. Esra Albayrak (animal handling in retro-orbital injections), Dr. Neslihan Meric and Dr. Zafer Gulbas (BM sample collection), Dr. Safa Aydin (technical assistance of using electroporater).

Funding

We thank the support from The International Centre for Genetic Engineering and Biotechnology—ICGEB 2015 Early Career Return Grant [grant number CRP/TUR15-02_EC]. MU has been supported by TÜBİTAK 215Z071 and 118S540.

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Authors and Affiliations

  1. Regenerative Biology Research Laboratory, Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey

    Merve Uslu & Fatih Kocabaş

  2. Graduate School of Natural and Applied Sciences, Yeditepe University, Istanbul, Turkey

    Merve Uslu & Fatih Kocabaş

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  1. Merve Uslu
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MU performed the experiments, collected the data, prepared the figures, and wrote the draft of the article. FK designed the experiments, contributed to data analysis, figure preparations and wrote the manuscript.

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Correspondence to Fatih Kocabaş.

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All animal studies were approved with ethical permission from Institutional Animal Care and Use Committee of Yeditepe University (YUDHEK) with the decision number 651. All human studies were performed with consent to participate under the approval given by the Institutional Clinical Studies Ethical Committee of Yeditepe University with the permission decision numbers: 1067 and 944.

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Uslu, M., Kocabaş, F. Development of a novel and synthetic HematoMiR technology that broadly modulates quiescence of stem cells and enhances HSC expansion. Cell. Mol. Life Sci. 79, 68 (2022). https://doi.org/10.1007/s00018-021-04031-1

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