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Comparative Analysis of microRNAs that Stratify in vitro Mammary stem and Progenitor Activity Reveals Functionality of Human miR-92b-3p

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Abstract

Mammary stem/progenitor cells are fundamental for mammary gland development and function. However, much remains to be elucidated regarding their function in mammals beyond the traditionally studied rodents, human, and to a lesser extent, ruminants. Due to the growing appreciation for microRNAs (miRNAs) as regulators of stem cells and their progenitors, we compared miRNA expression in mammary stem/progenitor cells from mammals with varying mammary stem/progenitor activity in vitro, in order to identify miRNA candidates that regulate stem/progenitor self-renewal and function. Mammosphere-derived epithelial cells (MDECs), which are primary cell lines enriched in mammary stem and progenitor cells, were generated from six mammalian species (i.e., cow, human, pig, horse, dog, and rat) and small RNA sequencing was performed. We identified 9 miRNAs that were significantly differentially expressed in MDEC cultures with a low versus high mammary stem/progenitor activity. miR-92b-3p was selected for functional follow-up studies, as this miRNA is understudied in primary mammary cells but has well-described gene targets that are known to regulate mammary stem/progenitor activity. Altering the expression of miR-92b-3p in MDECs from species with low stem/progenitor activity (human and cow) and those with high stem/progenitor activity (dog and rat) via inhibition and overexpression, respectively, resulted in significantly decreased mammosphere formation of human MDECs, but showed no significant effects in cow, dog, or rat MDECs. This study is the first to perform small RNA sequencing in MDECs from various mammals and highlights that conserved miRNAs can have different functions in mammary stem/progenitor cells across species.

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Data Availability

The miRNA sequencing data are accessible through GEOSeries # GSE126424 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE126424).

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Acknowledgements

This work was supported in part by an unrestricted fund from the Harry M. Zweig Memorial Fund for Equine Research and by the Albert C. Bostwick Foundation to G. Van de Walle. These funding sources had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit this manuscript for publication. We would like to thank following individuals for collecting and providing us with mammary tissue samples: Dorothy Supp, Erin Daugherity, Stephanie Pierson, Luce Guanzini, Patrick Burke, Dwight Hoffman, Michelle Delco, Joy Tomlinson, Amy Vasquez, Ed Rice, and Charles Danko.

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  1. Baker Institute for Animal Health, Ithaca , United States

    James L. Miller, Gat Rauner, Kimaya M. Bakhle & Gerlinde R. Van de Walle

  2. Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA

    Matt Kanke & Praveen Sethupathy

  3. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, 14850, Ithaca, NY, USA

    Gerlinde R. Van de Walle

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Contributions

JM, MK, GR, PS and GVdW conceived and designed the study; JM, GR, and KB performed the wet-lab experiments; GR submitted samples for small RNA-seq; MK and PS analyzed the bioinformatics data; JM, MK, GR, KB, PS and GVdW interpreted the data; JM, GR and GVdW wrote the initial manuscript; MK and PS were major contributors in critically reviewing the manuscript. All authors reviewed this manuscript and approved the final version.

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Correspondence to Gerlinde R. Van de Walle.

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The authors declare that they have no conflicts of interest.

Research involving human participants and/or animals.

With exception of human breast tissue, all material used in this study was collected from animals after euthanasia or slaughter. Human tissue was obtained from discarded and de-identified breast tissue from reduction mammoplasty surgeries. No one involved in this study had any access to patient information, with exception of age and ethnicity.

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James L. Miller and Matt Kanke contributed equally to this work.

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Miller, J.L., Kanke, M., Rauner, G. et al. Comparative Analysis of microRNAs that Stratify in vitro Mammary stem and Progenitor Activity Reveals Functionality of Human miR-92b-3p. J Mammary Gland Biol Neoplasia 27, 253–269 (2022). https://doi.org/10.1007/s10911-022-09525-7

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