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Non-invasive characterization of human bone marrow by cell free messenger-RNA reveals response to growth factor stimulation and hematopoietic reconstitution after transplantation

By Arkaitz Ibarra, Yue Zhao, Neeraj S. Salathia, Jiali Zhuang, Vera Huang, Alexander D. Acosta, Jonathan Aballi, Shusuke Toden, Amy P. Karns, Intan Purnajo, Julianna R. Parks, Lucy Guo, James Mason, Darren Sigal, Tina S. Nova, Stephen R. Quake, Michael Nerenberg

Posted 10 Jan 2019
bioRxiv DOI: 10.1101/516666 (published DOI: 10.1038/s41467-019-14253-4)

Circulating cell free mRNA (cf-mRNA) holds great promise as a non-invasive diagnostic biomarker. However, the biological origin of cf-mRNA is still not well understood, limiting the clinical applications of this technology. Here, we use the bone marrow (BM) and pharmacologic manipulation of its resident cells as a window to study the origin of cf-mRNA. Using NGS-based profiling, we show that cf-mRNA is enriched in transcripts derived from the BM compared to circulating cells. Further, BM ablation experiments followed by hematopoietic stem cell transplants in cancer patients show that cf-mRNA levels reflect the transcriptional activity of BM resident hematopoietic lineages during marrow reconstitution. Finally, by stimulating specific BM cell populations in vivo using growth factor therapeutics (i.e. EPO, G-CSF), we show that cf-mRNA reveals dynamic functional changes in growing cell types, suggesting that, unlike other cell-free nucleic acids, cf-mRNA is secreted from living cells, rather than exclusively from apoptotic cells. Our results shed new light on the biology of cf-mRNA and demonstrate its potential applications in clinical practice.

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