miR‐15a‐5p regulates expression of multiple proteins in the megakaryocyte GPVI signaling pathway
Author(s): ,
Indranil Basak
Affiliations:
Molecular Medicine Program, University of Utah, Salt Lake City, USA
,
Seema Bhatlekar
Affiliations:
Molecular Medicine Program, University of Utah, Salt Lake City, USA
,
Bhanu K. Manne
Affiliations:
Molecular Medicine Program, University of Utah, Salt Lake City, USA
,
Micelle Stoller
Affiliations:
Molecular Medicine Program, University of Utah, Salt Lake City, USA
,
Sarah Hugo
Affiliations:
Molecular Medicine Program, University of Utah, Salt Lake City, USA
,
X. Kong
Affiliations:
The Cardeza Foundation for Hematologic Research and the Department of Medicine, Thomas Jefferson University, Jefferson Medical College, Philadelphia, USA
,
L. Ma
Affiliations:
The Cardeza Foundation for Hematologic Research and the Department of Medicine, Thomas Jefferson University, Jefferson Medical College, Philadelphia, USA
,
Matthew T. Rondina
Affiliations:
Molecular Medicine Program, University of Utah, Salt Lake City, USA. Division of General Internal Medicine, Department of Internal Medicine, University of Utah, Salt Lake City, USA. George E. Wahlen VAMC, Salt Lake City, USA
,
Andrew S. Weyrich
Affiliations:
Molecular Medicine Program, University of Utah, Salt Lake City, USA
,
Leonard C. Edelstein
Affiliations:
The Cardeza Foundation for Hematologic Research and the Department of Medicine, Thomas Jefferson University, Jefferson Medical College, Philadelphia, USA
Paul F. Bray
Affiliations:
Molecular Medicine Program, University of Utah, Salt Lake City, USA. Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, USA
Correspondence: Paul F. Bray, Eccles Institute of Human Genetics, 15 North 2030 East, Bldg., 533 Room 4160B, Salt Lake City, UT 84112, USA|Tel.: +1 801 585 0727|E‐mail: paul.bray@hsc.utah.edu
ISTH Academy. F. Bray P. Mar 1, 2019; 273391
Paul F. Bray
Paul  F. Bray
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Background
Megakaryocytes (MKs) invest their progeny platelets with proteins and RNAs. MicroRNAs (miRs), which inhibit mRNA translation into protein, are abundantly expressed in MKs and platelets. Although platelet miRs have been associated with platelet reactivity and disease, there is a paucity of information on the function of miRs in human MKs.
Objective
To identify MK miRs that regulate the GPVI signaling pathway in the MK‐platelet lineage.
Methods
Candidate miRs associated with GPVI‐mediated platelet aggregation were tested for functionality in cultured MKs derived from cord blood.
Results
An unbiased, transcriptome‐wide screen in 154 healthy donors identified platelet miR‐15a‐5p as significantly negatively associated with CRP‐induced platelet aggregation. Platelet agonist dose‐response curves demonstrated activation of αIIbβ3 in suspensions of cord blood‐derived cultured MKs. Overexpression and knockdown of miR‐15a‐5p in these MKs reduced and enhanced, respectively, CRP‐induced αIIbβ3 activation but did not alter thrombin or ADP stimulation. FYN, SRGN, FCER1G, MYLK. and PRKCQ, genes involved in GPVI signaling, were identified as miR‐15a‐5p targets and were inhibited or de‐repressed in MKs with miR‐15a‐5p overexpression or inhibition, respectively. Lentiviral overexpression of miR‐15a‐5p also inhibited GPVI‐FcRγ‐mediated phosphorylation of Syk and PLCγ2, GPVI downstream signaling molecules, but effects of miR‐15a‐5p on αIIbβ3 activation did not extend to other ITAM‐signaling receptors (FcγRIIa and CLEC‐2).
Conclusion
Cord blood‐derived MKs are a useful human system for studying the functional effects of candidate platelet genes. miR‐15a‐5p is a potential “master‐miR” for specifically regulating GPVI‐mediated MK‐platelet signaling. Targeting miR‐15a‐5p may have therapeutic potential in hemostasis and thrombosis.
Keyword(s)
GPVI, integrin activation, megakaryocytes, microRNAs, platelets
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