The role of megakaryocytes and platelets in infection and immunothrombosis

Megakaryocytes (MKs), one of the largest and rarest hematopoietic stem cells in the bone marrow, have traditionally played a primary role in hemostasis as precursors to platelets, which are importantly, one of the most abundant cell types in the peripheral circulation. While platelets are studied for their various roles in inflammation, the role of MKs within the innate immune system has not been explored. In a series of comprehensive in vitro experiments, we have demonstrated that both cord blood-derived MKs and MKs from a megakaryoblastic lineage have innate immune cell functions, including: phagocytosis, formation of extracellular traps, and chemotaxis towards pathogenic stimuli. MKs were also observed to directionally release platelets towards pathogenic stimuli. In addition to their primary role as immune cells, MKs were also shown to contain extranuclear histones, which the MKs release along with budding platelets into the circulation. These small packages of histones can play a major role in inflammation and immunothrombosis by promoting inflammation and coagulation. By evaluating blood and tissue samples from patients diagnosed with sepsis, we demonstrated that there is an increased MK concentration both in the peripheral circulation, as well as in the lungs and kidneys. Platelets from patients with sepsis also appeared to have a specific phenotype, including increased DNA and histone staining. MK number in the circulation and end-organs, as well as platelet histone expression appeared to be correlated with both prognosis and type of infection. This newly recognized role of MKs as functional innate immune cells may have significant implications for the role of MKs in conditions such as sepsis and, pending a more profound mechanistic understanding, may further lead to the development of novel targets for the treatment of sepsis.

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Biological Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2018

Author dc:creator

• Frydman, Galit Hocsman

Advisor dc:contributor.advisor

• James G. Fox.

• Biological Engineering.

Statement dc:rights

• MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/115756

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/115756