# The Biogenesis of Platelet-Derived Extracellular Vesicles and their Impact on Megakaryocyte Maturation

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2024 · $565,731

## Abstract

The Biogenesis of Platelet-Derived Extracellular Vesicles and their Impact on
Megakaryocyte Maturation
Abstract
Thrombocytopenia is a major clinical problem encountered in multiple conditions, and severe
thrombocytopenia (platelet counts <50 x 10^9/L) can lead to life threatening bleeding. Current treatment
options have severe side effects, are in limited supply, involve blood products, and the platelet response
typically takes up to 12 days. Therefore, there is an urgent need to identify new thrombopoietic agents that
increase platelet counts for patients. In many inflammatory conditions platelet counts rise, resulting in
thrombocytosis, but what initiates this platelet up-regulation is not well understood. Our lab uses inflammation
as a model of exacerbated thrombopoiesis that results in differences in platelet quality and quantity in order to
1) gain a better understanding of the basic biology of megakaryocyte (MK) maturation their production of
platelets, 2) identify thrombopoietin (TPO) independent pathways of MK maturation, and 3) determine ways to
reduce platelet-related morbidity and mortality in inflammation. We have discovered a novel regulator of MK
maturation during inflammation: platelet-derived extracellular vesicles (PEVs) in the bone marrow. Our
preliminary data indicate that platelets package and shed MVs in an agonist-specific mechanism dependent on
Rho GTPase signaling; the mechanism of Rho-mediated regulation of PEV formation and packaging will be
explored in Aim 1. We also found that PEVs enter the bone marrow from the plasma, and bind to and are
endocytosed by MKs both in vitro and in vivo. In Aim 2, we will examine how platelet-derived MVs interact with
MKs. Specifically, we will determine the mechanisms by which they bind to and are internalized by MKs and
how their cargo transferred. In inflammatory conditions such as SLE, ongoing platelet activation increases
levels of circulating PEVs. These PEVs deliver disease-related changes from the plasma milieu directly to MKs
in the bone marrow, reprogramming the MKs to make more pathogenic platelets. In Aim 3, we will identify the
PEV factors that alter MK gene expression and platelet content in SLE. Successful completion of the proposed
experiments will, for the first time, provide a detailed roadmap of how PEVs alter the hematopoietic
environment in the setting of inflammatory disease. The insights gained may identify novel therapeutic targets
that (i) alter PEV poduction independent of platelet activation (Aim 1), (ii) hijack the PEV/MK interaction to alter
MK maturation (Aim 2), and (iii) inhibit pathologic MK reprogramming during SLE and other inflammatory
diseases (Aim 3).

## Key facts

- **NIH application ID:** 10814387
- **Project number:** 5R01HL151494-04
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Kellie Rae Machlus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $565,731
- **Award type:** 5
- **Project period:** 2021-04-20 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814387

## Citation

> US National Institutes of Health, RePORTER application 10814387, The Biogenesis of Platelet-Derived Extracellular Vesicles and their Impact on Megakaryocyte Maturation (5R01HL151494-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10814387. Licensed CC0.

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