# Carbohydrate-Mediated Platelet Clearance

> **NIH NIH R01** · VERSITI BLOOD HEALTH, INC. · 2024 · $90,453

## Abstract

ABSTRACT
Maintenance of normal hematopoiesis depends on developmental programs for the hematopoietic stem and
progenitor cell (HSPC). Still, these programs require guidance by cell-extrinsic mechanisms that correctly convey
the dynamically changing needs of the blood cells. Our prior work established that the hepatocyte-specific
Ashwell-Morell receptor (AMR), a multimeric endocytic receptor, binds to aged platelets, inducing JAK-STAT
signaling and production of thrombopoietin (TPO), the cytokine responsible for megakaryocyte maturation and
differentiation, platelet production, and maintenance of HSPCs. In addition to regulating TPO production and
removing aged platelets, we uncovered an unexpected mechanism by which the AMR regulates erythropoiesis.
Our preliminary data suggest a role for the hepatic AMR in regulating Neuregulin 4 (Nrg4) levels, the specific
ligand for ErbB4 (also known as HER4), the fourth member of the receptor tyrosine kinase family that includes
the epidermal growth factor (EGF) receptor (EGFR/HER1), ErbB2/HER2, and ErbB3/HER3. A genome-wide
association study (GWAS) shows that NRG4 variants are associated with changes in hemoglobin levels, and
ErbB4 signaling contributes to human and mouse erythropoiesis.
Our data shows that an increase in Nrg4 affects ErbB4 expression and signaling in bone marrow mesenchymal
stem cells (MSCs), leading to defective erythropoiesis and increased expression levels of S100a8 and S100a9,
members of the calcium-binding S100 protein family, known as Calgranulin A and B, respectively. Recombinant,
extracellular, and increased S100a8 expression levels in erythrocyte progenitors induce an erythroid
differentiation defect. We seek to define how Nrg4/ErbB4 affects HSPC homeostasis and erythropoiesis,
including erythroblastic islands (Aim 1). We will interrogate the mechanism by which Nrg4/ErbB4 affect MSC
function, calgranulin expression, and erythropoiesis (Aim 2). We use a multipronged approach of genetic mouse
modeling, inhibitors, transcriptomics, and biochemical approaches to allow mechanistic exploration into the
participation of the Nrg4/ErbB4/calgranulin axis in contributing to erythropoiesis. The proposed investigation will
further drive therapeutic development to ameliorate erythropoietic deficiencies in blood disease, including in
patients with myeloproliferative neoplasms and myelodysplastic syndrome.

## Key facts

- **NIH application ID:** 11062244
- **Project number:** 3R01HL089224-16S1
- **Recipient organization:** VERSITI BLOOD HEALTH, INC.
- **Principal Investigator:** Karin Maria Hoffmeister
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $90,453
- **Award type:** 3
- **Project period:** 2023-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11062244

## Citation

> US National Institutes of Health, RePORTER application 11062244, Carbohydrate-Mediated Platelet Clearance (3R01HL089224-16S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11062244. Licensed CC0.

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