# Project 1: Megakaryocytes as Organizers of the Hematopoietic Environment

> **NIH NIH P01** · VERSITI BLOOD HEALTH, INC. · 2021 · $689,749

## Abstract

Insufficient megakaryopoiesis and thrombopoiesis remain the main cause of persistent thrombocytopenia after
hematopoietic stem and progenitor cell (HSPC) transplantation and after radiochemotherapy. Platelet
transfusions are required to support patients with consequent increased risk of transfusion reactions, platelet
alloimmunization, and transfusion-associated viral infections. Significant efforts are focused on identifying the
most suitable cellular and molecular targets to enhance platelet production after bone marrow (BM)
transplantation, chemotherapy, and to maximize the efficacy of in vitro human platelet production as an
alternative method to increase the platelet supply for transfusion. Our ability to therapeutically optimize platelet
recovery and in vitro platelet production is hindered by our paucity of knowledge of the molecular determinants
that govern thrombopoiesis. Megakaryocytes (MKs) reside in the BM and maintain the continuous production of
billions of circulating platelets in order to prevent bleeding. Recent work shows that MKs also maintain a
functionally specific BM niche to support MK-biased HSPCs. Preliminary data suggest that: 1) MK-biased HSPCs
express unusually high levels of α2,6-sialic acid (α2,6-Sia) which is unparalleled by cell intrinsic St6gal1 mRNA
expression; 2) systemic ST6GAL1 deficiency promotes a myeloid skewed hematopoietic development profile,
suggesting that α2,6-sialylation is a checkpoint of a particular HSPC population (Project 2); 3) B4galt1 deletion
in MKs renders β1 integrin hyperactive and unexpectedly also regulates heparin sulfate proteoglycan (HS PG)
and heparinase expression in MKs thereby severely impairing thrombopoiesis at steady state and following
myeloablative injury; 4) Heparinase and glycosaminoglycan (GAG) mimetics improved thrombopoiesis in wild
type and B4galt1-/- MKs, suggesting a role for GAGs in thrombopoiesis. The overarching hypothesis of this
program is that “distinct cell-intrinsic and extrinsic glycan-mediated mechanisms regulate maintenance,
differentiation, and function of hematopoietic cells”. Project 1 will test the specific hypothesis that glycosylation
regulates MK-biased HSCs and thrombopoiesis in three aims: In Aim 1, a functionally defined MK-biased
hematopoietic stem cell will be investigated together with Project 2, especially with respect to the heavily α2,6-
sialylated cell surface despite the absence of St6gal1 expression necessary to generate this structure. We will
establish the role of α2,6-Sia in MK-biased HSPCs. Based on the known requirement of the
galactosyltransferase β4GalT1 in thrombopoiesis, Project 1 will also investigate the roles of β4GalT1,
glycosaminoglycans (GAGs)/HS PG in thrombopoiesis at steady-state (Aim 2) and following myeloablative
stress (Aim 3) using the novel combined shared “omics” together with Project 3 and standard approaches. A
previously unknown role of β4GalT1 to regulate MK expression of HS PG will also be investigated. This P...

## Key facts

- **NIH application ID:** 10088968
- **Project number:** 1P01HL151333-01A1
- **Recipient organization:** VERSITI BLOOD HEALTH, INC.
- **Principal Investigator:** Karin Maria Hoffmeister
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $689,749
- **Award type:** 1
- **Project period:** 2021-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10088968

## Citation

> US National Institutes of Health, RePORTER application 10088968, Project 1: Megakaryocytes as Organizers of the Hematopoietic Environment (1P01HL151333-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10088968. Licensed CC0.

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