# The roles of mDia2 in hematopoietic stem and progenitor cell engraftment and migration

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $505,041

## Abstract

PROJECT SUMMARY
Failure in engraftment is one of the major limitations of hematopoietic stem cell transplantation, which is critical
for the treatment of many benign and malignant hematologic disorders. Besides immune-mediated rejection of
the transplanted cells, ineffective migration, adhesion, and engraftment of the hematopoietic stem and
progenitor cells (HSPCs) to the bone marrow niche are important causes of engraftment failure. The
intracellular signaling pathways regulating HSPC engraftment and migration to the bone marrow often directly
or indirectly target the actin cytoskeleton network through proteins that regulate actin polymerization. The mDia
formins are a major actin-nucleating family, but their functions in HSPCs are unknown. Our preliminary studies
using our recently generated mDia2 hematopoietic-specific knockout mice showed that loss of mDia2 resulted
in significant defects in HSPC adhesion and bone marrow engraftment in competitive transplantation assays.
Loss of mDia2 also markedly reduced G-CSF-induced HSPC mobilization out of the bone marrow. We also
found that beta2 integrins including CD11a/CD18 (LFA1) and CD11b/CD18 (Mac1) were significantly
downregulated with the loss of mDia2. These results led us to hypothesize that mDia2 is critical for the
engraftment, adhesion, and migration of the hematopoietic stem and progenitor cells. We proposed three
specific aims to test this hypothesis. First, we will determine the functional roles of mDia2 in HSPC
engraftment, adhesion, and migration to the bone marrow. Specifically, we will investigate the role of mDia2 in
the in vitro and in vivo migration and adhesion of HSPCs and their relationship with the bone marrow niche.
We will also use an mDia activator in vivo to explore a pre-clinical model of mDia activation for enhancing stem
cell mobilization and engraftment. In these experiments, relatively pure SLAM+ hematopoietic stem cell
population will also be tested. Second, we will determine the mechanisms of mDia2 in regulating HSPC
engraftment, adhesion, and migration through a novel mDia2-MAL-SRF-LFA1/Mac1 pathway. Third, based on
our preliminary studies that acetylation of mDia2 affects its activity in actin polymerization, we will determine
whether and how acetylation or other post-translational modifications of mDia2 influence its functions in HSPC
engraftment and migration. The overall goal of this proposed study is to understand the roles of mDia2 in
HSPC engraftment, adhesion, and migration and elucidate its mechanisms using in vivo mouse models and
transplantation assays. A better understanding of these processes may lead to the identification of novel
targets for therapeutic strategies in hematopoietic stem cell transplantation.

## Key facts

- **NIH application ID:** 10130616
- **Project number:** 5R01HL148012-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Peng Ji
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $505,041
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130616

## Citation

> US National Institutes of Health, RePORTER application 10130616, The roles of mDia2 in hematopoietic stem and progenitor cell engraftment and migration (5R01HL148012-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10130616. Licensed CC0.

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