# The role of beta 2 integrins in macrophage fusion

> **NIH NIH R01** · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · 2024 · $512,705

## Abstract

PROJECT SUMMARY
Macrophage fusion resulting in the formation of multinucleated giant cells (MGCs) accompanies a variety of
disorders associated with chronic inflammation, including the foreign body response (FBR) elicited by
implanted biomaterials. MGCs are a major factor contributing to long-term failures in human vascular
prosthetic grafts, pacemaker leads, and other implanted medical devices. Despite the long history of
research, the molecular and cellular mechanisms of macrophage fusion and, generally, cell-to-cell fusion
remain poorly understood. During the current funding period, we have shown that fibrin polymer, but not its
precursor, fibrinogen, deposited on the surface of implanted biomaterials, drives macrophage fusion. Our
preliminary in vitro studies found that fibrinogen deposited on the surface at its physiological concentration
does not support macrophage fusion, consistent with our previous findings that, upon contact with various
surfaces, fibrinogen undergoes self-assembly forming nonadhesive soft matrices. Surprisingly, although
the three-dimensional (3D) fibrin gel supports adhesion, it does not support fusion. However, removing the
gel, leaving a "2D footprint" consisting of fibrils attached to the rigid surface, restores macrophage fusion.
We hypothesize that adsorbed fibrinogen and deposited fibrin polymer form matrices with different
mechanical properties and surface patterns, which macrophages sense, initiating different
mechanotransduction responses. Specific Aim 1 is to determine why and how the fibrin polymer drives
macrophage fusion during the foreign body reaction to implanted biomaterials. Using cell signaling assays
with mechanosensitive molecules, ultrastructural studies, the hydrogels with different stiffness, and
micropatterned surfaces, we will examine differential sensing by macrophages of the mechanical properties
of 3D and 2D matrices prepared from wild-type and mutant fibrin(ogens) and characterize their
architectural features. The knowledge obtained will be translated into generating biomaterials with a
reduced ability to support macrophage fusion and testing their properties in vivo bioimplant models.
Specific Aim 2 will determine the cellular and molecular organization of the macrophage fusion site.
Following our finding that macrophage fusion is initiated by an actin-based protrusion and some preliminary
data, we hypothesize that a strong actin-propelled protrusion is formed at the leading edge of a donor
macrophage enriched in podosomes and situated within the interface restricted by zipper-forming proteins.
Taking advantage of our methodological platform consisting of high-resolution microscopy, live cell
imaging, mice with myeloid cell-specific knockouts, and macrophages with knockdowns of selected
regulators of branched actin network, we will determine the cellular and molecular determinants of the
fusion site and fusion pore formation. Overalls, these studies will define the novel biology of macro...

## Key facts

- **NIH application ID:** 10883397
- **Project number:** 2R01HL063199-23
- **Recipient organization:** ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
- **Principal Investigator:** Tatiana P Ugarova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $512,705
- **Award type:** 2
- **Project period:** 1999-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883397

## Citation

> US National Institutes of Health, RePORTER application 10883397, The role of beta 2 integrins in macrophage fusion (2R01HL063199-23). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10883397. Licensed CC0.

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