# Training human iPSC-derived neutrophils for antimicrobial function

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $233,250

## Abstract

PROJECT SUMMARY
Neutrophils are terminally differentiated cells of the innate immune system that are necessary for host defense.
Emerging evidence suggests that neutrophils have more heterogeneity and plasticity than previously thought.
However, there is a gap in understanding neutrophil developmental heterogeneity and function because they
are short-lived ex vivo and are not genetically tractable. Induced pluripotent stem cells (iPSC)-derived human
neutrophils (iNeutrophls) offer the opportunity to genetically and developmentally program neutrophils for
designed properties that may be used both to understand neutrophil biology and provide an avenue for
engineering neutrophils for human treatment. We have engineered GMP-compatible human iNeutrophils that
show antimicrobial function in vitro but display significant heterogeneity with distinct subtypes based on
preliminary single cell analysis. Our preliminary data also suggest that LPS treatment of progenitor cells “trains”
the iNeutrophils for an increased responsiveness to secondary stimuli. Here we propose to use single-cell
multi-omics to understand the heterogeneity and function of iNeutrophils and to test the hypothesis that
iNeutrophils can be used to understand the metabolic and genomic mechanisms of trained immunity of
human neutrophils. Specifically, will use single-cell multi-omics and optical metabolic imaging to identify the
transcriptional, epigenetic and metabolic heterogeneity that could inform functions of distinct iNeutrophil subsets
and the effects of immune training. We will also develop zebrafish larvae as an in vivo model to screen for
iNeutrophil antimicrobial functions in models of bacterial and fungal infection. The proposed work will provide a
genetically tractable system to understand the heterogeneity of human neutrophils, and the effect of immune
training on neutrophil function that may optimize for antimicrobial effects.

## Key facts

- **NIH application ID:** 10935012
- **Project number:** 1R21AI184357-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Anna Huttenlocher
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $233,250
- **Award type:** 1
- **Project period:** 2024-06-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935012

## Citation

> US National Institutes of Health, RePORTER application 10935012, Training human iPSC-derived neutrophils for antimicrobial function (1R21AI184357-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10935012. Licensed CC0.

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