# Lysyl oxidases are novel regulators of definitive hematopoiesis

> **NIH NIH F32** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $69,802

## Abstract

Project Summary/Abstract
Hematopoietic stem cells (HSCs) are self-renewing, transplantable cells that have the capacity to reconstitute
all blood lineages for life. Consequently, HSC transplantation (HSCT) is used in treatment of leukemia and other
blood disorders. In principle, induced pluripotent stem cell (iPSC)-derived HSCs could provide an unlimited
source of HSCs for transplant, patient-specific in vitro studies, drug studies and as a vector for delivery of gene
therapy. However, to date, it has not been possible to generate bona fide HSCs from iPSCs with high engraftment
potential and multilineage reconstitution. One means of generating HSCs from iPSCs would be to reproduce the
normal embryonic specification of HSCs in vitro. HSCs arise from hemogenic endothelial (HE) cells in the
embryonic dorsal aorta (DA). The extracellular matrix (ECM) provides the physical environment in which HSC
precursors receive signals that induce their commitment to the hematopoietic lineage. Despite the likely
importance of the ECM, we do not yet understand how or whether the ECM influences HSC specification. The
lysyl oxidase (Lox) family of ECM-modifying enzymes controls ECM stiffness, display of growth factor signals,
and other properties by catalyzing the cross-linking of ECM proteins including collagen and fibronectin. Using
the zebrafish model of hematopoietic development, I have shown that Lox activity is required for specification of
the earliest HSCs. My preliminary studies indicate that at least three Lox family members are required for proper
specification and maturation of the definitive hematopoietic system.
In Aim 1, I will systematically examine Lox family contribution to HSC specification.
In Aim 2, I will determine the mechanism of Lox regulation of HSC specification to distinguish between
the most likely possibilities: Lox-induced ECM stiffness regulates HSCs directly through integrin-ECM
interactions, indirectly through modulating existing growth factor signals, or both.
The research and training proposed in this F32 application will take place under the guidance of my mentor, Dr.
Wilson Clements and my mentorship team at St. Jude Children’s Research Hospital. The proposal describes
research that will provide exceptional training opportunities and generate original and meaningful scientific
findings to launch my career as an independent scientist. The aims build on my prior experience while
simultaneously providing training in the field of HSC biology. I will gain expertise in genome editing and cutting-
edge techniques for visualization and analysis of ECM, including second harmonic generation (SHG) and
polarized light microscopy. In addition, I will take advantage of numerous career development resources.

## Key facts

- **NIH application ID:** 10386197
- **Project number:** 1F32DK128979-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Elizabeth Coffey
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $69,802
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10386197

## Citation

> US National Institutes of Health, RePORTER application 10386197, Lysyl oxidases are novel regulators of definitive hematopoiesis (1F32DK128979-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10386197. Licensed CC0.

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