# Developmental Activation of the Inflammasome Controls Hematopoietic Stem Cell Production

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $559,320

## Abstract

SUMMARY
 Hematopoietic stem cells (HSCs) supply the lifelong foundation of the blood and immune systems. HSCs
are therapeutically valuable as HSC transplantation is the standard of care for many hematological diseases.
However, treatment availability remains problematic due to immune incompatibility and donor shortage.
Likewise, while the number of transplanted HSCs directly impacts outcome, there are currently no established
clinical protocols to successfully expand donor-harvested HSCs, nor to differentiate embryonic or induced
pluripotent stem cells (iPSCs) into functional HSCs in vitro. Therefore, the identification of novel modifiers of de
novo production of HSCs with long-term self-renewal and differentiation capacity is a major unmet clinical need.
Despite decades of research, current protocols rely primarily on transcription factor overexpression of force cells
into an “HSC-like” program; however, transplantation of these in vitro-derived HSCs yields only limited long-term
engraftment and multilineage potential. These observations imply that current in vitro differentiation
strategies are missing critical cues which are essential to unlock or maintain full HSC function in vivo.
 HSCs are first formed in the vertebrate embryo from a unique population of mesodermal precursors
termed hemogenic endothelium through a highly conserved process known as endothelial-to-hematopoietic
transition. We have previously utilized the zebrafish model to discover novel regulators of HSC formation,
including the first therapeutic identified in zebrafish to be used in FDA-approved clinical trials. In addition, we
have demonstrated that key extrinsic signals occurring during embryogenesis coordinate the timing and scale of
HSC production. More recently, our lab revealed an essential role for inflammatory signaling in developmental
HSPC formation. However, the mechanism by which sterile inflammation originates in the embryo has not been
determined. Our preliminary data indicate that physiological changes in metabolic state during embryogenesis
initiate sterile inflammatory signaling to stimulate HSC commitment and expansion, without loss of multi-potency.
Our central hypothesis is that “developmental stressors”, such as onset of metabolic activity, activate the
NLRP3-inflammasome to drive sterile IL1β-mediated commitment to HSC production. Our proposed work
will demonstrate the essential role of developmental inflammasome activation in establishing HSPC commitment
and expansion in vivo in zebrafish embryos and in vitro in human iPSC culture. Defining the molecular signaling
pathways that mediate productive HSC formation in vivo will reveal new targets for optimizing the directed
expansion and/or de novo production of human HSCs for therapeutic use.

## Key facts

- **NIH application ID:** 10071431
- **Project number:** 1R01HL154580-01
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** TRISTA E. NORTH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $559,320
- **Award type:** 1
- **Project period:** 2020-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071431

## Citation

> US National Institutes of Health, RePORTER application 10071431, Developmental Activation of the Inflammasome Controls Hematopoietic Stem Cell Production (1R01HL154580-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071431. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*