# FSTL-1 Regulated Pathways in Hematopoietic Stem Cell Homeostasis and Transplantation

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $194,715

## Abstract

Hematopoietic stem cell transplantation (HSCT) cures a range of fatal conditions including
immunodeficiency, bone marrow (BM) failure, and malignancy, and more than 20,000 HSCTs
occur annually in the U.S. Decades of research have reduced post-transplant morbidity and
improved survival, but barriers remain substantial including the need for optimal engraftment of
donor stem cells. Indeed, knowledge about the genetic and molecular constituents necessary
for HSC homeostasis and post-transplant engraftment remain incomplete. We have identified
that follistatin-like 1 (FSTL-1) is critical for multilineage reconstitution following HSCT, but the
mechanism remains unknown. Transcriptionally, FSTL-1 is most highly expressed in the rare
population of self-renewing Long-term HSC (LT-HSC). Our preliminary data and reports from
the literature lead us to hypothesize that Fstl1 is critical for both HSC homeostasis and
post-transplant cellular engraftment through its promotion of LT-HSC quiescence. This
idea will be tested in two Specific Aims.
 Aim 1 will determine the impact of FSTL-1 deficiency on HSC homeostasis. Using a
FSTL-1 conditional knock-out (CKO) model, we will determine which HSC populations and
cellular pathways are impacted by FSTL-1 deficiency under homeostatic conditions as well as
the response of FSTL-1 deficient cells to 5-flurouracil induced cell-cycling toxicity.
 Aim 2 will determine the impact of FSTL-1 modulation on HSC and bone marrow
engraftment. Here, using FSTL-1 CKO cells, we will determine the impact of FSTL-1
deficiency directly in a highly purified LT-HSCs population and will determine FSTL-1 role in
HSC self-renewal using serial transplantation and in vitro colony-forming assays. Separately, we
will develop a lentiviral system for ectopic FSTL-1 expression, followed by efforts to rescue the
diminished engraftment of FSTL-1-deficient cells. Finally, we will test whether lentiviral-driven
FSTL-1 expression can enhance HSCT engraftment independent of FSTL-1 deficiency.
 Cumulatively, the proposed studies will focus on defining the role of FSTL-1 in HSC
homeostasis and immune reconstitution. The findings will benefit the fields of stem cell biology,
immune system development, and preclinical modeling of cellular transplantation, as well as the
study of FSTL-1 cellular and molecular signaling. Ultimately, this work will inform novel
approaches to improve human disease in the fields of primary immunodeficiency and impaired
HSC function, and blood and marrow transplantation.

## Key facts

- **NIH application ID:** 10354774
- **Project number:** 1R21AI166697-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Craig Alan Byersdorfer
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $194,715
- **Award type:** 1
- **Project period:** 2022-05-05 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10354774

## Citation

> US National Institutes of Health, RePORTER application 10354774, FSTL-1 Regulated Pathways in Hematopoietic Stem Cell Homeostasis and Transplantation (1R21AI166697-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10354774. Licensed CC0.

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