# Small-molecule combinationsexpand hematopoietic stem cell ex vivo and in vivo

> **NIH NIH R41** · ADVAC THERAPEUTIC, LLC · 2020 · $203,302

## Abstract

Small-molecule combinations expand hematopoietic stem cell ex vivo and in vivo
Abstract
Hematopoietic stem cells (HSCs) are featured by their self-renewal potential and ability to differentiate into
multiple blood lineages. Hematopoietic stem cell transplant (HSCT) is a mainstay of life-saving therapy for
hematopoietic malignancies and hypoproliferative disorders. The use of noninvasively accessible umbilical
cord blood (UCB)-derived HSCs provides many advantages over bone marrow and peripheral blood HSC,
including less stringent requirement for human leukocyte antigen (HLA) match, decreased risk of graft-versus-
host disease (GVHD), etc. However, limited cell dose in a UCB unit may lead to significant problems such as
delayed engraftment, engraftment failure, and severe infectious complications. The expansion of HSCs from
UCB has remained an important goal to develop advanced cell therapies for enhancing transplantation efficacy
and providing potential cure for various hematological diseases.
Recent studies have achieved ex vivo expansion of HSCs using cytokine cocktails combined with small
molecules, including pyrimidoindole derivative (UM171), aryl hydrocarbon receptor antagonist (SR1). The
major disadvantage with these approaches is that it is only effective in the presence of high concentration of
cytokines. Cytokines have been known to induce differentiation and affect the function of primitive HSC, they
might have long-term deleterious effect on humans due to skewed reconstitution of the hematopoietic system.
The small-molecule combinations with minimal cytokines would be ideal for clinical applications. Our published
studies demonstrated a combination of two inhibitors (2i) allows the ex vivo maintenance of human and mouse
long-term HSCs and doing so under cytokine-free condition. The combination of two clinical drugs (lithium plus
rapamycin) leads to increase of long-term mouse HSCs in vivo. In our recent studies, we found that 2i works
synergistically with SR1 under low cytokine condition, significantly expanded long-term functional HSC ex vivo.
In this project, we will carry out studies to optimize culture condition of small-molecule combination regimens.
Furthermore, we will test and optimize the in vivo expansion method, which will greatly improve the successful
rate of HSC transplantation. Our major goal is to develop new clinical protocols for expanding functional UCB-
derived HSCs for therapeutic applications.

## Key facts

- **NIH application ID:** 10018098
- **Project number:** 5R41HL145877-02
- **Recipient organization:** ADVAC THERAPEUTIC, LLC
- **Principal Investigator:** Jian Huang
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $203,302
- **Award type:** 5
- **Project period:** 2019-09-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018098

## Citation

> US National Institutes of Health, RePORTER application 10018098, Small-molecule combinationsexpand hematopoietic stem cell ex vivo and in vivo (5R41HL145877-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10018098. Licensed CC0.

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