# Mechanism and Function of Endoplasmic Reticulum Protein Quality Control Machinery In The Maintenance of Hematopoietic Stem Cells

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $506,177

## Abstract

ABSTRACT
Hematopoietic stem cells (HSCs) maintain tissue homeostasis and replenish blood system upon stresses.
HSCs have evolved unique mechanisms to maintain genome and proteome integrity throughout life. While the
genome integrity safeguard mechanisms have been extensively studied, little is known about how proteome
integrity is maintained in HSCs and how dormant HSCs are protected from protein damage during
development and physiological stresses. This proposal will address this knowledge gap. We recently found
that the Sel1L ER-associated degradation (ERAD) pathway plays an essential role in the maintenance of
HSCs. ERAD is the principal protein quality control mechanism responsible for targeting misfolded proteins in
the ER for cytosolic proteasomal degradation. The Sel1L-Hrd1 complex is the most conserved branch of
ERAD. Using a conditional knockout mouse model, we found that Sel1L deletion in hematopoietic cells
significantly reduced steady-state HSC frequency and led to complete loss of HSC reconstitution capacity in
stress conditions including bone marrow transplantation and 5-fluorouracil (5-FU) mediated myeloablation.
Interestingly, Sel1L deletion did not induce apoptosis or impair HSC engraftment. In contrast, we observed
increased HSC cycling and reduced numbers of quiescent HSCs in Sel1L knockout mice. These data
demonstrate the critical function of Sel1L ERAD in HSC maintenance and suggest a novel role for ER protein
quality control machinery in regulating stem cell quiescence and self-renewal. ERAD monitors and regulates
the maturation of transmembrane proteins. We found markedly decreased surface expression of CXCR4 and
MPL, two master regulators of HSC quiescence and niche interaction, in Sel1L-knockout HSCs. Tracking HSC
and niche cells at the single cell level in vivo showed aberrant localization of Sel1L-deficient HSCs in the bone
marrow niche. We hypothesize that Sel1L ERAD governs HSC quiescence and self-renewal by regulating HSC
transmembrane receptor maturation and HSC-niche interaction. We will establish the physiological significance
of Sel1L ERAD in the maintenance of HSCs (Aim 1), determine the significance and mechanism of the ERAD-
Unfolded Protein Response (UPR) crosstalk in HSCs (Aim 2), and elucidate the mechanism and significance of
Sel1L ERAD in HSC-niche interactions (Aim 3). This study will provide significant insight into the post-
translational regulation of HSC quiescence, self-renewal, and niche interaction by ER protein quality control
mechanisms, and further identify novel determinants of HSC fates.

## Key facts

- **NIH application ID:** 9899308
- **Project number:** 5R01HL146642-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Xi Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $506,177
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899308

## Citation

> US National Institutes of Health, RePORTER application 9899308, Mechanism and Function of Endoplasmic Reticulum Protein Quality Control Machinery In The Maintenance of Hematopoietic Stem Cells (5R01HL146642-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9899308. Licensed CC0.

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