# CD47-SIRPalpha Signaling in Mesenchymal Stem Cell-Mediated Immune Regulation in Liver Transplant Inflammatory Injury

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $234,000

## Abstract

PROJECT SUMMARY
Innate immune-driven local inflammation response induced by ischemia-reperfusion injury (IRI) causes hepatic
dysfunction and failure following liver transplantation. Mesenchymal stem cells (MSCs) has provided new
insights into their potential clinical application, particularly for treating a variety of immune-mediated diseases.
Previous studies have shown that crosstalk between MSCs and inflammatory cells is crucial in the mechanism
of MSC-mediated immune modulation and tissue repair. Indeed, MSC-based therapy has been successfully
applied in various human diseases. However, a number of clinical phase III trials of MSC immunotherapy failed
to meet the primary endpoints because of the low efficacy of engrafted cells. Thus, increasing the
immunosuppressive property of MSC by exploring novel immunoregulatory mechanisms emerges as one of
the key challenges of MSC therapy. CD47 (integrin-associated protein, IAP) is a cell surface protein and
expressed by virtually all cells in the body. CD47 expression is increased in hematopoietic stem cells (HSCs)
after mobilization or induced inflammation. Ligation of CD47 can induce intracellular signaling resulting in cell
differentiation and activation in response to stress. By binding to the cell surface glycoprotein, signal regulatory
protein alpha (SIRPα), an inhibitory transmembrane receptor present on myeloid cells, CD47 can regulate cell
function in the monocyte/macrophage lineage. Indeed, SIRPα is abundantly expressed in macrophages and
has been implicated in regulating innate immunity during inflammatory response. SIRPα deficiency enhanced
macrophage NF-κB activation and increased pro-inflammatory mediators, implying that SIRPα is an essential
endogenous regulator of the innate immunity. A previous study has shown that Notch1 signaling regulates
macrophage function and TLR4/NF-κB-driven inflammatory responses in IR-stressed mouse livers. It has also
documented that Notch1 signaling alleviates the hepatocellular damage in orthotopic liver transplantation
(OLT) in humans. Thus, CD47/SIRPα and Notch1 pathways are likely essential in the MSC-mediated
regulation of innate immune responses in OLT. The overall goal of this proposal is to dissect the function of
intracellular CD47/SIRPα signaling in MSC-mediated immune regulation and enhance MSC therapeutic
efficacy by genetically modifying CD47/SIRPα in murine OLT. The hypothesis is that CD47/SIRPα signaling
controls TLR4-driven inflammation in OLT recipients through activation of the Notch-Hes1 axis in MSC-
mediated immune regulation. To test this hypothesis, the following specific aims are proposed: 1) Analyze the
role of the CD47-SIRPα interaction in regulating TLR4-driven inflammatory response in MSC-mediated
immune regulation in vitro; 2) Investigate the ability of immune regulation by CD47-modified MSC in vivo.
These studies will increase understanding of CD47/SIRPα-mediated regulatory networks in MSC-mediated
immunotherapy. Indeed, geneti...

## Key facts

- **NIH application ID:** 9949648
- **Project number:** 5R21AI146742-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Bibo Ke
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $234,000
- **Award type:** 5
- **Project period:** 2019-06-11 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949648

## Citation

> US National Institutes of Health, RePORTER application 9949648, CD47-SIRPalpha Signaling in Mesenchymal Stem Cell-Mediated Immune Regulation in Liver Transplant Inflammatory Injury (5R21AI146742-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9949648. Licensed CC0.

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