# Novel mechanisms involving complement cascade in stem cell trafficking

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2020 · $346,500

## Abstract

Modified Project Summary/Abstract Section
The main hypothesis of this competing renewal is based on new exciting data that further supports the pivotal
role of the complement cascade (ComC) and other elements of innate immunity in the mobilization of
hematopoietic stem/progenitor cells (HSPCs). The ComC is activated by the i) classical, ii) mannan-binding
lectin (Mbl), and iii) alternative pathways, and, as we already reported, mice that lack the common distal
component of the ComC (C5–/– mice), are poor mobilizers. To our surprise, however, we found that mice that
do not activate the classical ComC (C1q–/– mice) are normal mobilizers. This “discrepancy” is now explained by
our latest results that show the pivotal involvement of the Mbl-dependent ComC pathway and not the classical
pathway in mobilization. We also recently found that two stress-induced enzymes, heme oxygenase 1 (HO-1)
and inducible nitric oxide synthetase (iNOS), are negative regulators of cell migration. Based on these findings,
we have assembled a proposal that, in a comprehensive way, addresses the involvement of elements of innate
immunity (ComC, Gr-1+ granulocytes/monocytes, naturally occurring antibodies) in the mobilization of HSPCs.
In three interrelated specific aims, we address the crucial: i) inititation, ii) amplification, and execution phases of
mobilization. Specific Aim 1. The initiation phase of mobilization is explained by Mbl-mediated ComC
activation. We have maintained that the classical ComC activation pathway plays a crucial role in triggering
mobilization. However, as we discovered recently, it is not the classical but the Mbl pathway that is crucial in
this process. The main target cells for mobilizing agents are Gr-1+ cells, which, in addition to proteolytic and
lipolytic enzymes, also secrete ROS and danger-associated molecular pattern molecules (DAMPs). While
proteolyic and lipolytic enzymes perturb the retention of HSPCs in bone marrow (BM) niches, ROS-exposed
neoepitope antigens bound by naturally occurring IgM antibodies and DAMPs released from Gr-1+ cells are
recognized by the circulating pattern recognition receptor (PRR) Mbl, which, via mannan-binding lectin serine
proteases (MASPs), activates the ComC and coagulation cascade (CoaC). Specific Aim 2. The amplification
phase of mobilization - the generation of C5 convertase. Since C5 cleavage is crucial for egress of HSPCs
from BM, the main function of this phase is generation of C5 convertase activity. This enzyme is generated as
a result of C3 cleavage, which provides elements of classical C5 convertase, and additionally by thrombin,
which has C5 “convertase-like” activity. The amplification phase is also modulated by a spontaneous
amplification loop of C3 activation and by possible involvement of an alternative pathway of ComC activation
and will be studied in detail in this aim. Specific Aim 3. Execution phase of ComC-mediated mobilization.
Our recent results show that egress of HSPCs from BM is n...

## Key facts

- **NIH application ID:** 9984349
- **Project number:** 5R01DK074720-13
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Mariusz Z Ratajczak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $346,500
- **Award type:** 5
- **Project period:** 2007-03-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984349

## Citation

> US National Institutes of Health, RePORTER application 9984349, Novel mechanisms involving complement cascade in stem cell trafficking (5R01DK074720-13). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9984349. Licensed CC0.

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