Novel Evidence That Alternative Pathway of Complement Cascade Activation is Required for Optimal Homing and Engraftment of Hematopoietic Stem/progenitor Cells

Mateusz Adamiak,Magdalena Kucia,Janina Ratajczak,Andrzej Ciechanowicz,Kamila Bujko,Vira Chumak,Mariusz Z Ratajczak,Katarzyna Brzezniakiewicz-Janus

doi:10.1007/s12015-021-10318-4

Abstract

We reported in the past that activation of the third (C3) and fifth element (C5) of complement cascade (ComC) is required for a proper homing and engraftment of transplanted hematopoietic stem/progenitor cells (HSPCs). Since myeloablative conditioning for transplantation triggers in recipient bone marrow (BM) state of sterile inflammation, we have become interested in the role of complement in this process and the potential involvement of alternative pathway of ComC activation. We noticed that factor B deficient mice (FB-KO) that do not activate properly alternative pathway, engraft poorly with BM cells from normal wild type (WT) mice. We observed defects both in homing and engraftment of transplanted HSPCs. To shed more light on these phenomena, we found that myeloablative lethal irradiation conditioning for transplantation activates purinergic signaling, ComC, and Nlrp3 inflammasome in WT mice, which is significantly impaired in FB-KO animals. Our proteomics analysis revealed that conditioned for transplantation lethally irradiated FB-KO compared to normal control animals have lower expression of several proteins involved in positive regulation of cell migration, trans-endothelial migration, immune system, cellular signaling protein, and metabolic pathways. Overall, our recent study further supports the role of innate immunity in homing and engraftment of HSPCs.Graphical

Highlights

We postulated that myeloablative conditioning for hematopoietic stem/progenitor cells (HSPCs) transplantation induces in bone marrow (BM) of transplant recipients a state of sterile inflammation [1, 2] as a result of activation
The seminal observation of this report is that an alternative pathway of complement cascade (ComC) is required for optimal homing and engraftment of transplanted HSPCs
Our current work with mice that show a defect in activation of alternative pathway of ComC further supports a role of innate immunity in orchestrating homing and engraftment of HSPCs

Summary

Introduction

Stem Cell Reviews and Reports (2022) 18:1355–1365 of innate immunity cellular and soluble component arms. The cellular arm is composed of cells that survive in BM myeloablative treatment – e.g., radioresistant macrophages, and the soluble arm of the innate immune system comprises complement cascade (Com) proteins [3–5]. The ComC consists of several zymogen proteins that become activated by proteolytic cleavage in a cascade-mediated manner, and this activation is triggered by (i) classical, (ii) mannan-binding lectin (MBL), or (iii) alternative pathways [9, 10]. Previous data from our laboratory demonstrated a pivotal role of ComC in the optimal pharmacological mobilization of HSPCs in response to cytokine granulocyte colony-stimulating factor (G-CSF) or a smallmolecule inhibitor of the chemokine receptor CXCR4 that is AMD3100 [11]. Mice that did not activate MBL and alternative ComC pathways properly were found to be poor mobilizers of HSPCs [12, 13]

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