The Complement System Is Essential for the Phagocytosis of Mesenchymal Stromal Cells by Monocytes.

Caroline Gavin,Kathleen Anne Heck,Nina Heldring,Katarina Le Blanc,Adnane Achour,Nadir Kadri,Stephan Meinke,Ellen Iacobaeus,Petter Höglund

doi:10.3389/fimmu.2019.02249

Abstract

Mesenchymal stromal cell (MSC) therapy is a promising tool in the treatment of chronic inflammatory diseases. This has been ascribed to the capacity of MSC to release a large variety of immune-modulatory factors. However, all aspects of the mode of therapeutic MSC action in different diseases remain unresolved, mainly because most of the infused MSC are undetectable in the circulation within hours after infusion. The aim of this study was to elucidate the fate of MSC after contact with plasma. We found that upon contact with blood, complement proteins including C3b/iC3b are deposited on MSC. Importantly, we also found that complement bound to MSC enhanced their phagocytosis by classical and intermediate monocytes via a mechanism that involves C3 but not C5. Thus, we describe for the first time a mechanism which might explain, at least partly, why MSC are not found in the blood circulation after infusion. Our results indicate that MSC immune-modulatory effects could be mediated by monocytes that have phagocytosed them.

Highlights

Mesenchymal stromal cells (MSC) have emerged as a possible new treatment for several chronic inflammatory diseases including diabetes, graft versus host disease, and multiple sclerosis [1]
We report that MSC survive and conserve their phenotypic and functional activities if they are in contact with complement active plasma
Our results demonstrate that the complement factor C3 facilitates phagocytosis of live MSC by classical and intermediate monocytes

Summary

Introduction

Mesenchymal stromal cells (MSC) have emerged as a possible new treatment for several chronic inflammatory diseases including diabetes, graft versus host disease, and multiple sclerosis [1]. Their immune-modulatory function has mainly been ascribed to paracrine mechanisms associated with secretion of immunoregulatory mediators including cytokines and growth factors which modulate inflammatory response and balance immune profiles [2]. MSC have been infused to the circulation [4] but the infused cells have been difficult to detect in the blood already at short time points after infusion [5]. The actual modes of action of intravenous infusion of MSC in several diseases remain unresolved

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