Embryonic stem cell-derived macrophages: a novel approach to developing anti-inflammatory macrophages for cell therapy

Abstract

Ischemia /reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) that is associated with high morbidity and mortality. Macrophages (Mφ) are multifunctional cells involved in the initiation, progression and resolution of kidney inflammation response. The enzyme hemeoxygenase -1 (HO -1) is upregulated in response to cell stress and metabolises heme- containing proteins to carbon monoxide (CO) and bilirubin that possess anti -apoptotic and anti -oxidant properties. Previous work has shown that Mcp can be used as therapeutic vectors with the administration of bone marrow -derived macrophages (BMDM) overexpressing HO -1 being protective in murine renal IRI (Ferenbach et al., 2010). However, these studies used primary BMDM that are inherently heterogeneous with the genetic manipulation achieved by adenoviral transduction that is not suitable for use in patients. Previous work has shown that pure Mq populations may be generated from murine and human embryonic stem cells (ESC) in vitro, providing an essentially limitless source of Mcp that can be derived from genetically manipulated cells. This project has adopted an ESC approach to develop anti -inflammatory ESC -derived macrophages (ESDM) overexpressing HO -1 for therapeutic use in experimental models of AKI. We successfully generated Mq from ESC and demonstrate that ESDM are comparable to BMDM in all properties that we tested. ESDM are large mononuclear cells and express Mcp cell surface markers (F4/80ʰᶦᵍʰ CD11bʰᶦᵍʰ CD11cʰᶦᵍʰ MHC class Ilˡᵒʷ) ESDM are phagocytic and produce pro -inflammatory mediators when activated by lipopolysaccharide and interferon -y (LPS and IFNγ).