Cell Therapy for Mood Disorders: Modulation of Immune Activation to Protect the Brain
Denis Gallagher1, Fyyaz Siddiqui1 Siddiq Moolla1, Andrée Gauthier Fisher1, and Clifford Librach1,2,3,4,5,6
1CReATe Fertility Centre; 2Department of Obstetrics and Gynaecology, University of Toronto, Toronto, ON, Canada, 3Institute of Medical Sciences and 4Department of Physiology, University of Toronto, Toronto, ON, Canada; 5Department of Gynecology, Women's College Hospital, Toronto, ON, Canada; 6Sunnybrook Health Sciences Centre, Toronto, ON, Canada
Mood disorders, including major depressive disorder (MDD), are a leading cause of disability worldwide and current treatment approaches remain ineffective or promote unwanted side-effects in many patients. Recent studies using stress-based rodent models and clinical data from MDD patients have implicated aberrant innate immune activation, originating outside the central nervous system, in the emergence of depressive and anxiety-like behaviors. Mesenchymal stromal cells (MSCs) have demonstrated a remarkable ability to interact with cells of the innate immune system and promote resolution of inflammation in chronic inflammatory conditions and may represent a novel therapeutic option for MDD via modulation of peripheral and central immune responses. Here, we demonstrate that intravenous delivery of human umbilical cord-derived MSCs potently modulates peripheral markers of innate immune activation in response to social defeat stress or lipopolysaccharide challenge. MSC infusion also modulates pro-inflammatory mediators in the hippocampus and medial prefrontal cortex and reduces depressive and anxiety-like behaviors. Whole-body biodistribution analyses following MSC infusion indicate that the vast majority of infused cells are located in peripheral organs and tissues suggesting that modulation of neuroinflammation and behavior may occur indirectly via modulation of systemic innate immunity. To our knowledge, this is the first demonstration that peripheral delivery of MSCs modulates CNS inflammatory processes and aberrant behavioral patterns in a stress-based rodent model of MDD / anxiety. These data may open a novel avenue of translational MSC research and potentially identify unexpected targets in the periphery for the treatment of MDD.