STEM CELL-DERIVED ENGINEERED EXTRACELLULAR VESICLE-BASED THERAPEUTIC: A RESOLUTIVE IMMUNOTHERAPY FOR FIBROTIC AND INFLAMMATORY DISEASES

Abstract

Background & Aim Background & Aim: In fibrotic and inflammatory diseases, CD47 is overexpressed in pathological lesions and aggravates the conditions. CD47 on dying cells transfers ‘don't eat me’ signal to immune cells, disturbs efferocytosis, and consequently deteriorates inflammatory response. To address fibrotic and inflammatory diseases, we developed resolutive immunotherapeutic, signal regulatory protein alpha (SIRPα) overexpressed stem cell derived extracellular vesicles (SIRP-EVs). SIRP-EVs efficiently block CD47 on pathological lesions, accelerate clearance of pathological cells, and reduce inflammatory response.

Methods, Results & Conclusion: Methods To validate CD47 as a promising therapeutic target in fibrotic and inflammatory diseases, we evaluated CD47 expression in mouse models; Non-alcoholic Steatohepatitis (NASH), Idiopathic Pulmonary Fibrosis (IPF), Acute Liver Injury (ALI) models. Furthermore, we analyzed human histology and spatial data to confirm the correlation of inflammation and CD47 expression. Using the IVIS Spectrum in vivo imaging system, we validated the biodistribution of SIRP-EV comparing with normal and mouse disease models. We confirmed therapeutic effect of SIRP-EVs in NASH, IPF, ALI models by analyzing biochemistry, histological assessments, survival rate and alleviation of inflammation by cytokine analysis.

Results & Conclusion In fibrotic and inflammatory disease models and human disease tissue, histologic analysis showed that CD47 was overexpressed on pathological lesions compared with normal tissue. Furthermore, human spatial data indicated significant correlation among CD47, macrophage and inflammation. We confirmed that SIRP-EVs preferentially accumulated in pathological lesion in CD47-dependent manner as compared with na？ve MSC derived EVs and pre-blocking with CD47 antibody. Therapeutic effects of SIRP-EVs were confirmed that SIRP-EVs improved histology of disease tissues, biochemistry, survival rate and immune cell profiles from pro-inflammatory state to pro-resolutive state. Moreover, SIRP-EVs showed therapeutic superiority over na？ve MSC-derived EV, CD47 antibody, and conventional treatments in mouse disease models. In conclusion, CD47 is a potential therapeutic target for fibrotic and inflammatory diseases, and SIRP-EVs is promising therapeutic for fibrotic and inflammatory diseases as it alleviates inflammatory response and inducing pro-resolutive state.