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Exosome/microvesicle content is altered in leucine‐rich repeat kinase 2 mutant induced pluripotent stem cell‐derived neural cells
Author(s) -
Candelario Kate M.,
Balaj Leonora,
Zheng Tong,
Skog Johan,
Scheffler Bjorn,
Breakefield Xandra,
Schüle Birgitt,
Steindler Dennis A.
Publication year - 2020
Publication title -
journal of comparative neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.855
H-Index - 209
eISSN - 1096-9861
pISSN - 0021-9967
DOI - 10.1002/cne.24819
Subject(s) - induced pluripotent stem cell , biology , microvesicles , microbiology and biotechnology , microvesicle , progenitor cell , neural stem cell , stem cell , gene expression profiling , exosome , gene , gene expression , microrna , genetics , embryonic stem cell
Extracellular vesicles, including exosomes/microvesicles (EMVs), have been described as sensitive biomarkers that represent disease states and response to therapies. In light of recent reports of disease‐mirroring EMV molecular signatures, the present study profiled two EMVs from different Parkinson's disease (PD) tissue sources: (a) neural progenitor cells derived from an endogenous adult stem/progenitor cell, called adult human neural progenitor (AHNP) cells, that we found to be pathological when isolated from postmortem PD patients' substantia nigra; and (b) leucine‐rich repeat kinase 2 (LRRK2) gene identified patient induced pluripotent stem cells (iPSCs), which were used to isolate EMVs and begin to characterize their cargoes. Initial characterization of EMVs derived from idiopathic patients (AHNPs) and mutant LRRK2 patients showed differences between both phenotypes and when compared with a sibling control in EMV size and release based on Nanosight analysis. Furthermore, molecular profiling disclosed that neurodegenerative‐related gene pathways altered in PD can be reversed using gene‐editing approaches. In fact, the EMV cargo genes exhibited normal expression patterns after gene editing. This study shows that EMVs have the potential to serve as sensitive biomarkers of disease state in both idiopathic and gene‐identified PD patients and that following gene‐editing, EMVs reflect a corrected state. This is relevant for both prodromal and symptomatic patient populations where potential responses to therapies can be monitored via non‐invasive liquid biopsies and EMV characterizations.