Abstract
Evidence suggests that adult stem cell types and progenitor cells act collectively in a given tissue to maintain and heal organs, such as muscle, through a release of a multitude of molecules packaged into exosomes from the different cell types. Using this principle for the development of bioinspired therapeutics that induces homeostatic renormalization, here we show that the collection of molecules released from four cell types, including mesenchymal stem cells, fibroblast, neural stem cells, and astrocytes, rescues degenerating neurons and cells. Specifically, oxidative stress induced in a human recombinant TDP‐43‐ or FUS‐tGFP U2OS cell line by exposure to sodium arsenite was shown to be significantly reduced by our collection of molecules using in vitro imaging of FUS and TDP‐43 stress granules. Furthermore, we also show that the collective secretome rescues cortical neurons from glutamate toxicity as evidenced by increased neurite outgrowth, reduced LDH release, and reduced caspase 3/7 activity. These data are the first in a series supporting the development of stem cell‐based exosome systems therapeutics that uses a physiological renormalization strategy to treat neurodegenerative diseases.
Highlights
Physiological renormalization of the immune system instead of enhancement and direct attack is a new strategy in the successful development of recent chemotherapeutics for cancer (Sanmamed and Chen 2018), a strategy for which the 2018 Nobel Prize in Physiology or Medicine was awarded
Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society
The results we present here show a significant reduction in FUS and TDP-43 stress granule formation, LDH release, and caspase 3/7 activation, along with an increase in neurite outgrowth in the presence of our collective secretome when the neurons were challenged with glutamate
Summary
Physiological renormalization of the immune system instead of enhancement and direct attack is a new strategy in the successful development of recent chemotherapeutics for cancer (Sanmamed and Chen 2018), a strategy for which the 2018 Nobel Prize in Physiology or Medicine was awarded. Strategies of immune normalization therapy instead of enhancement of the immune system or a therapeutic direct attack of the cancer cells, has renormalized T-cell physiology to perform their normal attack of cancer cells through the B7-H1/ PD-1 pathway, bringing many new oncology “checkpoint blockade” drugs to the market (Zappasodi et al 2018). Using a physiological renormalization process to treat diseases may be a therapeutic development strategy that is more efficacious and safer than targeted, genomic approaches that dominate today, and have been overhyped in the USA and elsewhere (Woloshin et al 2009; Prasad 2016).
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