Astrocyte-derived extracellular vesicles enhance the survival and electrophysiological function of human cortical neurons in vitro

Changho Chun; Alec S T Smith; Hyejin Kim; Dana S Kamenz; Jung Hyun Lee; Jong Bum Lee; David L Mack; Mark Bothwell; Claire D Clelland; Deok-Ho Kim

doi:10.1016/j.biomaterials.2021.120700

Astrocyte-derived extracellular vesicles enhance the survival and electrophysiological function of human cortical neurons in vitro

Biomaterials. 2021 Apr:271:120700. doi: 10.1016/j.biomaterials.2021.120700. Epub 2021 Feb 3.

Authors

Affiliations

¹ Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA.
² Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, 98109, USA; Department of Physiology & Biophysics, University of Washington, Seattle, WA, 98195, USA.
³ Department of Chemical Engineering, University of Seoul, Seoul, South Korea.
⁴ Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, 98109, USA; Division of Dermatology, School of Medicine, University of Washington, Seattle, WA, 98195, USA.
⁵ Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, 98109, USA; Department of Rehabilitation Medicine, University of Washington, Seattle, WA, 98195, USA.
⁶ Gladstone Institute, San Francisco, CA, 94158, USA; Department of Neurology, University of California San Francisco, San Francisco, CA, 94143, USA.
⁷ Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, 98109, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21205, USA; Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA; Department of Physical Medicine and Rehabilitation, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. Electronic address: dhkim@jhu.edu.

Abstract

Neurons derived from human induced pluripotent stem cells (hiPSCs) are powerful tools for modeling neural pathophysiology and preclinical efficacy/toxicity screening of novel therapeutic compounds. However, human neurons cultured in vitro typically do not fully recapitulate the physiology of the human nervous system, especially in terms of exhibiting morphological maturation, longevity, and electrochemical signaling ability comparable to that of adult human neurons. In this study, we investigated the potential for astrocyte-derived extracellular vesicles (EVs) to modulate survival and electrophysiological function of human neurons in vitro. Specifically, we demonstrate that EVs obtained from human astrocytes promote enhanced single cell electrophysiological function and anti-apoptotic behavior in a homogeneous population of human iPSC-derived cortical neurons. Furthermore, EV-proteomic analysis was performed to identify cargo proteins with the potential to promote the physiological enhancement observed. EV cargos were found to include neuroprotective proteins such as heat shock proteins, alpha-synuclein, and lipoprotein receptor-related protein 1 (LRP1), as well as apolipoprotein E (APOE), which negatively regulates neuronal apoptosis, and a peroxidasin homolog that supports neuronal oxidative stress management. Proteins that positively regulate neuronal excitability and synaptic development were also detected, such as potassium channel tetramerization domain containing 12 (KCTD12), glucose-6- phosphate dehydrogenase (G6PD), kinesin family member 5B (KIF5B), spectrin-alpha non-erythrocytic1 (SPTAN1). The remarkable improvements in electrophysiological function and evident inhibition of apoptotic signaling in cultured neurons exposed to these cargos may hold significance for improving preclinical in vitro screening modalities. In addition, our collected data highlight the potential for EV-based therapeutics as a potential class of future clinical treatment for tackling inveterate central and peripheral neuropathies.

Keywords: Astrocyte; Electrophysiology; Extracellular vesicles; Human cortical neuron; Survival.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Astrocytes
Cells, Cultured
Extracellular Vesicles*
Humans
Induced Pluripotent Stem Cells*
Neurons
Peripheral Nervous System Diseases*
Proteomics

Abstract

Publication types

MeSH terms

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