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Cited by 180Extracellular vesicles in diseaseNanoparticle-Based Drug DeliveryMesenchymal stem cell research

Extracellular vesicles from human iPSC‐derived neural stem cells: miRNA and protein signatures, and anti‐inflammatory and neurogenic properties

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Upadhya, Raghavendra, Madhu, Leelavathi N., Attaluri, Sahithi, Gitaí, Daniel Leite Góes, Pinson, Marisa R, Kodali, Maheedhar, Shetty, Geetha, Zanirati, Gabriele +4 more·2020·Journal of Extracellular Vesicles
DOI 10.1080/20013078.2020.1809064PMC PMC7480597
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Abstract

Grafting of neural stem cells (NSCs) derived from human induced pluripotent stem cells (hiPSCs) has shown promise for brain repair after injury or disease, but safety issues have hindered their clinical application. Employing nano‐sized extracellular vesicles (EVs) derived from hiPSC‐NSCs appears to be a safer alternative because they likely have similar neuroreparative properties as NSCs and are amenable for non‐invasive administration as an autologous or allogeneic off‐the‐shelf product. However, reliable methods for isolation, characterization and testing the biological properties of EVs are critically needed for translation. We investigated signatures of miRNAs and proteins and the biological activity of EVs, isolated from hiPSC‐NSCs through a combination of anion‐exchange chromatography (AEC) and size‐exclusion chromatography (SEC). AEC and SEC facilitated the isolation of EVs with intact ultrastructure and expressing CD9, CD63, CD81, ALIX and TSG 101. Small RNA sequencing, proteomic analysis, pathway analysis and validation of select miRNAs and proteins revealed that EVs were enriched with miRNAs and proteins involved in neuroprotective, anti‐apoptotic, antioxidant, anti‐inflammatory, blood‐brain barrier repairing, neurogenic and Aβ reducing activities. Besides, EVs comprised miRNAs and/or proteins capable of promoting synaptogenesis, synaptic plasticity and better cognitive function. Investigations using an in vitro macrophage assay and a mouse model of status epilepticus confirmed the anti‐inflammatory activity of EVs. Furthermore, the intranasal administration of EVs resulted in the incorporation of EVs by neurons, microglia and astrocytes in virtually all adult rat and mouse brain regions, and enhancement of hippocampal neurogenesis. Thus, biologically active EVs containing miRNAs and proteins relevant to brain repair could be isolated from hiPSC‐NSC cultures, making them a suitable biologic for treating neurodegenerative disorders.

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  • A growing body of research has illuminated the therapeutic potential of EVs derived from diverse cell types, including MSCs, iPSCs, brain-derived NSCs, ESCs, and dendritic cells.

    “A growing body of research has illuminated the therapeutic potential of EVs derived from a diverse array of cell types [207, 208]. This includes MSCs [209–211], iPSCs [212], brain-derived NSCs [213], embryonic stem cells (ESCs) [214], and dendritic cells (DC) [215].”

    From Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions (2024) · cites this paper as [212]

    The Introduction and Discussion support therapeutic potential for EVs from neural stem cells derived from human iPSCs, including anti-inflammatory and neurogenic properties. But citation [212] is attached to “iPSCs,” whereas the EVs studied came from iPSC-derived neural stem cells, not directly from iPSCs. The other listed cell types have separate citations and are not attributed to this source. (LLM, conf=0.87)

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  • Stem cell-derived EVs have demonstrated similar neuroprotective, anti-inflammatory, and neurogenic properties as their parent cells, making them optimal particles for PD treatment.

    “Stem cell-derived EVs have demonstrated similar neuroprotective, anti-inflammatory, and neurogenic properties as their parent cells, making them optimal particles for PD treatment [212].”

    From Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions (2024) · cites this paper as [212]

    The Discussion reports that hiPSC-derived neural stem cell EVs showed anti-inflammatory and neurogenic effects, and that their cargo includes molecules with known neuroprotective activities. The Introduction describes EVs as potentially mimicking stem-cell properties, but the paper does not demonstrate equivalent neuroprotection or establish these EVs as optimal for Parkinson’s disease treatment; its Discussion frames use in neurodegenerative disorders as a possibility. (LLM, conf=0.88)

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Authors
Upadhya, R., Madhu, L. N., Attaluri, S., Gitaí, D. L. G., Pinson, M. R., Kodali, M., Shetty, G., Zanirati, G., Kumar, S., Shuai, B., Weintraub, S. T., & Shetty, A. K.
Affiliations
  • Texas A&M Health Science Center (US)
  • Universidade Federal de Alagoas (BR)
  • The University of Texas at San Antonio Health Science Center (US)
Corresponding author
Shetty, Ashok K.
ORCID
Venue
Journal of Extracellular Vesicles
Publisher
Wiley
Published
2020-08-26
Volume
9
Issue
1
Pages
1809064-1809064
ISSN
2001-3078 (ISSN-L)
DOI
10.1080/20013078.2020.1809064
PMC
PMC7480597
OpenAlex
W3081869224
Cited by
180
References
4
Citations by year
2026: 13 · 2025: 32 · 2024: 36 · 2023: 39 · 2022: 37 · 2021: 22 · 2020: 1
FWCI
8.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Extracellular Vesicles (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of Neurological Disorders and Stroke (1R01NS106907-01)
  • Texas Emerging Technology Fund (State of Texas)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
extracellular vesicles, human induced pluripotent stem cells, neural stem cells, microRNA, proteomic signatures, anti-inflammatory activity, neurogenesis, status epilepticus, intranasal administration, blood-brain barrier repair, synaptogenesis, synaptic plasticity, neurodegenerative diseases, brain repair, macrophages, vesicle isolation, anion exchange chromatography, size exclusion chromatography

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