Physiological oxygen conditions enhance the angiogenic properties of extracellular vesicles from human mesenchymal stem cells.

Adipose stem cells Angiogenesis Bioprocessing Cell-free therapy Cerebral microvascular endothelial cells Exosomes Extracellular vesicles Hypoxia Microvesicles Stroke

Journal

Stem cell research & therapy
ISSN: 1757-6512
Titre abrégé: Stem Cell Res Ther
Pays: England
ID NLM: 101527581

Informations de publication

Date de publication:
23 08 2023
Historique:
received: 30 05 2022
accepted: 01 08 2023
medline: 25 8 2023
pubmed: 24 8 2023
entrez: 23 8 2023
Statut: epublish

Résumé

Following an ischemic injury to the brain, the induction of angiogenesis is critical to neurological recovery. The angiogenic benefits of mesenchymal stem cells (MSCs) have been attributed at least in part to the actions of extracellular vesicles (EVs) that they secrete. EVs are membrane-bound vesicles that contain various angiogenic biomolecules capable of eliciting therapeutic responses and are of relevance in cerebral applications due to their ability to cross the blood-brain barrier (BBB). Though MSCs are commonly cultured under oxygen levels present in injected air, when MSCs are cultured under physiologically relevant oxygen conditions (2-9% O Human adipose-derived MSCs were grown in clinically relevant serum-free medium and exposed to either headspace oxygen concentrations of 18.4% O Compared to normoxic conditions, culturing MSCs under physioxic conditions increased their expression of angiogenic genes SDF1 and VEGF, and subsequently elevated VEGF-A content in the EV fraction. MSC-EVs demonstrated an ability to induce CMEC angiogenesis by promoting tube formation, with the EV fraction from physioxic cultures having the greatest effect. The physioxic EV fraction further upregulated the expression of CMEC angiogenic genes FGF2, HIF1, VEGF and TGFB1, as well as genes (OCLN and TJP1) involved in BBB maintenance. EVs from physioxic MSC cultures hold promise in the generation of a cell-free therapy to induce angiogenesis. Their positive angiogenic effect on cerebral microvascular endothelial cells demonstrates that they may have utility in treating ischemic cerebral conditions, where the induction of angiogenesis is critical to improving recovery and neurological function.

Sections du résumé

BACKGROUND
Following an ischemic injury to the brain, the induction of angiogenesis is critical to neurological recovery. The angiogenic benefits of mesenchymal stem cells (MSCs) have been attributed at least in part to the actions of extracellular vesicles (EVs) that they secrete. EVs are membrane-bound vesicles that contain various angiogenic biomolecules capable of eliciting therapeutic responses and are of relevance in cerebral applications due to their ability to cross the blood-brain barrier (BBB). Though MSCs are commonly cultured under oxygen levels present in injected air, when MSCs are cultured under physiologically relevant oxygen conditions (2-9% O
METHODS
Human adipose-derived MSCs were grown in clinically relevant serum-free medium and exposed to either headspace oxygen concentrations of 18.4% O
RESULTS
Compared to normoxic conditions, culturing MSCs under physioxic conditions increased their expression of angiogenic genes SDF1 and VEGF, and subsequently elevated VEGF-A content in the EV fraction. MSC-EVs demonstrated an ability to induce CMEC angiogenesis by promoting tube formation, with the EV fraction from physioxic cultures having the greatest effect. The physioxic EV fraction further upregulated the expression of CMEC angiogenic genes FGF2, HIF1, VEGF and TGFB1, as well as genes (OCLN and TJP1) involved in BBB maintenance.
CONCLUSIONS
EVs from physioxic MSC cultures hold promise in the generation of a cell-free therapy to induce angiogenesis. Their positive angiogenic effect on cerebral microvascular endothelial cells demonstrates that they may have utility in treating ischemic cerebral conditions, where the induction of angiogenesis is critical to improving recovery and neurological function.

Identifiants

pubmed: 37612731
doi: 10.1186/s13287-023-03439-9
pii: 10.1186/s13287-023-03439-9
pmc: PMC10463845
doi:

Substances chimiques

Vascular Endothelial Growth Factor A 0
Immunologic Factors 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

218

Informations de copyright

© 2023. BioMed Central Ltd., part of Springer Nature.

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Auteurs

Jolene Phelps (J)

Pharmaceutical Production Research Facility, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB, T2N 1N4, Canada.
Department of Biomedical Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB, T2N 1N4, Canada.
McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive N.W., Calgary, AB, T2N 4Z6, Canada.

David A Hart (DA)

Department of Biomedical Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB, T2N 1N4, Canada.
Department of Surgery, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB, T2N 4N1, Canada.
McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive N.W., Calgary, AB, T2N 4Z6, Canada.

Alim P Mitha (AP)

Department of Biomedical Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB, T2N 1N4, Canada.
Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, 3300 Hospital Drive N.W., Calgary, AB, T2N 4N1, Canada.

Neil A Duncan (NA)

Department of Biomedical Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB, T2N 1N4, Canada.
Department of Surgery, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB, T2N 4N1, Canada.
Department of Civil Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB, T2N 1N4, Canada.
Musculoskeletal Mechanobiology and Multiscale Mechanics Bioengineering Lab, Department of Civil Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB, T2N 1N4, Canada.
McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive N.W., Calgary, AB, T2N 4Z6, Canada.

Arindom Sen (A)

Pharmaceutical Production Research Facility, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB, T2N 1N4, Canada. asen@ucalgary.ca.
Department of Chemical and Petroleum Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB, T2N 1N4, Canada. asen@ucalgary.ca.
Department of Biomedical Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB, T2N 1N4, Canada. asen@ucalgary.ca.
McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive N.W., Calgary, AB, T2N 4Z6, Canada. asen@ucalgary.ca.

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