Cell motility and migration as determinants of stem cell efficacy.

Alzheimer Disease / therapy Animals Biomarkers Cell Movement Cell Survival Cell Tracking / methods Cells, Cultured Disease Models, Animal Gene Expression Gene Expression Profiling Humans Male Membrane Glycoproteins / genetics Mesenchymal Stem Cells / cytology Mice Mice, Transgenic Neural Stem Cells / cytology Oncolytic Virotherapy Stem Cell Transplantation Stem Cells / cytology Treatment Outcome

Alzheimer´s disease Glioblastoma Intranasal Mesenchymal stem cells Neural stem cells Oncovirolysis

Journal

EBioMedicine

ISSN: 2352-3964

Titre abrégé: EBioMedicine

Pays: Netherlands

ID NLM: 101647039

Informations de publication

Date de publication:
Oct 2020

Historique:

received: 14 04 2020

revised: 13 08 2020

accepted: 20 08 2020

pubmed: 14 9 2020

medline: 20 7 2021

entrez: 13 9 2020

Statut: ppublish

Résumé

Stem cells` (SC) functional heterogeneity and its poorly understood aetiology impedes clinical development of cell-based therapies in regenerative medicine and oncology. Recent studies suggest a strong correlation between the SC migration potential and their therapeutic efficacy in humans. Designating SC migration as a denominator of functional SC heterogeneity, we sought to identify highly migrating subpopulations within different SC classes and evaluate their therapeutic properties in comparison to the parental non-selected cells. We selected highly migrating subpopulations from mesenchymal and neural SC (sMSC and sNSC), characterized their features including but not limited to migratory potential, trophic factor release and transcriptomic signature. To assess lesion-targeted migration and therapeutic properties of isolated subpopulations in vivo, surgical transplantation and intranasal administration of MSCs in mouse models of glioblastoma and Alzheimer's disease respectively were performed. Comparison of parental non-selected cells with isolated subpopulations revealed superior motility and migratory potential of sMSC and sNSC in vitro. We identified podoplanin as a major regulator of migratory features of sMSC/sNSC. Podoplanin engineering improved oncovirolytic activity of virus-loaded NSC on distantly located glioblastoma cells. Finally, sMSC displayed more targeted migration to the tumour site in a mouse glioblastoma model and remarkably higher potency to reduce pathological hallmarks and memory deficits in transgenic Alzheimer's disease mice. Functional heterogeneity of SC is associated with their motility and migration potential which can serve as predictors of SC therapeutic efficacy. This work was supported in part by the Robert Bosch Stiftung (Stuttgart, Germany) and by the IZEPHA grant.

Sections du résumé

BACKGROUND BACKGROUND

METHODS METHODS

We selected highly migrating subpopulations from mesenchymal and neural SC (sMSC and sNSC), characterized their features including but not limited to migratory potential, trophic factor release and transcriptomic signature. To assess lesion-targeted migration and therapeutic properties of isolated subpopulations in vivo, surgical transplantation and intranasal administration of MSCs in mouse models of glioblastoma and Alzheimer's disease respectively were performed.

FINDINGS RESULTS

Comparison of parental non-selected cells with isolated subpopulations revealed superior motility and migratory potential of sMSC and sNSC in vitro. We identified podoplanin as a major regulator of migratory features of sMSC/sNSC. Podoplanin engineering improved oncovirolytic activity of virus-loaded NSC on distantly located glioblastoma cells. Finally, sMSC displayed more targeted migration to the tumour site in a mouse glioblastoma model and remarkably higher potency to reduce pathological hallmarks and memory deficits in transgenic Alzheimer's disease mice.

INTERPRETATION CONCLUSIONS

Functional heterogeneity of SC is associated with their motility and migration potential which can serve as predictors of SC therapeutic efficacy.

FUNDING BACKGROUND

This work was supported in part by the Robert Bosch Stiftung (Stuttgart, Germany) and by the IZEPHA grant.

Identifiants

DOI: 10.1016/j.ebiom.2020.102989 PMID: 32920368 PMC: PMC7494685

pubmed: 32920368

pii: S2352-3964(20)30365-0

doi: 10.1016/j.ebiom.2020.102989

pmc: PMC7494685

pii:

doi:

Substances chimiques

Biomarkers 0

Membrane Glycoproteins 0

PDPN protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

102989

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of Competing Interest Dr. Danielyan reports grants from IZEPHA, during the conduct of the study. Prof.. Schwab, Dr. Schaeffeler and Dr. Winter report grants from Robert Bosch Stiftung (Stuttgart, Germany), during the conduct of the study. Dr. Danielyan, Dr. Schäfer, Prof. Gleiter and Prof. Schwab have a patent US14/634,501, US14/634,484, PCT/EP2016/054055, DE102012107879, EP2888348 pending. All other authors have no competing interests.

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