2020 Modulating endothelial adhesion and migration impacts stem cell therapies efficacy

Authors:
Richard Schäfer, Matthias Schwab, Georg Siegel, Andreas von Ameln-Mayerhofer, Marine Buadze, Ali Lourhmati, et al

Journal:
Journal:  EBioMedicine , 60, 2020, 102987, doi.org/10.1016/j.ebiom.2020.102987.

Institute:

a Institute for Transfusion Medicine and Immunohematology, German Red Cross Blood Donor Service Baden-W€urttemberg-Hessen gGmbH, Goethe-University
Hospital, Frankfurt am Main, Germany
b Institute of Clinical and Experimental Transfusion Medicine, University Hospital T€ubingen, T€ubingen, Germany
c Department of Clinical Pharmacology, University Hospital T€ubingen, T€ubingen, Germany
d Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
e Department of Pharmacy, Sindelfingen-B€oblingen Medical Center, University of T€ubingen, Sindelfingen, Germany
f Departments of Thoracic, Cardiac and Vascular Surgery, University Hospital T€ubingen, T€ubingen, Germany
g Departments of Orthopaedic Surgery, University Hospital T€ubingen, T€ubingen, Germany
h Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital T€ubingen, T€ubingen, Germany
i Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, Modena, Italy
j Department of Neurology, University of Duisburg-Essen, Essen, Germany
k Department of Neurology, University Medical Center G€ottingen, G€ottingen, Germany
l 3T GmbH & Co. KG, Tuttlingen, Germany
m Institute of Transfusion Medicine and Immunology, German Red Cross Blood Service Baden-W€urttemberg− Hessen gGmbH, Medical Faculty Mannheim,
Heidelberg University, Germany
n Institute for Developmental Biology and Neurobiology, Johannes Gutenberg University Mainz, Mainz, Germany
o Neurobiology Laboratory for Brain Aging and Mental Health, Molecular and Cognitive Neuroscience, University of Basel, Basel, Switzerland
p Department of Radiology, University Hospital T€ubingen, T€ubingen, Germany
q Department of Pharmacy and Biochemistry, University of T€ubingen, T€ubingen, Germany
r Neuroscience Laboratory and Departments of Biochemistry and Clinical Pharmacology, Yerevan State Medical University, Yerevan, Armenia

Abstract:

Background: Limited knowledge of stem cell therapies` mechanisms of action hampers their sustainable implementation into the clinic. Specifically, the interactions of transplanted stem cells with the host vasculature and its implications for their therapeutic efficacy are not elucidated.We testedwhether adhesion receptors and chemokine receptors on stem cells can be functionally modulated, and consequently if such modulation may substantially affect therapeutically relevant stemcell interactionswith the host endothelium.
Methods: We investigated the effects of cationic molecule polyethylenimine (PEI) treatment with or without nanoparticles on the functions of adhesion receptors and chemokine receptors of human bone marrowderived Mesenchymal Stem Cells (MSC). Analyses included MSC functions in vitro, as well as homing and
therapeutic efficacy in rodent models of central nervous systems pathologies in vivo.
Findings: PEI treatment did not affect viability, immunomodulation or differentiation potential of MSC, but increased the CCR4 expression and functionally blocked their adhesion receptors, thus decreasing their adhesion capacity in vitro. Intravenously applied in a rat model of brain injury, the homing rate of PEI-MSC in thebrain was highly increased with decreased numbers of adherent PEI-MSC in the lung vasculature. Moreover, in comparison to untreated MSC, PEI-MSC featured increased tumour directed migration in a mouse glioblastoma model, and superior therapeutic efficacy in a murine model of stroke.
Interpretation: Balanced stem cell adhesion and migration in different parts of the vasculature and tissues together with the local microenvironment impacts their therapeutic efficacy.