Modulating endothelial adhesion and migration impacts stem cell therapies efficacy

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 tested whether adhesion receptors and chemokine receptors on stem cells can be functionally modulated, and consequently if such modulation may substantially affect therapeutically relevant stem cell interactions with 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 marrow-derived Mesenchymal Stem Cells (MSC). Analyses included MSC functions in vitro, as well as homing and therapeutic efficacy in rodent models of central nervous system´s 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 the brain 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. Funding Robert Bosch Stiftung, IZEPHA grant, EU grant 7 FP Health

Intravenous injection of mesenchymal stem cell spheroids improves the pulmonary delivery and prolongs in vivo survival

“…Regarding the location of intravenously injected m17.ASC spheroids in the lung, it was reported that intravenously administered MSCs were found outside the blood vessels of the lung. [ 26 ] In addition, another report indicated that MSCs co‐cultured with vascular endothelial cells migrated underneath the vascular endothelial cells. [ 27 ] These reports suggest that intravenously injected MSCs adhere to the vascular endothelial cells of the blood vessels in the lung and migrate to the lung tissue from the blood vessels.…”

More Human BM-MSC With Similar Subpopulation Composition and Functional Characteristics Can Be Produced With a GMP-Compatible Fabric Filter System Compared to Density Gradient Technique

“…Interestingly, the highest median doses have been given intravenously compared to other administration routes ( Kabat et al, 2020 ). Yet, it remains unclear if the known accumulation of MSCs in the lung after systemic application ( Kabat et al, 2020 ; Schäfer et al, 2020 ). is the rationale for such high-dose regimens.…”

“…Surface proteins such as CD271, CD146, MSCA-1, CD106, CD119, CD140a, or distinct mRNA signatures, defining cell clusters within MSC preparations, could be assigned to MSC functions such as differentiation, tissue regeneration, immunomodulation, or wound healing ( Jones and Schäfer, 2015 ; Wu et al, 2016 ; Khong et al, 2019 ; Kuci et al, 2019 ). Moreover, MSC subpopulations’ motility and adhesion capacities can affect their therapeutic efficacy ( Danielyan et al, 2020 ; Schäfer et al, 2020 ).…”

Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke

“…Furthermore, IV administration of PEI-MSCs in a rodent model increases homing rates to the brain and decreases the presence of PEI-MSCs in the lung vasculature. A cell’s ability to adhere and migrate within the local microenvironment influences therapeutic capabilities, as shown in a mouse glioblastoma model with non-PEI-MSCs conversely displays a heightened tumor migration [ 156 ]. Cell-free exosome therapy through the paracrine effect prevents difficulties when compared to cell therapies.…”