title: Cell surface structures influence lung clearance rate of systemically infused mesenchymal stromal cells.
abstract: The promising clinical effects of mesenchymal stromal/stem cells (MSCs) rely especially on paracrine and nonimmunogenic mechanisms. Delivery routes are essential for the efficacy of cell therapy and systemic delivery by infusion is the obvious goal for many forms of MSC therapy. Lung adhesion of MSCs might, however, be a major obstacle yet to overcome. Current knowledge does not allow us to make sound conclusions whether MSC lung entrapment is harmful or beneficial, and thus we wanted to explore MSC lung adhesion in greater detail. We found a striking difference in the lung clearance rate of systemically infused MSCs derived from two different clinical sources, namely bone marrow (BM-MSCs) and umbilical cord blood (UCB-MSCs). The BM-MSCs and UCB-MSCs used in this study differed in cell size, but our results also indicated other mechanisms behind the lung adherence. A detailed analysis of the cell surface profiles revealed differences in the expression of relevant adhesion molecules. The UCB-MSCs had higher expression levels of α4 integrin (CD49d, VLA-4), α6 integrin (CD49f, VLA-6), and the hepatocyte growth factor receptor (c-Met) and a higher general fucosylation level. Strikingly, the level of CD49d and CD49f expression could be functionally linked with the lung clearance rate. Additionally, we saw a possible link between MSC lung adherence and higher fibronectin expression and we show that the expression of fibronectin increases with MSC culture confluence. Future studies should aim at developing methods of transiently modifying the cell surface structures in order to improve the delivery of therapeutic cells.
authors.affiliation: Advanced Therapies and Product Development, Finnish Red Cross Blood Service, Helsinki, Finland. johanna.nystedt@bts.redcross.fi
authors.forename: Johanna
authors.initials: J
authors.lastname: Nystedt
authors.forename: Heidi
authors.initials: H
authors.lastname: Anderson
authors.forename: Jonne
authors.initials: J
authors.lastname: Tikkanen
authors.forename: Mika
authors.initials: M
authors.lastname: Pietilä
authors.forename: Tia
authors.initials: T
authors.lastname: Hirvonen
authors.forename: Reijo
authors.initials: R
authors.lastname: Takalo
authors.forename: Annamari
authors.initials: A
authors.lastname: Heiskanen
authors.forename: Tero
authors.initials: T
authors.lastname: Satomaa
authors.forename: Suvi
authors.initials: S
authors.lastname: Natunen
authors.forename: Siri
authors.initials: S
authors.lastname: Lehtonen
authors.forename: Tanja
authors.initials: T
authors.lastname: Hakkarainen
authors.forename: Matti
authors.initials: M
authors.lastname: Korhonen
authors.forename: Saara
authors.initials: S
authors.lastname: Laitinen
authors.forename: Leena
authors.initials: L
authors.lastname: Valmu
authors.forename: Petri
authors.initials: P
authors.lastname: Lehenkari
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002448:Cell Adhesion; D002454:Cell Differentiation; D036101:Cord Blood Stem Cell Transplantation; D005260:Female; D005312:Fetal Blood / Q000166:cytology* / Q000378:metabolism; D015870:Gene Expression; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D039441:Integrin alpha4 / Q000235:genetics / Q000378:metabolism; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000378:metabolism; D039503:Integrin alpha6 / Q000235:genetics / Q000378:metabolism; D039121:Integrin alpha6beta1 / Q000235:genetics / Q000378:metabolism; D007553:Isotope Labeling; D008168:Lung / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D017556:Technetium Compounds; D014183:Transplantation, Heterologous
chemical_list: D015415:Biomarkers; D039041:Integrin alpha4beta1; D039503:Integrin alpha6; D039121:Integrin alpha6beta1; D017556:Technetium Compounds; D039441:Integrin alpha4; D019859:Proto-Oncogene Proteins c-met