title: Transient proteolytic modification of mesenchymal stromal cells increases lung clearance rate and targeting to injured tissue.
abstract: Systemic infusion of therapeutic cells would be the most practical and least invasive method of administration in many cellular therapies. One of the main obstacles especially in intravenous delivery of cells is a massive cell retention in the lungs, which impairs homing to the target tissue and may decrease the therapeutic outcome. In this study we showed that an alternative cell detachment of mesenchymal stromal/stem cells (MSCs) with pronase instead of trypsin significantly accelerated the lung clearance of the cells and, importantly, increased their targeting to an area of injury. Cell detachment with pronase transiently altered the MSC surface protein profile without compromising cell viability, multipotent cell characteristics, or immunomodulative and angiogenic potential. The transient modification of the cell surface protein profile was sufficient to produce effective changes in cell rolling behavior in vitro and, importantly, in the in vivo biodistribution of the cells in mouse, rat, and porcine models. In conclusion, pronase detachment could be used as a method to improve the MSC lung clearance and targeting in vivo. This may have a major impact on the bioavailability of MSCs in future therapeutic regimes.
authors.affiliation: Advanced Therapies and Product Development, Finnish. erja.kerkela@bts.redcross.fi
authors.forename: Erja
authors.initials: E
authors.lastname: Kerkelä
authors.forename: Tanja
authors.initials: T
authors.lastname: Hakkarainen
authors.forename: Tuomas
authors.initials: T
authors.lastname: Mäkelä
authors.forename: Mari
authors.initials: M
authors.lastname: Raki
authors.forename: Oleg
authors.initials: O
authors.lastname: Kambur
authors.forename: Lotta
authors.initials: L
authors.lastname: Kilpinen
authors.forename: Janne
authors.initials: J
authors.lastname: Nikkilä
authors.forename: Siri
authors.initials: S
authors.lastname: Lehtonen
authors.forename: Ilja
authors.initials: I
authors.lastname: Ritamo
authors.forename: Roni
authors.initials: R
authors.lastname: Pernu
authors.forename: Mika
authors.initials: M
authors.lastname: Pietilä
authors.forename: Reijo
authors.initials: R
authors.lastname: Takalo
authors.forename: Tatu
authors.initials: T
authors.lastname: Juvonen
authors.forename: Kim
authors.initials: K
authors.lastname: Bergström
authors.forename: Eija
authors.initials: E
authors.lastname: Kalso
authors.forename: Leena
authors.initials: L
authors.lastname: Valmu
authors.forename: Saara
authors.initials: S
authors.lastname: Laitinen
authors.forename: Petri
authors.initials: P
authors.lastname: Lehenkari
authors.forename: Johanna
authors.initials: J
authors.lastname: Nystedt
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D002351:Carrageenan / Q000633:toxicity; D002454:Cell Differentiation / Q000502:physiology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D004195:Disease Models, Animal; D006085:Graft Survival / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000628:therapy*; D036904:Leukocyte Rolling / Q000502:physiology; D008168:Lung / Q000166:cytology* / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology; D011402:Pronase / Q000378:metabolism; D051381:Rats; D013552:Swine; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D002351:Carrageenan; D011402:Pronase
keywords: Bone marrow stromal cells; Cell adhesion molecules; Cell transplantation; Experimental models; Mesenchymal stem cells