title: Pharmacokinetics of natural and engineered secreted factors delivered by mesenchymal stromal cells.
abstract: Transient cell therapy is an emerging drug class that requires new approaches for pharmacological monitoring during use. Human mesenchymal stem cells (MSCs) are a clinically-tested transient cell therapeutic that naturally secrete anti-inflammatory factors to attenuate immune-mediated diseases. MSCs were used as a proof-of-concept with the hypothesis that measuring the release of secreted factors after cell transplantation, rather than the biodistribution of the cells alone, would be an alternative monitoring tool to understand the exposure of a subject to MSCs. By comparing cellular engraftment and the associated serum concentration of secreted factors released from the graft, we observed clear differences between the pharmacokinetics of MSCs and their secreted factors. Exploration of the effects of natural or engineered secreted proteins, active cellular secretion pathways, and clearance mechanisms revealed novel aspects that affect the systemic exposure of the host to secreted factors from a cellular therapeutic. We assert that a combined consideration of cell delivery strategies and molecular pharmacokinetics can provide a more predictive model for outcomes of MSC transplantation and potentially other transient cell therapeutics.
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospital for Children, Boston, Massachusetts, United States of America.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Elman
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Murray
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospital for Children, Boston, Massachusetts, United States of America.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Murray
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospital for Children, Boston, Massachusetts, United States of America.
authors.forename: Fangjing
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospital for Children, Boston, Massachusetts, United States of America.
authors.forename: Keyue
authors.initials: K
authors.lastname: Shen
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospital for Children, Boston, Massachusetts, United States of America.
authors.forename: Shan
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Neurology, Experimental Therapeutics and Molecular Imaging Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Conway
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospital for Children, Boston, Massachusetts, United States of America ; Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, United States of America.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush
authors.affiliation: Department of Neurology, Experimental Therapeutics and Molecular Imaging Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Bakhos A
authors.initials: BA
authors.lastname: Tannous
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospital for Children, Boston, Massachusetts, United States of America ; Harvard Stem Cell Institute, Boston, Massachusetts, United States of America.
authors.forename: Biju
authors.initials: B
authors.lastname: Parekkadan
mesh_terms: D000818:Animals; D001682:Biological Availability; D017077:Culture Media, Conditioned; D016503:Drug Delivery Systems; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015850:Interleukin-6 / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude
chemical_list: D017077:Culture Media, Conditioned; D015850:Interleukin-6