title: Detection of Stem Cell Transplant Rejection with Ferumoxytol MR Imaging: Correlation of MR Imaging Findings with Those at Intravital Microscopy.
abstract: Purpose To determine whether endogenous labeling of macrophages with clinically applicable nanoparticles enables noninvasive detection of innate immune responses to stem cell transplants with magnetic resonance (MR) imaging. Materials and Methods Work with human stem cells was approved by the institutional review board and the stem cell research oversight committee, and animal experiments were approved by the administrative panel on laboratory animal care. Nine immunocompetent Sprague-Dawley rats received intravenous injection of ferumoxytol, and 18 Jax C57BL/6-Tg (Csf1r-EGFP-NGFR/FKBP1A/TNFRSF6) 2Bck/J mice received rhodamine-conjugated ferumoxytol. Then, 48 hours later, immune-matched or mismatched stem cells were implanted into osteochondral defects of the knee joints of experimental rats and calvarial defects of Jax mice. All animals underwent serial MR imaging and intravital microscopy (IVM) up to 4 weeks after surgery. Macrophages of Jax C57BL/6-Tg (Csf1r-EGFP-NGFR/FKBP1A/TNFRSF6) 2Bck/J mice express enhanced green fluorescent protein (GFP), which enables in vivo correlation of ferumoxytol enhancement at MR imaging with macrophage quantities at IVM. All quantitative data were compared between experimental groups by using a mixed linear model and t tests. Results Immune-mismatched stem cell implants demonstrated stronger ferumoxytol enhancement than did matched stem cell implants. At 4 weeks, T2 values of mismatched implants were significantly lower than those of matched implants in osteochondral defects of female rats (mean, 10.72 msec for human stem cells and 11.55 msec for male rat stem cells vs 15.45 msec for sex-matched rat stem cells; P = .02 and P = .04, respectively) and calvarial defects of recipient mice (mean, 21.7 msec vs 27.1 msec, respectively; P = .0444). This corresponded to increased recruitment of enhanced GFP- and rhodamine-ferumoxytol-positive macrophages into stem cell transplants, as visualized with IVM and histopathologic examination. Conclusion Endogenous labeling of macrophages with ferumoxytol enables noninvasive detection of innate immune responses to stem cell transplants with MR imaging.©RSNA, 2017 Online supplemental material is available for this article.
authors.affiliation: From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614.
authors.forename: Heike E
authors.initials: HE
authors.lastname: Daldrup-Link
authors.affiliation: From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614.
authors.forename: Carmel
authors.initials: C
authors.lastname: Chan
authors.affiliation: From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614.
authors.forename: Olga
authors.initials: O
authors.lastname: Lenkov
authors.affiliation: From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614.
authors.forename: Seyedmeghdad
authors.initials: S
authors.lastname: Taghavigarmestani
authors.affiliation: From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614.
authors.forename: Toktam
authors.initials: T
authors.lastname: Nazekati
authors.affiliation: From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614.
authors.forename: Hossein
authors.initials: H
authors.lastname: Nejadnik
authors.affiliation: From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614.
authors.forename: Fanny
authors.initials: F
authors.lastname: Chapelin
authors.affiliation: From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614.
authors.forename: Aman
authors.initials: A
authors.lastname: Khurana
authors.affiliation: From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614.
authors.forename: Xinming
authors.initials: X
authors.lastname: Tong
authors.affiliation: From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614.
authors.forename: Laura
authors.initials: L
authors.lastname: Pisani
authors.affiliation: From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614.
authors.forename: Michael
authors.initials: M
authors.lastname: Longaker
authors.affiliation: From the Department of Radiology, Molecular Imaging Program at Stanford (MIPS) (H.E.D.L., C.C., O.L., S.T., T.N., H.N., F.C., A.K., F.Y., L.P., M.L., S.S.G.), Department of Pediatrics (H.E.D.L.), Institute for Stem Cell Biology and Regenerative Medicine (H.E.D.L.), Department of Orthopaedic Surgery (X.T., F.Y.), Department of Bioengineering (F.Y., S.S.G.), Department of Surgery, Division of Plastic and Reconstructive Surgery (M.L.), and Department of Materials Science and Engineering (M.L., S.S.G.), Stanford University, 725 Welch Rd, Room 1665, Stanford, CA 94305-5614.
authors.forename: Sanjiv Sam
authors.initials: SS
authors.lastname: Gambhir
mesh_terms: D000328:Adult; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D052203:Ferrosoferric Oxide / Q000008:administration & dosage; D006084:Graft Rejection / Q000000981:diagnostic imaging*; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation
chemical_list: D052203:Ferrosoferric Oxide