title: MR signal characteristics of viable and apoptotic human mesenchymal stem cells in matrix-associated stem cell implants for treatment of osteoarthritis.
abstract: OBJECTIVE
  To compare magnetic resonance (MR) signal characteristics of contrast agent-labeled apoptotic and viable human mesenchymal stem cells (hMSCs) in matrix-associated stem cell implants.
  
  
  METHODS
  hMSCs were labeled with Food and Drug Administration-approved ferumoxides nanoparticles. One group (A) remained untreated whereas a second group (B) underwent mitomycin C-induced apoptosis induction. Viability of group A and apoptosis of group B was confirmed by caspase-assays and terminal dUTP nick-end labeling (TUNEL) stains. Labeled viable hMSCs, unlabeled viable hMSCs, labeled apoptotic hMSCs, and unlabeled apoptotic hMSCs (n = 7 samples each) in an agarose scaffold were implanted into cartilage defects of porcine patellae specimens and underwent MR imaging at 7 T, using T1-weighted spin-echo sequences, T2-weighted spin-echo sequences, and T2*-weighted gradient-echo sequences. Signal-to-noise ratios (SNR) of the implants were calculated and compared between different experimental groups using linear mixed regression models.
  
  
  RESULTS
  Ferumoxides-labeled hMSCs provided a strong negative T2 and T2*-enhancement. Corresponding SNR data of labeled hMSCs were significantly lower compared with unlabeled controls (P < 0.05). Apoptosis induction resulted in a significant signal decline of ferumoxides-labeled hMSC transplants on short echo time T2-weighted spinecho sequences. SNR data of labeled apoptotic hMSCs were significantly lower compared with labeled viable hMSCs (P < 0.05).
  
  
  CONCLUSIONS
  Apoptosis of transplanted ferumoxides-labeled stem cells in cartilage defects can be visualized noninvasively by a significant signal decline on T2-weighted MR images. The described MR signal characteristics may serve as a noninvasive outcome measure for the assessment of matrix-associated stem cell implants in clinical practice. Additional studies are needed to further enhance the observed differences between viable and apoptotic cells, for example, by further optimizing the applied MR pulse sequence parameters or intracellular contrast agent concentration.
authors.affiliation: Department of Radiology and Biomedical Imaging, UCSF Medical Center, University of California, San Francisco, CA 94143, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Nedopil
authors.forename: Christopher
authors.initials: C
authors.lastname: Klenk
authors.forename: Cy
authors.initials: C
authors.lastname: Kim
authors.forename: Siyuan
authors.initials: S
authors.lastname: Liu
authors.forename: Mike
authors.initials: M
authors.lastname: Wendland
authors.forename: Daniel
authors.initials: D
authors.lastname: Golovko
authors.forename: Tibor
authors.initials: T
authors.lastname: Schuster
authors.forename: Barbara
authors.initials: B
authors.lastname: Sennino
authors.forename: Donald M
authors.initials: DM
authors.lastname: McDonald
authors.forename: Heike E
authors.initials: HE
authors.lastname: Daldrup-Link
mesh_terms: D000818:Animals; D017209:Apoptosis; D002357:Cartilage Diseases / Q000000981:diagnostic imaging; D019902:Chondrocytes; D016001:Confidence Intervals; D003287:Contrast Media; D003911:Dextrans; D005290:Ferric Compounds; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D058185:Magnetite Nanoparticles; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D018613:Microscopy, Confocal; D016685:Mitomycin; D053758:Nanoparticles; D010003:Osteoarthritis / Q000628:therapy*; D011877:Radionuclide Imaging; D013552:Swine
chemical_list: D003287:Contrast Media; D003911:Dextrans; D005290:Ferric Compounds; D058185:Magnetite Nanoparticles; C000499:ferric oxide; D016685:Mitomycin; C065507:ferumoxides
references.citation: N Engl J Med. 1994 Oct 6;331(14):889-95
references.pmid: 8078550
references.citation: Osteoarthritis Cartilage. 2002 Mar;10(3):199-206
references.pmid: 11869080
references.citation: Anat Histol Embryol. 2002 Aug;31(4):214-23
references.pmid: 12196263
references.citation: Arthritis Res Ther. 2007;9(3):213
references.pmid: 17561986
references.citation: Cornea. 2008 Jul;27(6):686-92
references.pmid: 18580261
references.citation: Am J Sports Med. 2008 Nov;36(11):2091-9
references.pmid: 18801942
references.citation: Knee Surg Sports Traumatol Arthrosc. 2009 Nov;17(11):1289-97
references.pmid: 19333576
references.citation: Tissue Eng. 2006 May;12(5):1151-68
references.pmid: 16771631
references.citation: Curr Opin Biotechnol. 2004 Oct;15(5):406-10
references.pmid: 15464369
references.citation: J Magn Reson Imaging. 1994 Sep-Oct;4(5):653-7
references.pmid: 7526912
references.citation: Blood. 1996 Mar 1;87(5):1951-6
references.pmid: 8634443
references.citation: Magn Reson Med. 1986 Apr;3(2):217-25
references.pmid: 3713487
references.citation: Nat Med. 2009 Aug;15(8):967-73
references.pmid: 19597506
references.citation: Blood. 2004 Nov 1;104(9):2761-6
references.pmid: 15242875
references.citation: AJR Am J Roentgenol. 2008 Nov;191(5):1391-6
references.pmid: 18941075
references.citation: Invest Ophthalmol Vis Sci. 1997 Sep;38(10):1998-2007
references.pmid: 9331263
references.citation: Cell Death Differ. 2001 Oct;8(10):1022-8
references.pmid: 11598800
references.citation: Magn Reson Med. 2009 Aug;62(2):325-32
references.pmid: 19353670
references.citation: Drug Chem Toxicol. 2009;32(2):158-68
references.pmid: 19514952
references.citation: Microvasc Res. 2009 May;77(3):370-6
references.pmid: 19249320
references.citation: J Vis Exp. 2010 Apr 05;(38):
references.pmid: 20368696
references.citation: Cell Tissue Res. 2000 Jul;301(1):5-17
references.pmid: 10928277
references.citation: Magn Reson Med. 2001 Jun;45(6):1014-20
references.pmid: 11378879
references.citation: Contrast Media Mol Imaging. 2009 Jul-Aug;4(4):165-73
references.pmid: 19670250
references.citation: Magn Reson Med. 2002 Feb;47(2):257-63
references.pmid: 11810668
references.citation: Osteoarthritis Cartilage. 2006 Feb;14(2):179-89
references.pmid: 16257243
references.citation: Nat Med. 2001 Nov;7(11):1241-4
references.pmid: 11689890
references.citation: Br J Cancer. 1972 Aug;26(4):239-57
references.pmid: 4561027
references.citation: J Nucl Med. 2005 May;46(5):807-15
references.pmid: 15872355
references.citation: Magn Reson Med. 2002 Jul;48(1):52-61
references.pmid: 12111931
references.citation: Top Magn Reson Imaging. 1991 Mar;3(2):1-18
references.pmid: 2025431
references.citation: Eur J Nucl Med Mol Imaging. 2004 Jun;31(6):887-919
references.pmid: 15138718
references.citation: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6349-54
references.pmid: 9600968
references.citation: Radiology. 2007 Nov;245(2):449-57
references.pmid: 17848680
references.citation: Contrast Media Mol Imaging. 2008 Nov-Dec;3(6):223-32
references.pmid: 19072771