TY - JOUR
T1 - Molecular imaging of bone marrow mononuclear cell survival and homing in murine peripheral artery disease
AU - Van Der Bogt, Koen E.A.
AU - Hellingman, Alwine A.
AU - Lijkwan, Maarten A.
AU - Bos, Ernst Jan
AU - De Vries, Margreet R.
AU - Van Rappard, Juliaan R.M.
AU - Fischbein, Michael P.
AU - Quax, Paul H.
AU - Robbins, Robert C.
AU - Hamming, Jaap F.
AU - Wu, Joseph C.
N1 - Funding Information:
Dr. van der Bogt is supported by the Michaël van Vloten fund. Dr. Hellingman is supported by the TeRM Smart Mix Program of the Netherlands Ministry of Economic Affairs and the Netherlands Ministry of Education, Culture and Science. Dr. Robbins is supported by National Institutes of Health Grant No. U01HL099776 . Dr. Wu is supported by the Burroughs Wellcome Foundation Career Award for Medical Scientists and National Institutes of Health Grants No. RC1HL099117 , R01HL093172 , and R01EB009689 . All authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. van der Bogt and Hellingman contributed equally to this study.
PY - 2012/1
Y1 - 2012/1
N2 - This study aims to provide insight into cellular kinetics using molecular imaging after different transplantation methods of bone marrowderived mononuclear cells (MNCs) in a mouse model of peripheral artery disease (PAD). MNC therapy is a promising treatment for PAD. Although clinical translation has already been established, there is a lack of knowledge about cell behavior after transplantation and about the mechanism whereby MNC therapy might ameliorate complaints of PAD. MNCs were isolated from F6 transgenic mice (FVB background) that express firefly luciferase (Fluc) and green fluorescence protein (GFP). Male FVB and C57Bl6 mice (n = 50) underwent femoral artery ligation and were randomized into 4 groups receiving the following: 1) single intramuscular (IM) injection of 2 × 10 6 MNCs; 2) 4 weekly IM injections of 5 × 10 5 MNCs; 3) 2 × 10 6 MNCs intravenously; and 4) phosphate-buffered saline as control. Cells were characterized by flow cytometry and in vitro bioluminescence imaging (BLI). Cell survival, proliferation, and migration were monitored by in vivo BLI, which was validated by ex vivo BLI, post-mortem immunohistochemistry, and flow cytometry. Paw perfusion and neovascularization was measured with laser Doppler perfusion imaging (LDPI) and histology, respectively. In vivo BLI revealed near-complete donor cell death 4 weeks after IM transplantation. After intravenous transplantation, BLI revealed that cells migrated to the injured area in the limb, as well as to the liver, spleen, and bone marrow. Ex vivo BLI showed presence of MNCs in the scar tissue and adductor muscle. However, no significant effects on neovascularization were observed, as monitored by LDPI and histology. This is one of the first studies to assess kinetics of transplanted MNCs in PAD using in vivo molecular imaging. MNC survival is short-lived, MNCs do not preferentially home to injured areas, and MNCs do not significantly stimulate perfusion in this particular model.
AB - This study aims to provide insight into cellular kinetics using molecular imaging after different transplantation methods of bone marrowderived mononuclear cells (MNCs) in a mouse model of peripheral artery disease (PAD). MNC therapy is a promising treatment for PAD. Although clinical translation has already been established, there is a lack of knowledge about cell behavior after transplantation and about the mechanism whereby MNC therapy might ameliorate complaints of PAD. MNCs were isolated from F6 transgenic mice (FVB background) that express firefly luciferase (Fluc) and green fluorescence protein (GFP). Male FVB and C57Bl6 mice (n = 50) underwent femoral artery ligation and were randomized into 4 groups receiving the following: 1) single intramuscular (IM) injection of 2 × 10 6 MNCs; 2) 4 weekly IM injections of 5 × 10 5 MNCs; 3) 2 × 10 6 MNCs intravenously; and 4) phosphate-buffered saline as control. Cells were characterized by flow cytometry and in vitro bioluminescence imaging (BLI). Cell survival, proliferation, and migration were monitored by in vivo BLI, which was validated by ex vivo BLI, post-mortem immunohistochemistry, and flow cytometry. Paw perfusion and neovascularization was measured with laser Doppler perfusion imaging (LDPI) and histology, respectively. In vivo BLI revealed near-complete donor cell death 4 weeks after IM transplantation. After intravenous transplantation, BLI revealed that cells migrated to the injured area in the limb, as well as to the liver, spleen, and bone marrow. Ex vivo BLI showed presence of MNCs in the scar tissue and adductor muscle. However, no significant effects on neovascularization were observed, as monitored by LDPI and histology. This is one of the first studies to assess kinetics of transplanted MNCs in PAD using in vivo molecular imaging. MNC survival is short-lived, MNCs do not preferentially home to injured areas, and MNCs do not significantly stimulate perfusion in this particular model.
KW - cardiovascular disease
KW - cell therapy
KW - molecular imaging
KW - peripheral artery disease
UR - http://www.scopus.com/inward/record.url?scp=84862908312&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862908312&partnerID=8YFLogxK
U2 - 10.1016/j.jcmg.2011.07.011
DO - 10.1016/j.jcmg.2011.07.011
M3 - Article
C2 - 22239892
AN - SCOPUS:84862908312
VL - 5
SP - 46
EP - 55
JO - JACC: Cardiovascular Imaging
JF - JACC: Cardiovascular Imaging
SN - 1936-878X
IS - 1
ER -