Intravenous Administration of ^99mTc-HMPAO-Labeled Human Mesenchymal Stem Cells after Stroke: In Vivo Imaging and Biodistribution

Abstract

Human mesenchymal stem cells (hMSC) are a promising source for cell therapy after stroke. To deliver these cells, an IV injection appears safer than a local graft. We aimed to assess the whole-body biodistribution of IV-injected (99m)Tc-HMPAO-labeled hMSC in normal rats (n = 9) and following a right middle cerebral artery occlusion (MCAo, n = 9). Whole-body nuclear imaging, isolated organ counting (at 2 and 20 h after injection) and histology were performed. A higher activity was observed in the right damaged hemisphere of the MCAo group [6.5 +/- 0.9 x 10(-3) % of injected dose (ID)/g] than in the control group (3.6 +/- 1.2 x 10(-3) %ID/g), 20 h after injection. In MCAo rats, right hemisphere activity was higher than that observed in the contralateral hemisphere at 2 h after injection (11.6 +/- 2.8 vs. 9.8 +/- 1.7 x 10(-3) %ID/g). Following an initial hMSC lung accumulation, there was a decrease in pulmonary activity from 2 to 20 h after injection in both groups. The spleen was the only organ in which activity increased between 2 and 20 h. The presence of hMSC was documented in the spleen, liver, lung, and brain following histology. IV-injected hMSC are transiently trapped in the lungs, can be sequestered in the spleen, and are predominantly eliminated by kidneys. After 20 h, more hMSC are found in the ischemic lesion than into the undamaged cerebral tissue. IV delivery of hMSC could be the initial route for a clinical trial of tolerance.

A Proposed Novel Stem Cell Therapy Protocol for Liver Cirrhosis

“…Of these routes, IV is a convenient strategy for cell delivery and has been shown to produce therapeutic effects to the delivery site. However, IV-injected MSCs may be transiently trapped in the lungs, sequestered in the spleen, and are often eliminated by kidneys (7). Initial accumulation of MSCs in the lungs may induce secretion of secondary anti-inflammatory effector molecules (15).…”

Mesenchymal Stem Cells as Vehicles for Targeted Therapies

“…One hour after MSC injection, the radioactivity in infarcted hearts was 23-fold higher than in control hearts, and a week later DAPI-labeled MSCs were still detected in the infarcted areas of the heart (Assis et al, 2010). In a similar study, 99m Tc-hMSCs were injected into the saphenous vein of rats one week after cerebral ischemia (Detante et al, 2009). After initial entrapment of the cells in the lungs, they were able to migrate towards the ischemic brain lesion.…”

“…In case of tissue damage, MSCs can be mobilized by signals such as cytokines and chemokines released from the damaged tissue and migrate to the sites of injury to participate in wound repair and tissue regeneration (Ramirez et al, 2006). Animal studies demonstrated that MSCs migrate to injured sites in the body, including the heart (Assis et al, 2010;Detante et al, 2009;Kraitchman et al, 2005;Wu et al, 2003), kidney (Herrera et al, 2007;Morigi et al, 2004), skin (Li et al, 2006), and bone (Horwitz et al, 1999;Mackenzie & Flake, 2001;Mosca et al, 2000). In rats bearing Lewis cardiac allografts, Wu et al (Wu et al, 2003) found that IV injected -galactosidase (lacZ) labeled MSCs can migrate into lesions of chronic rejection in the cardiac grafts and home to the bone marrow.…”

Stem Cell Monitoring with a Direct or Indirect Labeling Method

“…Therefore, it can provide dynamic tracking imaging and the tissue distribution of transplanted stem cells injected as a therapeutic agent. Direct labeling agents for cell tracking have been developed for in vivo imaging [38,39], such as 18 F-FDG, N-succymidyl-4-18 F-fluorobenzoate ( 18 F-FSB), hexadecyl-4-18 F-fluorobenzoate ( 18 F-HFB), 99m Tc-HMPAO, and 111 Inoxine [40][41][42]. Most radionuclides used for direct labeling have a limitation for long-term monitoring due to their short halflives ( 18 F, t 1/2 =110 min; 99m Tc, t 1/2 =6 h; 111 In, t 1/2 =2.8 d).…”