Short‐, middle‐ and long‐term safety of superparamagnetic iron oxide‐labeled allogeneic bone marrow stromal cell transplantation in rat model of lacunar infarction

Abstract

Recently, both basic and clinical studies demonstrated that bone marrow stromal cell (BMSC) transplantation therapy can promote functional recovery of patients with CNS disorders. A non-invasive method for cell tracking using MRI and superparamagnetic iron oxide (SPIO)-based labeling agents has been applied to elucidate the behavior of transplanted cells. However, the long-term safety of SPIO-labeled BMSCs still remains unclear. The aim of this study was to investigate the short-, middle- and long-term safety of the SPIO-labeled allogeneic BMSC transplantation. For this purpose, BMSCs were isolated from transgenic rats expressing green fluorescent protein (GFP) and were labeled with SPIO. The Na/K ATPase pump inhibitor ouabain or vehicle was stereotactically injected into the right striatum of wild-type rats to induce a lacunar lesion (n = 22). Seven days after the insult, either BMSCs or SPIO solution were stereotactically injected into the left striatum. A 7.0-Tesla MRI was performed to serially monitor the behavior of BMSCs in the host brain. The animals were sacrificed after 7 days (n = 7), 6 weeks (n = 6) or 10 months (n = 9) after the transplantation. MRI demonstrated that BMSCs migrated to the damage area through the corpus callosum. Histological analysis showed that activated microglia were present around the bolus of donor cells 7 days after the allogeneic cell transplantation, although an immunosuppressive drug was administered. The SPIO-labeled BMSCs resided and started to proliferate around the route of the cell transplantation. Within 6 weeks, large numbers of SPIO-labeled BMSCs reached the lacunar infarction area from the transplantation region through the corpus callosum. Some SPIO nanoparticles were phagocytized by microglia. After 10 months, the number of SPIO-positive cells was lower compared with the 7-day and 6-week groups. There was no tumorigenesis or severe injury observed in any of the animals. These findings suggest that BMSCs are safe after cell transplantation for the treatment of stroke.

Feasibility and Efficiency of Human Bone Marrow Stromal Cell Culture with Allogeneic Platelet Lysate‐Supplementation for Cell Therapy against Stroke

“…Cell labeling with SPIO was employed to track donor cells in the host brain by means of MRI. Cultured hBMSCs can uptake SPIO nanoparticles into their cytoplasm when the particles are added to the culture medium [7]. In the present study, Turnbull's Blue staining analysis showed that 34% hBMSCs in a chamber slide contained SPIO nanoparticles.…”

“…In the present study, Turnbull's Blue staining analysis showed that 34% hBMSCs in a chamber slide contained SPIO nanoparticles. Because SPIO nanoparticles have clearly detectable signal extinctions, SPIO-labeled cells were easily tracked anatomically with QSM MR images [7]. Histological analysis gained the same hBMSC distribution compared with MRI.…”

“…A number of experimental studies have demonstrated that transplanted BMSCs can extensively migrate towards lesions, express the phenotypes of neural cells, and improve neurological function [7, 9, 10]. Although these results are encouraging, several problems still remain unresolved, thus impeding their clinical applications.…”

Rat white matter injury model induced by endothelin-1 injection: technical modification and pathological evaluation

“…However, these models also affect the whole brain (including the gray matter), and the lesions mimic more chronic leukoaraiosis rather than sudden onset focal ischemic white matter infarction (Wakita et al 1994, Kaiser et al 2014. Selective white matter lesions can be induced by stereotactic injection of ouabain, a Na/K ATPase pump inhibitor, as previously reported (Janowski et al 2008, Shichinohe et al 2013, Tan et al 2015). Ouabain's mechanism of injury is different from that of ischemia, but because the lesion mimics stroke according to MR imaging evaluation, this model may become an equivalent to the ET-1 method of white matter injury (Veldhuis et al 2003).…”

Short-Lived Human Umbilical Cord-Blood-Derived Neural Stem Cells Influence the Endogenous Secretome and Increase the Number of Endogenous Neural Progenitors in a Rat Model of Lacunar Stroke

“…Thus, our group developed a reproducible, reliable, and efficient method of ischemia-like injury in the deep-brain structures of rodents that closely mimics the lacunar stroke [6]. In the last few years, this model has been successfully used by other groups to study the safety and functionality of MSC transplantation [7, 8]. …”