Early Tissue Distribution of Bone Marrow Mononuclear Cells After Intra-Arterial Delivery in a Patient With Chronic Stroke

Abstract

A 24-year-old man with a cerebral infarct within the left middle cerebral artery (MCA) territory was enrolled in a study to assess the safety of autologous bone marrow mononuclear cell (BMMC) transplantation in patients with ischemic stroke (NCT00473057). His National Institutes of Health Stroke Scale score was 7. Computed tomography ( Figure 1A) and technetium-99m ethyl cysteinate dimer ( 99m Tc ECD) single photon emission computed tomography (SPECT) (Figures 1B and 2 and Movie I in the online-only Data Supplement) indicated the location of the infarct. Sixty-seven days after onset of symptoms, the patient underwent BMMC transplantation. Bone marrow blood was aspirated under local anesthesia from both iliac crests and processed to isolate the mononuclear cell fraction. A total of 5ϫ10 8 BMMCs was suspended into a volume of 10 mL, and 1 mL of the cell suspension was radiolabeled with 99m Tc (radioactivity 111 MBq, physical half-life 6 hours), as described previously, 1,2 and then added back to the unlabeled cell suspension. After catheter navigation via femoral artery access under local anesthesia and conscious sedation, cells were injected into the M1 portion of the MCA, and the infusion was completed within Ϸ10 minutes. To monitor the fate of transplanted BMMCs, whole-body and planar scintigraphies were performed at 2, 24, and 48 hours after cell therapy. The patient had no complications during the procedure or follow-up.Planar and SPECT views revealed uptake and retention of the labeled BMMCs in the territory of the left MCA for up to 48 hours ( Figures 1C, 3, and 4 and Movie II in the online-only Data Supplement). The remaining uptake occurred mainly in the liver and spleen (Figure 4). To our knowledge, there has been only 1 report of BMMC homing in cerebral infarction, which indicated the retention of BMMCs 8 hours after intra-arterial injection in 1 patient in the subacute phase, 9 days after stroke. 3 We here report for the first time the migration and homing of BMMCs to the brain of a patient in the chronic phase of stroke, Ͼ2 months after the onset of symptoms. The mechanisms involved in the possible therapeutic effect of BMMC therapy are still largely unknown, but accumulating evidence from animal studies suggests that these cells may behave as minipumps producing cytokines and/or trophic factors that support cell survival in the penumbra area and stimulate neurogenesis and angiogenesis, increasing brain remodeling and functional regeneration after ischemia. 4 In vivo tracking of BMMCs after grafting is of great importance because the retention of transplanted cells at the site of the lesion may be critical for the success of cell therapy. 3,4 In animal models, different methods have been used to track the transplanted cells, and it has been suggested that signals that are involved in the transit of inflammatory cells to injured tissue may also direct the transplanted bone marrow-derived cells. 4 Our results indicate that labeling BMMCs with 99m Tc is feasible and that noninvasive imaging may be used ...

Stem Cell Therapy as an Emerging Paradigm for Stroke (STEPS) II

“…Although there are no accepted techniques to label and monitor cells for clinical testing, several approaches are currently available, including iron, indium, thallium, gadolinium-based agents, etc. 14,15 More investigation is urgently needed to develop safe and reliable labeling techniques for deployment in clinical trials. Whatever labeling approach is chosen, it is important to assess that the label does not impair viability of the cellular product.…”

Perspectives on Assessment of Stem Cell Therapy in Stroke by 18F-FDG PET

“…Local 18 F-FDG uptake increased at varying degrees approximately 6 mo after cell therapy (19). 99m Tc-labeled bone marrow mononuclear cells accumulated in the area of middle cerebral artery stroke demonstrated by 99m Tcethyl cysteinate dimer 2 h after cell transplantation (20). Similarly, 99m Tchexamethylpropylene amine oximelabeled autologous bone marrow mononuclear cells accumulated in the area of stroke within 8 h after cell delivery, whereas whole-body images showed tracer distribution in the liver and spleen (21).…”

The Rise of Cell Therapy Trials for Stroke: Review of Published and Registered Studies

“…Barbosa da Fonseca et al [86,87] and Battistella et al [88], respectively, reported the imaging and clinical results of a trial that included six patients 59 to 82 days after an MCA ischemic stroke. Afterward, another case where cells were injected 19 days after the stroke was also reported [89].…”