Intravenous Autologous Bone Marrow Mononuclear Cell Transplantation for Stroke: Phase1/2a Clinical Trial in a Homogeneous Group of Stroke Patients

Abstract

The goal of this clinical trial was to assess the feasibility and safety of transplanting autologous bone marrow mononuclear cells into patients suffering severe embolic stroke. Major inclusion criteria included patients with cerebral embolism, age 20-75 years, National Institute of Health Stroke Scale (NIHSS) score displaying improvement of ≤ 5 points during the first 7 days after stroke, and NIHSS score of ≥ 10 on day 7 after stroke. Bone marrow aspiration (25 or 50 mL; N = 6 patients in each case) was performed 7-10 days poststroke, and bone marrow mononuclear cells were administrated intravenously. Mean total transplanted cell numbers were 2.5 × 10(8) and 3.4 × 10(8) cells in the lower and higher dose groups, respectively. No apparent adverse effects of administering bone marrow cells were observed. Compared with the lower dose, patients receiving the higher dose of bone marrow cells displayed a trend toward improved neurologic outcomes. Compared with 1 month after treatment, patients receiving cell therapy displayed a trend toward improved cerebral blood flow and metabolic rate of oxygen consumption 6 months after treatment. In comparison with historical controls, patients receiving cell therapy had significantly better neurologic outcomes. Our results indicated that intravenous transplantation of autologous bone marrow mononuclear cells is safe and feasible. Positive results and trends favoring neurologic recovery and improvement in cerebral blood flow and metabolism by cell therapy underscore the relevance of larger scale randomized controlled trials using this approach.

FIG. 1.

Outline of clinical trial design. Patients with a severe embolic stroke who did not show significant improvement in the first 7 days and were expected to have poor outcomes were enrolled in this study. Autologous bone marrow (BM) harvest and transplantation of purified bone marrow mononuclear cells were performed 7–10 days after first detection of stroke.

FIG. 2.

MRI's of enrolled patients. MRI fluid-attenuated inversion recovery image at 1 month after cell therapy in cases 1–12. All patients demonstrate significant strokes, which include the middle cerebral artery area.

FIG. 3.

Assessment of neurologic outcomes: time course and dependence on administered dose of bone marrow mononuclear cells. (a) Temporal change in average NIHSS score of all patients before and after cell treatment. (b–d) Temporal change of average of all patients in modified Rankin Scale (mRS) (b), ratio of favorable outcome (c), and Barthel Index (d) on days 30, 60, and 90 after treatment. (e) Temporal change in NIHSS scores of the lower (blue line) and higher (red line) dose group. (f) The improvement in NIHSS score between day 7 after onset of stroke and day 30 after cell transplantation. (g–i) Time course of change in mRS score (g), proportion of patients with the favorable outcome (h), and Barthel Index (i) in each group. Blue and red lines indicate lower and higher dose groups, respectively (e, g–i).

FIG. 4.

Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) images of enrolled patients. (a) Nonquantitative SPECT images in the 48 h before cell transplantation. (b, c) CBF (b) and CMRO₂ (c) images at 1 (1M) and 6 (6M) months after cell transplantation. Remaining luxury perfusion was still observed at 1 month in cases 7 and 9. The red arrow indicates the area of luxury perfusion with low rCMRO₂.

FIG. 5.

Average cerebral blood flow and metabolism in 7 patients: effect of autologous bone marrow mononuclear cell transplantation. (a) Change in CBF in the ipsilateral (red line) and contralateral hemispheres (black line) at 1 month (1M) and 6 months (6M) after transplantation. (b, c) Changes in CBF in the cortex of the anterior (green line), middle (yellow line), and posterior (blue line) cerebral artery territory, and at thalamus (red dashed line) and basal ganglion (black dashed line) in the ipsilateral (b) and contralateral hemispheres (c). (d) Changes in CMRO₂ in the ipsilateral (red line) and contralateral hemispheres (black line). (e, f) Changes in CMRO₂ in the cortex of anterior (green line), middle (yellow line), and posterior (blue line) cerebral artery territory, and at thalamus (red dashed line) and basal ganglion (black dashed line) in the ipsilateral (e) and contralateral hemispheres (f). (g) Changes in OEF in the ipsilateral (red line) and contralateral hemispheres (black line). (h–j) Changes in CBF (h), CMRO₂ (i), and OEF (j) in the ipsilateral (red line) and contralateral cerebellums (black line).

FIG. 6.

Comparison between enrolled patients and historical controls at the time of discharge from the hospital. (a) Proportion of the patients with change for the worse in NIHSS score between day 7 after onset of stroke and discharge. (b, c) Significant improvement was observed in patients undergoing cell transplantation in NIHSS score (b, *P < 0.05) and improvement in NIHSS (day 7 after onset of stroke vs discharge) (c, *P < 0.05). (d–f) Although there was no statistical significant difference between groups in the level of mRS (d), ratio of favorable outcome (e), and Barthel Index (d), a trend toward improvement was observed in the cell therapy group in each case, compared with historical controls.