Journal
STROKE
Volume 51, Issue 2, Pages 601-611Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.119.026589
Keywords
bone marrow; infarction; mice; mitochondria; stem cells
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology/Japan Agency for Medical Research and Development Translational Research Network Program [19lm0203026h0003]
- Japan Society for the Promotion of Science (JSPS) [17H01583]
- SENSHIN Medical Research Foundation
- Life Science Institute Inc.
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Background and Purpose-Multilineage-differentiating stress-enduring cells are endogenous nontumorigenic reparative pluripotent-like stem cells found in bone marrow, peripheral blood, and connective tissues. Topically administered human multilineage-differentiating stress-enduring cells into rat/mouse stroke models differentiated into neural cells and promoted clinically relevant functional recovery. However, critical questions on the appropriate timing and dose, and safety of the less invasive intravenous administration of clinical-grade multilineage-differentiating stress-enduring cell-based product CL2020 remain unanswered. Methods-Using an immunodeficient mouse lacunar model, CL2020 was administered via the cervical vein in different doses (high dose=5x10(4) cells/body; medium dose=1x10(4) cells/body; low dose=5x10(3) cells/body) at subacute phase (approximate to 9 days after onset) and chronic phase (approximate to 30 days). Cylinder test, depletion of human cells by diphtheria toxin administration, immunohistochemistry, and human specific-genome detection were performed. Results-Tumorigenesis and adverse effects were not detected for up to 22 weeks. The high-dose group displayed significant functional recovery compared with the vehicle group in cylinder test in subacute-phase-treated and chronic-phase-treated animals after 6 weeks and 8 weeks post-injection, respectively. In the high-dose group of subacute-phase-treated animals, robust and stable recovery in cylinder test persisted up to 22 weeks compared with the vehicle group. In both groups, intraperitoneal injection of diphtheria toxin abrogated the functional recovery. Anti-human mitochondria revealed CL2020 distributed mainly in the peri-infarct area at 1, 10, and 22 weeks and expressed NeuN (neuronal nuclei)- and MAP-2 (microtubule-associated protein-2)-immunoreactivity. Conclusions-Intravenously administered CL2020 was safe, migrated to the peri-infarct area, and afforded functional recovery in experimental stroke. Visual Overview-An online visual overview is available for this article.
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