Abstract
The present study used in vitro and in vivo stroke models to demonstrate the safety, efficacy, and mechanism of action of adult human bone marrow‐derived NCS‐01 cells. Coculture with NCS‐01 cells protected primary rat cortical cells or human neural progenitor cells from oxygen glucose deprivation. Adult rats that were subjected to middle cerebral artery occlusion, transiently or permanently, and subsequently received intracarotid artery or intravenous transplants of NCS‐01 cells displayed dose‐dependent improvements in motor and neurological behaviors, and reductions in infarct area and peri‐infarct cell loss, much better than intravenous administration. The optimal dose was 7.5 × 106 cells/mL when delivered via the intracarotid artery within 3 days poststroke, although therapeutic effects persisted even when administered at 1 week after stroke. Compared with other mesenchymal stem cells, NCS‐01 cells ameliorated both the structural and functional deficits after stroke through a broad therapeutic window. NCS‐01 cells secreted therapeutic molecules, such as basic fibroblast growth factor and interleukin‐6, but equally importantly we observed for the first time the formation of filopodia by NCS‐01 cells under stroke conditions, characterized by cadherin‐positive processes extending from the stem cells toward the ischemic cells. Collectively, the present efficacy readouts and the novel filopodia‐mediated mechanism of action provide solid lab‐to‐clinic evidence supporting the use of NCS‐01 cells for treatment of stroke in the clinical setting.
Highlights
Stroke remains as one of the most prevalent causes of disability and death among adult populations around the world,[1] significantly costing the United States billions of dollars each year.[2]
We evaluated the efficacy, safety, and mechanism of action of NCS-01 cells in standard in vitro and in vivo models of ischemic stroke
We showed that NCS-01 cells rescue ischemic cells in a dosedependent manner in the oxygen glucose deprivation (OGD) model
Summary
Stroke remains as one of the most prevalent causes of disability and death among adult populations around the world,[1] significantly costing the United States billions of dollars each year.[2]. The study tested a human bone marrow-derived mesenchymal stem cell line called NCS-01 in oxygen glucose deprivation and middle cerebral artery occlusion models, which revealed the optimal dose of 7.5 × 106 cells/mL via the intracarotid artery within 3 days poststroke. BFGF and IL-6, and filopodia formation, are potential mechanisms Based on these preclinical data, the FDA in July 2019 approved intracarotid NCS-01 cell transplantation in ischemic stroke patients. In identifying transplantable bone marrow-derived MSCs for clinical application, we used lab-to-clinic translational research criteria, namely the cells need to be of human origin, clinical grade, ample supply, and with well-defined phenotypic markers. To this end, the adult bone marrow-derived NCS-01 cells satisfy all these criteria. Based on the preclinical data presented here, we recently received in early July 2019 the FDA's approval to proceed with the clinical application of intracarotid artery (ICA) transplantation of NCS-01 cells in ischemic stroke patients
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