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Towards an Optimized MSC-based Treatment of Ischemic Stroke

Review of “Translating intracarotid artery transplantation of bone marrow-derived NCS-01 cells for ischemic stroke: behavioral and histological readouts and mechanistic insights into stem cell therapy” from STEM CELLS Translational Medicine by Stuart P. Atkinson

While stroke remains a significant cause of disability and death around the world, we still lack adequate treatment options accessible to most patients. With regards to advancements in cell‐based regenerative medicine, encouraging in vitro findings have prompted many clinical trials evaluating the potential of mesenchymal stem cell (MSC)-based approaches; however, while results have provided evidence of safety, they failed to reveal efficacy [1, 2]. 

Researchers led by Cesar V. Borlongan (University of South Florida, Tampa, FL, USA) believed that a lack of translation of optimal laboratory parameters may explain the lack of encouraging clinical outcomes [3] and, therefore, the team assessed the potential of a well-characterized adult human bone marrow‐derived MSC line (NCS‐01) in highly translational stroke models in the hope of improving cell‐based regenerative approaches in stroke patients [4]. Encouragingly, the results of this fascinating study prompted the FDA to approve a trial evaluating the infusion of MSCs via the intracarotid artery ischemic stroke patients (NCT03915431).

In their new STEM CELLS Translational Medicine study, Kaneko et al. employed an in vitro oxygen-glucose deprivation cell coculture stroke model [5] and an in vivo transient and permanent middle cerebral artery occlusion rat stroke model [6] to evaluate MSC therapy as a treatment for stroke. Initial in vitro analyses revealed that coculture of MSCs with primary rat cortical cells or human neural progenitor cells protected these cells against glucose deprivation in a dose-dependent manner, with at least some of this effect deriving from the secretion of pro-regenerative/anti-inflammatory factor such as basic fibroblast growth factor and interleukin‐6. Fascinatingly, the authors also report, for the first time, the formation of filopodia as a potential therapeutic mechanism, with cadherin‐positive processes extending from MSCs toward ischemic cells.

The in vivo model provided evidence for dose‐dependent improvements in motor and neurological behaviors and reductions in the infarct area and peri‐infarct cell loss following the administration of MSCs via the intracarotid artery or intravenous injection. The authors reported the best results following the early administration (within three days of the stroke-causing event) of around 7.5 million cells/mL via the intracarotid artery, perhaps due to the heightened capacity of this administration route to deliver more cells and therapeutic molecules into the ischemic brain. However, they also reported appreciable therapeutic effects after later MSC administration (after around one week). Of note, the delivery of cells via the intracarotid artery failed to elicit alterations in the cerebrospinal fluid or microembolic events, suggesting overall safety.

Even given these encouraging findings, the authors highlight some limitations to their study; these include the need to undertake studies in large animal models, to analyze models that involve the comorbidities often associated with stroke, to explore both the therapeutic mechanism more profoundly and the interactions between MSCs and other neural cell types, and to undertake further safety studies. Hopefully, studies such as these combined with the clinical trial results will further support the implementation of MSC therapy for the treatment of stroke in a clinical setting.

For more on the optimization of MSC therapy for the treatment of ischemic stroke, stay tuned to the Stem Cells Portal!

References

  1. Bang OY, Lee JS, Lee PH, et al., Autologous mesenchymal stem cell transplantation in stroke patients. Annals of Neurology 2005;57:874-882.
  2. Lee JS, Hong JM, Moon GJ, et al., A Long-Term Follow-Up Study of Intravenous Autologous Mesenchymal Stem Cell Transplantation in Patients With Ischemic Stroke. STEM CELLS 2010;28:1099-1106.
  3. Borlongan CV, Concise Review: Stem Cell Therapy for Stroke Patients: Are We There Yet? STEM CELLS Translational Medicine 2019;8:983-988.
  4. Kaneko Y, Lee J-Y, Tajiri N, et al., Translating intracarotid artery transplantation of bone marrow-derived NCS-01 cells for ischemic stroke: Behavioral and histological readouts and mechanistic insights into stem cell therapy. STEM CELLS Translational Medicine 2020;9:203-220.
  5. Malagelada C, Xifró X, Badiola N, et al., Histamine H2-Receptor Antagonist Ranitidine Protects Against Neural Death Induced by Oxygen-Glucose Deprivation. Stroke 2004;35:2396-2401.
  6. Ishikawa H, Tajiri N, Vasconcellos J, et al., Ischemic Stroke Brain Sends Indirect Cell Death Signals to the Heart. Stroke 2013;44:3175-3182.