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Allogeneic modified bone marrow-derived human mesenchymal stromal/stem cells (hMSC-SB623 cells) are in clinical development for the treatment of chronic motor deficits after traumatic brain injury and cerebral ischemic stroke. However, their exact mechanisms of action remain unclear. Here, we investigated the effects of this cell therapy on cortical network excitability, brain tissue, and peripheral blood at a chronic stage after ischemic stroke in a rat model. One month after focal cortical ischemic stroke, hMSC-SB623 cells or the vehicle solution were injected into the peri-stroke cortex. Starting one week after treatment, cortical excitability was assessed ex vivo. hMSC-SB623 cell transplants reduced stroke-induced cortical hyperexcitability, restoring cortical excitability to control levels. The histology of brain tissue revealed an increase of factors relevant to neuroregeneration, and synaptic and cellular plasticity. Whole-blood RNA sequencing and serum protein analyses showed that intra-cortical hMSC-SB623 cell transplantation reversed effects of stroke on peripheral blood factors known to be involved in stroke pathophysiology. Our findings demonstrate that intra-cortical transplants of hMSC-SB623 cells correct stroke-induced circuit disruptions even at the chronic stage, suggesting broad usefulness as a therapeutic for neurological conditions with network hyperexcitability. Additionally, the transplanted cells exert far-reaching immunomodulatory effects whose therapeutic impact remains to be explored., Competing Interests: Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: B.K., P.M.L., A.S., S.S.M., J.B., W.C.C., Y.A.Z., B.N., and Z.W. were/are SanBio, Inc., employees and/or paid consultants, and may have received stock options as part of their compensation. SanBio, Inc., filed a provisional patent application entitled, "Therapeutic methods and composition for restoring cortical excitability and neural plasticity after stroke" (inventors B.K., Y.A.Z, Z.W., and J.T.P.)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) more...