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Stem cell-mediated recovery in stroke: partnering with the immune system

Nature Reviews Neuroscience volume 27, pages 23–43 (2026)Cite this article

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Abstract

Stroke remains a leading cause of disability owing to the irreversible neuronal loss that it causes and the limited regenerative capacity of the CNS. Although reperfusion therapies such as thrombolysis and mechanical thrombectomy can restore blood flow after stroke, their stringent eligibility criteria leave many patients without treatment options. The immune response, involving complex interactions between brain-resident and peripheral immune cells, has a critical role in stroke recovery. Stem cell-based therapies, particularly those involving neural stem cells and mesenchymal stem cells, may be able to reshape the inflammatory microenvironment after stroke, mitigating secondary injury and promoting tissue repair. However, the precise mechanisms driving their effects remain incompletely understood, hindering clinical translation. In this Review, we highlight the bidirectional crosstalk between stem cells and immune cells (including microglia, T cells and peripheral immune cells) and discuss how these interactions influence neuroinflammation, neural plasticity and circuit remodelling in stroke recovery. We examine key determinants of stem cell therapy efficacy, emphasizing the role of stem cell–immune cell interactions, and discuss targeted strategies to enhance immune modulation and neuroprotection.

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Fig. 1: Schematic representation of the post-ischaemic inflammatory response in stroke.
Fig. 2: Comparison of select stem cell delivery methods.
Fig. 3: Overview of the potential immune-based mechanisms of stem cell therapy for ischaemic stroke.

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Authors and Affiliations

  1. Divisions of Stroke, Cerebrovascular, and Critical Care Neurology, Department of Neurology, Mass General Brigham, Harvard Medical School, Boston, MA, USA

    Nadia McMillan, Taha Yahya, Stelios Smirnakis & Saef Izzy

  2. Immunology of CNS Injury Program at Ann Romney Center for Neurological Disease, Brigham and Women’s Hospital, Boston, MA, USA

    Nadia McMillan, Pien Kiliaan, Taha Yahya, Howard Weiner & Saef Izzy

  3. Department of Otolaryngology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA

    Alexandra McMillan

  4. Departments of Neurology and Neurosurgery, Jackson Memorial Hospital and University of Miami Miller School of Medicine, Miami, FL, USA

    Roshni Thakkar & Dileep Yavagal

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Contributions

N.M., A.M., P.K., T.Y., R.T. and S.I. researched data for the article. N.M., A.M., H.W., S.S., D.Y. and S.F. provided substantial contributions to the discussion of its content. The authors all contributed to writing the article and reviewing and editing the manuscript before submission.

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McMillan, N., McMillan, A., Kiliaan, P. et al. Stem cell-mediated recovery in stroke: partnering with the immune system. Nat. Rev. Neurosci. 27, 23–43 (2026). https://doi.org/10.1038/s41583-025-00985-4

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