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Cell-based therapies for neurological disorders — the bioreactor hypothesis

Nature Reviews Neurology volume 19, pages 9–18 (2023)Cite this article

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Abstract

Cell-based therapies are an emerging biopharmaceutical paradigm under investigation for the treatment of a range of neurological disorders. Accumulating evidence is demonstrating that cell-based therapies might be effective, but the mechanism of action remains unclear. In this Review, we synthesize results from over 20 years of animal studies that illustrate how transdifferentiation, cell replacement and restoration of damaged tissues in the CNS are highly unlikely mechanisms. We consider the evidence for an alternative model that we refer to as the bioreactor hypothesis, in which exogenous cells migrate to peripheral organs and modulate and reprogramme host immune cells to generate an anti-inflammatory, regenerative environment. The results of clinical trials clearly demonstrate a role for immunomodulation in the effects of cell-based therapies. Greater understanding of these mechanisms could facilitate the optimization of cell-based therapies for a variety of neurological disorders.

Key points

  • Cell-based therapies have high potential as novel therapeutics for a range of neurological disorders.

  • Transdifferentiation, cell replacement and restoration of damaged tissue in the CNS are unlikely mechanisms for the majority of cell-based therapies under development for neurological disorders.

  • An alternative model is the bioreactor hypothesis, in which exogenous cells migrate to peripheral organs and modulate and reprogramme host immune cells to generate an anti-inflammatory, regenerative environment.

  • The spleen and lungs are immediate therapeutic targets of intravenously administered cell-based therapies for neurological disorders.

  • Bioreactor mechanisms are important even when cell-based therapies are administered to the brain parenchyma.

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Fig. 1: The bioreactor hypothesis of cell-based therapy.

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Authors and Affiliations

  1. Institute for Stroke and Cerebrovascular Disease, University of Texas Health Science Center, Houston, TX, USA

    Sean I. Savitz

  2. Department of Neurology, University of Texas Health Science Center, Houston, TX, USA

    Sean I. Savitz

  3. Department of Pediatric Surgery, University of Texas Health Science Center, Houston, TX, USA

    Charles S. Cox Jr

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S.I.S. researched data for the article. Both authors contributed to writing the article and reviewed and edited the manuscript before submission.

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Correspondence to Sean I. Savitz.

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Competing interests

S.I.S. has served in the following roles as an employee of UTHealth: site investigator in clinical trials sponsored by Athersys, KM Pharma, ReNeuron and SanBio, for which UTHealth has received payments on the basis of clinical trial contracts; investigator on clinical trials supported by the Cord Blood Registry Systems, the Department of Defense, Let’s Cure CP, NIH, and the TIRR Foundation; investigator in the Clinical and Translational Science Awards (CTSA) Program funded by the NIH; principal investigator or co-investigator on NIH-funded grants in basic science and clinical research; investigator for an imaging analysis centre for clinical trials sponsored by Athersys, ReNeuron and SanBio. He has also provided consulting services on behalf of UTHealth to Abbvie, ArunA, Deck Therapeutics, KM Pharma, Lumosa, Neurastasis, Neurexcell and ReNeuron. All compensation from such consulting arrangements has been paid to UTHealth. C.S.C. has royalty, equity and advisory board interests in Cellvation, which is developing cell therapies and an ex vivo mechanotransductive bioreactor for cell expansion. He also has sponsored research agreements with Athersys, Biostage and Generate Life Sciences, has served on the advisory board for Biostage and Generate Life Sciences, and is a consultant for Stream Biomedical.

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Savitz, S.I., Cox, C.S. Cell-based therapies for neurological disorders — the bioreactor hypothesis. Nat Rev Neurol 19, 9–18 (2023). https://doi.org/10.1038/s41582-022-00736-4

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