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Related Experiment Video

Updated: Jan 10, 2026

Transplantation of Human Induced Pluripotent Stem Cell-Derived Microglia in Immunocompetent Mice Brain via Non-Invasive Transnasal Route
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Controlled Delivery of a Neurotrophic Factor in the Adult Mouse Brain Using Engineered Microglia.

Rohan J Hofland1, Marta Grońska-Pęski1,2, Hiroko Nobuta1,3

  • 1Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.

Biorxiv : the Preprint Server for Biology
|November 24, 2025
PubMed
Summary

Engineered microglia successfully repopulated mouse brains after ablation, delivering therapeutic Brain-Derived Neurotrophic Factor (BDNF). Constitutively active CSF1R enhanced transplant spread, showing microglia’s potential for targeted brain therapies.

Keywords:
Biological SciencesMicroglia transplantationbiologic deliverycell-based therapylentiviral cell engineering

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Area of Science:

  • Neuroscience
  • Immunology
  • Biotechnology

Background:

  • Microglia, the brain's immune cells, can be engineered for therapeutic delivery.
  • Current microglia replacement methods have limited clinical applicability.
  • CSF1R inhibitors offer a translational approach for microglia ablation but face engraftment challenges.

Purpose of the Study:

  • To develop a clinically relevant method for ablating endogenous microglia and repopulating the brain with engineered microglia.
  • To assess the therapeutic potential of microglia engineered to express Brain-Derived Neurotrophic Factor (BDNF).
  • To enhance transplanted microglia engraftment and spread using a constitutively active CSF1R mutant (caCSF1R).

Main Methods:

  • Adult mice underwent microglia ablation using a CSF1R inhibitor.
  • Genetically engineered microglia expressing BDNF and caCSF1R were transplanted.
  • Doxycycline-inducible system controlled BDNF expression.
  • Engraftment, morphology, transcriptional profile, and functional responses of transplanted microglia were analyzed.

Main Results:

  • Transplanted microglia successfully ablated endogenous microglia and repopulated brain parenchyma.
  • Engineered microglia exhibited morphology and transcriptional profiles similar to host microglia.
  • Doxycycline treatment induced BDNF expression and TrkB phosphorylation in the host brain.
  • caCSF1R expression accelerated transplanted microglia spread and provided a competitive advantage.

Conclusions:

  • Genetically engineered microglia are a viable tool for delivering neurotrophic factors like BDNF to the brain in a controlled manner.
  • The use of CSF1R inhibitors and caCSF1R expression enhances the therapeutic potential and engraftment efficiency of transplanted microglia.
  • This study demonstrates a promising, translational strategy for microglia-based brain therapies.