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Extracellular Vesicles Secreted by Human Stem Cell-derived M2 Microglia-like Cells for Stroke

Award Number: R01NS143631
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/03/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Extracellular Vesicles Secreted by Human Stem Cell-derived M2 Microglia-like Cells for Stroke - PROJECT SUMMARY/ABSTRACT The objective of this research is to engineer and bio-manufacture extracellular vesicles (EVs) secreted by M2 microglia-like cells derived from human induced pluripotent stem cells (hiPSCs) in order to promote neural regeneration in ischemic stroke. Microglia, the resident macrophage-like cells in the human brain, account for 5 to 20 percent of total neural cells in the parenchyma and are limited in accessibility. Published in 2023 Nature, the signaling provided by microglia is found to be critical for brain organoid maturation and tissue development. Extracellular vesicles, the membrane-bound nanovesicles (30-1000 nm), secreted by microglia contain protein, lipid, and microRNA cargo that reflect or enrich therapeutic function of the parent cells by regulating cell-cell communications. In particular, exosomes are the therapeutic small subpopulation (30-200 nm) of the EVs. The central hypotheses of this research include: (1) EVs of M2 microglia-like cells in brain-region-specific organoids promote neurogenesis and synaptogenesis, enhancing the brain-like microenvironment of the specific brain region; and (2) by integration the isolated EVs with organoids of different brain regions, the EVs upregulate neural protective function and suppresses pro-inflammatory signaling, maintaining homeostatic state. Specifically, four aims are proposed: (1) To test the hypothesis that metabolic monitoring promotes bio-manufacturing of EVs secreted by M2 microglia-like cells derived from hiPSCs in a Vertical-Wheel bioreactor; (2) To test the hypothesis that EVs secreted by M2 microglia-like cells possess therapeutic cargo and immunomodulation properties; and (3) and (4) To test the hypothesis that EVs secreted by M2 microglia-like cells promote neural regeneration and synaptic activities (3) in vitro using brain organoid models and (4) in vivo. The novelty of the proposed study in contrast to previous study is that the M2 primed microglia-like cells secrete the EVs that are integrated by cells of brain region-specific organoids (e.g., forebrain, cerebellar, spinal cord, etc.), better promoting phenotype and function of human brain-like tissue. The function of EVs of microglia-like cells will be characterized under pro-inflammatory (M1 phenotype) or anti-inflammatory (M2 phenotype) stimulations. The proposed research will use multi-omics tool (transcriptome analysis of EVs and cells, microRNA-sequencing to analyze EV microRNA cargo, quantitative lipidomics to analyze EV lipid composition, and proteomics to analyze EV protein cargo) to correlate with in vitro and in vivo functional studies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $448,943 )
2026	2026	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/3/2026	NEW	$448,943
														Subtotal = $448,943

Grand Total All Awards = $448,943

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Extracellular Vesicles Secreted by Human Stem Cell-derived M2 Microglia-like Cells for Stroke

Award Number: R01NS143631

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/03/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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