Cell-free treatment reduces brain damage and improves recovery after stroke in mice

by Chonnam National University

edited by Swati Mestri, reviewed by Robert Egan

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Ischemic stroke can leave lasting neurological damage after the initial vascular event, with oxidative stress, neuroinflammation, neuronal death and disruption of neural connectivity contributing to impaired recovery. Although current interventions provide partial protection, their ability to prevent delayed neuronal injury remains limited, highlighting a major barrier to functional recovery.

The human dental pulp stem cell (hDPSC) secretome contains extracellular vesicles, growth factors, antioxidant enzymes and immunomodulatory proteins and may offer a cell-free therapeutic approach. However, understanding of its therapeutic impact on delayed neuronal injury after reperfusion is limited.

A study led by professor Won-Jae Kim from the Stem Cell Secretome Research Center, Department of Oral Physiology, School of Dentistry, Chonnam National University, South Korea, investigated whether the hDPSC secretome could improve functional recovery in a photothrombotic mouse model and examined the biological processes associated with its effects.

The study is published in the journal Advanced Science.

"By utilizing the bioactive factors secreted by stem cells rather than the cells themselves, secretome-based therapy overcomes the classic hurdles of cell transplantation, such as poor cell survival, immune rejection and tumorigenesis," explained Kim. "We wanted to investigate if the hDPSC secretome could be deployed as a safe, supportive treatment to mitigate secondary brain injury, modulate neuroinflammation and accelerate neural repair post-stroke."

Antioxidant defense and neural repair

The study identified 299 proteins uniquely present in the hDPSC secretome, which were primarily associated with extracellular vesicles, immunomodulation, neuroprotection, angiogenesis, apoptosis regulation and oxidative stress resistance. Several of these proteins were particularly associated with antioxidant defense. While SOD2, GSR and GSTP1 were tied directly to the brain's antioxidant defense network, proteins like GRN, CSF1 and LRP1 emerged as key regulators of microglial phenotype.

The hDPSC secretome improved microglial cell viability, reduced oxidative stress and restored mitochondrial function in the in vitro study. It restored expression of the mitochondrial fusion protein Mfn2 and antioxidant enzyme SOD1 while reducing hypoxia-associated HIF-1α expression. Additionally, the hDPSC secretome suppressed microglial migration and inflammation, promoting a shift from the pro-inflammatory M1 phenotype toward the pro-healing M2 phenotype.

In a photothrombotic mouse model, the hDPSC secretome significantly reduced stroke infarct volume and neuronal apoptosis in the cortex and hippocampus. It further mitigated oxidative stress and inflammation by activating the Nrf2/HO-1 pathway and suppressing TLR4, NOX1–NOX4 and NF-κB signaling. The hDPSC secretome also modulated M1 microglial activation and increased M2 microglial polarization while promoting neural stem cell proliferation and neuronal differentiation. It also restored vascular density and rebuilt synaptic architecture by upregulating key synaptic proteins like synaptophysin and PSD95.

Gains in movement and memory

These biological changes were accompanied by measurable behavioral improvements. Stroke-injured mice treated with the secretome showed dramatic improvements in physical balance, motor coordination and sensorimotor responses.

The hDPSC secretome also rescued multiple cognitive domains, significantly improving spatial learning, working memory and associative memory across Barnes maze, cross-maze and fear-conditioning trials while reducing post-stroke anxiety behaviors.

Toward standardized secretome treatments

In the longer term, this research could help establish a new therapeutic platform for neurological diseases based on stem cell-derived secretome. Standardizing the active therapeutic components of the hDPSC secretome could soon provide stroke survivors with safer, more reliable and widely accessible treatments.

"Over the next decade, secretome-based therapies could transform stroke care by limiting brain damage and actively repairing neural networks. Because this approach targets fundamental mechanisms like inflammation and cellular stress, it could eventually be extended to treat other devastating brain disorders, including Alzheimer's and Parkinson's," concludes Kim.

Publication details

Kyung‐Joo Seong et al, Human Dental Pulp Stem Cell Secretome Restores Ischemic Stroke–Impaired Motor and Cognitive Functions by Reprogramming Redox and Inflammatory Signaling, Advanced Science (2026). DOI: 10.1002/advs.76717

Journal information: Advanced Science

Key medical concepts

Ischemic StrokeOxidative Stress

Clinical categories

Neurology Provided by Chonnam National University Who's behind this story?

Swati Mestri

Swati Mestri holds a bachelor's degree in Electronics Engineering and has worked as a content editor since 2019. She has experience editing research documents across technology, health care, and materials science, and has a particular interest in technology and space. Full profile →

Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

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