Human dental pulp stem cell secretome boosts stroke recovery

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 potential cell-free therapeutic approach. However, understanding of their therapeutic impact on delayed neuronal injury after reperfusion is limited.

Now, 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. Their study was made available online on July 23, 2026, 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. 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."

Professor Won-Jae Kim, Stem Cell Secretome Research Center, Department of Oral Physiology, School of Dentistry, Chonnam National University, South Korea

The study identified 299 proteins uniquely present in the hDPSC secretome, which were majorly 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 regulation.

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, 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 increasing 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.

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 sensory-motor responses.

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

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 Prof. Kim.